Coping with Stress related effects on the Brain ndash Role of Neuro-nutraceuticals and Gut

microbes

Pathak S1 Suhanya P1 Sushmitha S1 Murugesan R1 Fang He2 Marotta F3 Banerjee A1

Authorsrsquo Affiliations

1 Department of Allied Health Sciences Chettinad Hospital amp Research Institute

(CHRI) Chettinad Academy of Research and Education (CARE) Kelambakkam

Chennai-603103 India

2 Department of Nutrition and Food Hygiene West China School of Public Health

Sichuan University China

3 ReGenera RampD International for Aging Intervention Milano Italy and San Babila

Clinic Healthy Aging Unit by Genomics and Biotechnology Milano Italy

Corresponding Author Antara Banerjee Chettinad Hospital amp Research Institute

(CHRI) Chettinad Academy of Research and Education (CARE) Kelambakkam Chennai-

603103 India E-mail antarabanerjee27gmailcom Contact +91 9566072596

Francesco Marotta ReGenera RampD International for Aging Intervention Milano Italy and

San Babila Clinic Healthy Aging Unit by Genomics and Biotechnology Milano Italy

Email fmarchimedeliberoit

Number of pages in manuscript 20

Number of figures (Black and white) 4

Number of tables 1

Keywords Brain development depression gut microbes hippocampus nutraceuticals

stress

Running title Role of nutraceuticals in brain

1

Abstract

Human brain is the control system of body which helps in coordinating the function of every

organ and maintaining homeostasis A functioning brain receives information from the body

and interprets information guiding the bodyrsquos response to it There is found to be an

interaction between the brain and the intestinal flora of the body Apart from known benefits

of microbes such as digestion and host defense the gut microbiome also impacts mental

health Stress is being the major cause of occurrence of various mental health problems

Neuroinflammation and neurodegeneration are the pathophysiological implications of stress

as it disturbs the generation of neurons Gut microbes have been found to help ease the effects

of stress such as anxiety depression but there is a negative consequence of their composition

being altered in case of chronic stress or emotional trauma Specific food supplements

maintain the gut population as well as protects the brain from stress induced debilitating

effects Nutraceuticals synthesized to nutrify the microbiome and influence cognitive

functions and development of brain can be referred as neuro-nutraceuticals This review aims

to highlight the multi-targeted action of nutraceuticals and gut-microbiota upon brain during

stress and their specific effects on normal brain functioning and development

2

INTRODUCTION

Gut Microbiome

Every individual being is host to a diverse population of microbial organisms with varying

complexity About a 100 trillion (1014) microbes is present which is equivalent to 1011-

1012 cellsg colonic content with a biomass of gt1 kg This includes close to over 500 different

species (Eckburg et al 2005) These microbes are in a symbiotic relationship of mutualism

with the host and maintain a state of homeostasis with the hostrsquos immune system The gut

microbe is distinct for each individual depending on age geographic location diet

medication host related factors They are also found to differ within the same individual

according to the body niche Predominantly anaerobes make up the population of microbes

in the host The oral cavity contains a complex population of anaerobes such as

Bifidobacteria Bacteroides Leptotrichia Propionibacteria Fusobacteria Veillonella and

Peptostreptococci Anaerobes like Propionibacteria along with aerobes such as

Staphylococci and Coryne bacteria reside on the skin The stomach region has gram positive

aerobes like Lactobacillus Helicobacter pylori and Streptococci Likewise the composition

varies for the intestinal regions and vagina The microflora acquire nutrients like dietary

fibres starch oligosaccharides sugars lipids proteins from the host intestinal tract and

endogenous mucins sloughed epithelial enterocyte tissues bile acids and cholesterol

Experimental studies using germ-free mice have demonstrated the relevance of commensal

microbial organisms in normal physiological and metabolic activities Deregulation in the

gut microbial communities has resulted in various health implications Human gut

microbiome is the focal point of research impacting the functional aspects of the human

body and can be exploited for their potential therapeutic effects (Ravinder Nagpal et

al2014)Change in the diet can bring about a major transformation in the gut microbiota

The various other disruptive factors which impact the hostrsquos normal flora include use of

3

antibiotics immune suppression stress pathological condition and surgery (Figure 1)

Microbiome characteristics

The functions performed by the microbiota are referred to as microflora associated

characteristics (MAC) by various researchers (Collinder et al 1998) Among several

functions the important ones include digestion of metabolite substrates vitamin K and B

production drug metabolism mucosal cell development stimulation of immune system

protection against pathogenic organisms where it has been found to induce antimicrobial

proteins such as cathelicidins C-type lectins and (pro) defensins The microbial gene

products impact the metabolism and health status of the host Recent research findings on the

interaction of gut microbiome and the brain have paved the way for more in-depth studies on

understanding the impact of these simple microbes on the complex distant organ the brain

thereby transforming neurosciences opening frontiers for therapeutic strategies for

neurodevelopment disorders

Gut-brain signalling

There is increasing evidence of the critical role played by gut microflora in neuro and

immune modulatory functions during development and adulthood The normal microbiota is

responsible for synaptogenesis to occur and its absence denotes behavioral and

histopathological abnormalities (Cryan et al 2012) A homeostatic communication is

maintained between the brain and the gut intraluminal milieu through various signals

including neural hormonal and immunological A more recent observation has been the

pathogenesis of several Central nervous system disorders correlated with a perturbed gut-

microbiota population (Catanzaro R et al2015)During infancy there are innumerable

synaptic connections which provide the essential substrate for functional brain activities such

as cognition perception and action A study shows that the commensal microbiota is

necessary for the development of brain (Heijtz et al 2011) The authors hypothesized that

4

gut microbiota modulates synaptogenesis Intestinal microorganisms are also critical for

activation of systemic immunity They regulate the function of macrophages that reside in the

lamina propria of the intestine The pathways that link the intestinal flora to the brain are (1)

Via the activation of the vagus nerve from mature enteric nervous system (ENS) to central

nervous system (CNS) (Forsythe et al 2014) (2) Through circulatory system various

metabolites pass through intestine barriers and then across the blood brain barrier to regulate

neurological function (3) Via immune cells- Microbe associated molecular pattern

(MAMPPAMPs) such as bacterial lipoprotein lipopolysaccharide and polysaccharide A

Signals are sent to brain through cytokines like dendritic cells macrophages T cells and B

cells

Microbiota mediated alterations in behaviour and mood

The intestinal microbes send signals affecting the hypothalamic-pituitary-adrenal axis (HPA)

which reveals a bidirectional communication system between the host gut and brain (Figure

2) There are a high proportion of neurotransmitters in the gut which have the potential to

modulate activity of vagus nerve which is the primary nerve connecting enteric nervous

system to CNS and subsequently influence brain function (Bravo et al 2011) During fetal

development the microbiota plays a crucial role in programming the phenotype they

influence the levels of serotonin (5-HT 5 hydroxy tryptamine) BDNF (Brain derived

neurotropic factor) in regions of Amygdala and Hippocampus These factors play a regulatory

role in neurogenesis and synaptic plasticity

BDNF is a protein encoded by BDNF gene important for long term memory helps support

survival of existing neurons and encourage growth and differentiation of new neurons

generation of synapses The symbiotic organisms residing in the GI tract largely affect the

production and regulation of its function Reduced levels of BDNF are seen in neurological

5

conditions like schizophrenia depression Alzheimerrsquos mood disorders like anxiety and

epilepsy (Foster et al 2013)

Serotonin is a monoamine neurotransmitter acquired from the amino acid tryptophan It is

responsible for the well-being regulation of mood sleep and cognitive functions Deficit of

serotonin causes depression 5-HT synthesis requires tryptophan and this is generated by the

intestinal microbiota which can cross the blood brain barrier for the synthesis

Neurophysiology can be changed by actions of the microbiome such as by altering the

permeability of blood brain barrier allowing flux of metabolites into and out of the brain

(Bercik et al 2014) In absence of microbes there is a decreased level of neurotransmitters

such as dopamine and GABA Specific intestinal bacteria produce small molecules such as

serotonin dopamine epinephrine and norepinephrine (Wall et al 2014 Lyte et al 2013)

Mechanism of action

The microbes send signals to enterochromaffin cells which produce neurotransmitters and

enteric neurons glia The decarboxylation of the amino acid tryptophan by neurotransmitter

tryptamine is initiated by specific microbes residing in the namely Clostridium sporogenes

and Ruminococccus gnavus (Williams et al 2014) In the brain tryptamine a monoamine

alkaloid is a non-selective serotonin receptor agonist which plays an inhibitory role in the

response to serotonin and modulate mood and appetite (Zucchi et al 2006) while in the gut

tryptamine can also induce enterochromaffin cells to release 5-HT The gut microbiota is also

responsible for release of another neuromodulator tyramine which has higher affinity for

TAAR1 receptor found in the brain Lactic acid bacteria such as Lbrevis and enterococcus

species act locally via vagus nerve via the periphery (Barett et al 2012)

Studies have shown that microbiota derived signals can induce non-inflammatory cytokine

pathways For instance the plasma G-CSF can cross the blood brain barrier and acts to

6

stimulate neurogenesis in the brain (Zhao et al 2007) Through G-CSF production the

microbiota influences the rate of neurogenesis

With the knowledge of the important role played by microbes in neurological activities

research studies and findings progress towards maintaining this rich microbiota and

stimulating them to contribute to the host a positive effect Dietary macronutrients have a

great effect on the gut microbiome Bacteroidetes Firmicutes Actinobacteria are 3 major

phyla that inhabit the large intestine The diet can significantly change the composition of the

microbiota From birth the diet is involved in the development of microbial communities in

GI tract

Stress and its effects on brain

Human beings are susceptible to stress factors at some point of time irrespective of age

gender economic status As a matter of fact all organisms have some form of exposure to

stress It weakens the physiological functioning of the entire body and fails to maintain

homeostasis Stress has been known to cause many unfavorable effects in the body the first

among them equals derangement of gut mucosa permeability and compromised intestinal

morphology which indirectly impacts the brain leading to increased inflammation in

conditions like depression A symbiotic composition of Saccharomyces boulardii lysate has

been investigated to impede the stress induced gut hyper-permeability and other related

parameters were monitored (Takadanohara H et al 2012) It also triggers a chemical change

in the brain that modifies the synapses thereby disturbing the neuronal connectivity During

the period of exposure to stress there is elevated levels of cortisol commonly referred to as

ldquostress hormonerdquo is the bodyrsquos natural response to stress Response to stress is an essential

part of survival However while enabling the body to manage the effects of stress this

hormone has devastating effects on the brain The high levels of glucocorticoid activity are

associated with reduced neurogenic activity (Gould et al 1997a 1999b Lagace DC et al

7

2010) The hypothalamic-pituitary-adrenal axis (HPA) is considered as the central response

system in the body it reticulates the central nervous system and endocrine system and

coordinates a defective response to stress factors HPA axis is responsible for the prominent

increase in behaviour altering chemicals including glucocorticoids catecholamines and

mineralocorticoids Its activity is regulated by afferent nerve fibres of the parasympathetic

system such as vagus nerves oculomotor nerves limbic system which includes hippocampus

amygdala basal ganglia and sympathetic systems

The hippocampus is a horse shaped region near to the amygdala in the midbrain Our

experiences emotions memory retention rely entirely on the hippocampus to function

correctly Neuroscientists have confirmed that chronic stress can damage the brain severely

and have a long-term effect involving changes in brain structure such as shrinking the

hippocampus volume loss of memory retention neuroinflammation suppressing the neural

activity and increasing the size of amygdala which heightens flightfight response The

maintenance of stability in the brain is disturbed due to continual exposure of stress Raised

levels of cortisol is involved in the synthesis of neurotransmitter glutamate which is a

chemical used to transmit signals to other nerve cells This excitatory neurotransmitter when

released in high amounts has neurotoxic effects by generating free radicals Cortisol also

damages the receptors of the neurotransmitters serotonin and dopamine which are regulators

of mood pleasure happiness and motivation Prolonged stress is known to alter the blood

brain barrier permitting the entry of pathogens heavy metal toxins which damage the brain

cells (Figure 3) There is an immense loss of neurons and brain cells due to inhibitory action

of cortisol on the brain derived neurotropic factor (BDNF) which is a protein used to

maintain healthy brain cells and for synthesis of new cells in the brain

8

Role of nutraceuticals

The term ldquonutraceuticalrdquo was coined by Stephen L Defelice in 1979 According to Defelice

it is defined as food or parts of food that dispense medicalhealth benefits including

prevention and treatment It is a composite of nutrition and pharmaceutical which helps to

maintain the physiological functions of the body These nutrient factors provide sufficient

nutrients to meet the fundamental nutritional requirements for quality living balance and

growth (Maddi et al 2007) They are also referred to as medical foods and designer foods

These products are derived from food sources with additional health benefits besides

providing the basic nutritional value in foods (Rishi et al 2006) Nutraceutical compounds

specifically targeting the neurodevelopment processes are referred to ldquoneuro-nutraceuticalsrdquo

a term that has been recently introduced These supplements are chemically identified

molecules that beneficially affect the brain at molecular level Their actions are directed to

aid in improvement of cognition improve memory positively impact the production of

neurotransmitters reduce inflammations and ageing of brain management of

neurodegenerative and neuropsychiatric disorders (Malik et al 2008) In line with the

subject they also are known to enhance the gut microbes and influence their activities A

healthy gut impacts the brain development and signalling mechanisms It helps to lower the

stress levels and maintain a good mood Foods can infuse our brains with energy to make us

think faster and better Nutraceuticals range from isolated nutrients such as vitamins

minerals fatty acids probiotics prebiotics antioxidants polyaminoacids polysaccharides

herbal products genetically engineered foods and phytochemicals which include

(Carotenoids- fruits vegetables and egg yolk Flavonoid polyphenolics- berries fruits

vegetables legumes are potent antioxidants Non-flavonoid polyphenolics- dark grapes

raisins berries peanuts turmeric roots)

9

Effects of nutrients on gut and brain

The diverse composition of gut microbiota in humans depends on dietary habits The key

mechanisms to maintain gut health are considered to increase the intake of high fibre diet

polysaccharides polyunsaturated fatty acids antioxidants and phytochemicals High-fibre

rich foods stimulate fermentation which proliferates the bacteria and increase biomass

Fermentation causes carbohydrates to undergo chemical changes which result in organic

acids that provide energy for the microbes Short chain fatty acids (SCFA) are the end

products of carbohydrate fermentation which help to inhibit the growth of pathogenic

microorganisms The intake of short-chain non-digestible carbohydrates which include

inulin-type fructans fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS) are

source of prebiotics that typically target growth of bacterial groups such as

Bifidobacterium and Lactobacillus These prebiotic fibres help to ease anxiety depression

restore healthy sleep patterns and protect beneficial gut bacteria Dietary saturated fats may

increase the number of existing pro-inflammatory gut microbes by stimulating formation of

taurine conjugated bile acids that promotes growth of these microbes (Devkota et al 2012)

Polyphenol containing berries metabolized by resident microbiota results in bioactive

products which impacts the health (Duthie et al 2003) Any gut malfunction has a negative

impact on human health therefore it is highly essential to incorporate foods that enhance the

microflora of the gut Artichokes have a strong probiotic potential the high content of inulin

which is insoluble fibre ferments into healthy microflora (Gibson et al 1995) Adequate

administration of probiotics is recognized to have balanced immunoregulatory activities

Investigations on a particular probiotic strain Lactobacillus Pentosus has been shown to

enhance the cytokine production especially IL-10 which is responsible for maintaining the

host immunity by normalizing the T regulatory cells (M Kimura et al2017) Lately a

fascinating finding has been that cocoa or chocolate the most craved food across the globe

10

may modulate the gut commensal population They are found to contain flavonoids including

procyanidins like catechin and epicatechin oligomers which enhance the action of the

neurotransmitters in the brain A Homayouni Rad and his colleagues formulated chocolate as

a potential carrier of probiotic culture strains including lactobacilluscasei and paracasei

positively sustaining the intestinal microbiota population and also releasing stress busting

endorphins Another notable strain is the lactic acid bacteria Streptococcus thermophilus

widely used in the commercial production of fermented dairy products Because of its

inability to survive in the healthy gastric pH of the stomach it has not been suggested as a

ideal probiotic candidate Nonetheless Xiaohong Kangaan and colleagues conducted an

intriguing study on the health promoting effects of milk fermented by Streptococcus

thermophilus in mice the fermented milk was found to have an enhanced cell-mediated

response and positive immunostimulatory effects (M Kimura et al2017) Bananas restore

health of the bacterial community and reduce inflammation It is found to maintain harmony

between the different phyla present in the gut Polenta is a corn-based complex carbohydrate

which has fermentable components that fosters healthy microbiota because of its high fiber

(Anderson et al 2009) Broccoli kale cauliflower cabbage consist of sulfur containing

metabolites namely glucosinolates which are fragmented by the microbes to release

substances that reduce inflammation (Li et al 2008)

Benefits of berry fruit polyphenols

Oxidative stress is a serious threat triggering widespread increase in the occurrence of major

diseases such as Alzheimerrsquos Parkinsonrsquos other neurodegenerative disorders and ageing

Foods rich in antioxidant activity help to prevent age-related changes (Figure 4) Berry fruit

polyphenols can neutralize the negative effects of free-radicals the harmful by-products of

cellular metabolism which contribute to age related diseases They also possess a multiplicity

of actions aside from antioxidant activity They stimulate brain activity neuronal

11

communication cognitive skills calcium buffering ability improve movement control and

prevent memory loss Supplements derived from berry fruits like blueberry cranberry

strawberry have been reported to be effective in reversing motor and behavioral deficits and

control sensory inputs These tiny fruits laden with healing properties are referred to as brain

protective fruits berries are rich in bioflavonoids such as anthocyanins and proanthocyanins

both of which are scavengers of free radicals Active phytochemicals present in the blueberry

confer the benefit of being able to cross the blood-brain-barrier Anthocyanins have been

shown to penetrate the brain and their concentrations correspond to appropriate cognitive

performances (Lacueva et al 2005) They upregulate TNF α IL-1β NF-κB and

consequently suppress ageing and improve blood flow to the brain Blueberries are

responsible for reducing expression of stress signals and results in increasing protective

signals and impact cell signalling molecule expression (Shukitt-Hale et al 2008) The

anthocyanins elevate the level of BDNF (Brain derived neurotropic factor) which is crucial to

boost neuronal communication influencing cognitive function Heat shock proteins are

known to fight free radicals and inflammation inducing agents to support healthy brain

tissues The ability to generate heat shock proteins declines with age dramatically However

researchers have found that consumption of blueberries could restore heat shock protein

response and help protect against neurodegeneration processes associated with ageing

Blueberries play an essential role in reducing the toxicity of kainic acid on hippocampal cells

Kainic acid is an amino acid which is naturally abundant in seaweeds and can be neurotoxic

because of its potent ability to stimulate neurons by activating receptors for glutamate This

aminoacid can be induced in laboratory animal models to study various neurodegenerative

disorders

12

PUFAs

Polyunsaturated fatty acids (PUFAs) are critical components of neuronal cell membranes and

are involved in neurotransmitter communication within the neural networks They are

responsible for maintaining membrane fluidity essential synaptic vesicle fusion and serve as

precursors for lipid messengers which participate in signalling processes to promote neuronal

protection (Bazan et al 2005) Flaxseeds fish soybeans walnuts are rich in PUFA

specifically omega- 6 fatty acid linoleic acid omega-3 α linolenic acid

Intake of PUFA supplements for improve cognitive function

In most neurological conditions inflammation manifests in the nervous tissue and this

inflammation is a therapeutic target by the pharmaceutical industries During high levels of

stress the body cannot regulate an inflammatory response which leads to a greater risk of

development of other diseases Anti-inflammatory agents containing nutraceuticals is the

focus of development Oxymatrine derived from the root of a Chinese herb Sophora

flavescens has been reported to have anti-inflammatory actions and decreases damage

observed after hypoxic- ischaemic brain injury in neonatal rat models (Zhao et al 2015)

Apocynin obtained from the root of Picrorhiza kurroa is also believed to have anti-

inflammatory properties and attenuate the cholesterol oxidation product induced apoptosis in

neuronal cells by preventing production of reactive oxygen species (Simonyi et al 2012)

Quercetin known to be found in vegetables fruits have antioxidant effects regulate proteins

transcription factors and kinase dependent signalling pathways Nutraceutical additive actions

of quercetin expedite optimal delivery and improve brain activity Naturally occurring 7 8-

dihydroxyflavone rescues cognition deficits and serve as a novel treatment for autism and

schizophrenia Trans-resveratrol and pterostilbene are plant derived synergistic phytonutrients

improving brain health and having diverse actions against oxidative stress (Poulose et al

2015) Creatine is a natural substance when taken as supplements in recommended dose is

13

beneficial to enhance brain function and improve cognitive function (Wallimann 2008) (Table

1)

Management of stress

Nutrient supplements have the potential to overcome the debilitating effects of stress They

act as prophylactic and therapeutic agents and are more efficient and safe in comparison to

pharmaceutical drugs (Pandey et al 2010) Botanically derived ingredients are used to treat

mild depression anxiety improve sleep patterns and maintain good health Since a persistent

level of cortisol in circulation is the chief cause of depression and stress naturally derived

products target this hormone to annihilate the stress factors and boost mental health and

cognition Researchers have studied the effects of probiotics against stress in a zebrafish

model by introducing the bacterial strain Lactobacillus plantarum into the tank (Davis et al

2016) The objective is to bring the body back to homeostasis maintaining a balanced level

of cortisol The actions of gut microbes and nutraceuticals work interdependently to help

reduce the dangerous outcomes of stress upon the body Experiments with germ free mice

have been used to probe the role of microbiota in adult hippocampal neurogenesis Also

disruptions of gut microbiome induced mice behaviour resulted in anxiety depression and

even autism Gut microbes are the key modulators of brain plasticity cognitive functions and

help to optimize the bodyrsquos response to stress by regulating their synthesis of

neurotransmitters like serotonin to lower the cortisol level Studies have shown that during

stress there is an increased population of certain bacterial strains in the gut such as

Enterobacteriaceae Proteobacteria Actinobacteria and this can be controlled by increasing

the administration of probiotics containing Lactobacillus and Bifidobacterium species

Experiments have been conducted with Bifidobacterium longum and results showed that this

strain was able to reverse hippocampal and BDNF abnormalities

14

CONCLUSION

In today lsquos ambitious world so much importance is being given to performance perfection

competition that it leads to an insidious increase in stress depression anxiety Stress is a

psychological issue which predisposes a person to various other ailments It is inevitable in

the life of any individual but the duration and intensity differs According to Hans Selye who

coined the term stress in 1936 it is the non- specific response of the body to any demand for

change Stress levels are rising worldwide it is a top health concern The damages that can be

caused by stress are often underestimated It primarily affects the nervous system but

prolonged exposure leads to cardiovascular musculoskeletal diseases and even affects the

reproductive system Claude Bernard (1865-1961) observed that the maintenance of life is

essentially dependent on keeping our internal milieu constant in the face of a changing

environment Thus sustaining a state of homeostasis is vital for a healthy life Workplace

stress and depression is on the rise it is the health epidemic of 21 st century a frequently

reported problem According to WHO depression is among the leading causes of disability

globally There is a compelling need to confront the ameliorating and deleterious effects of

stress inflicted on an individual These health risks can be prevented or managed A multi

targeted approach is required to tackle a problem as severe as stress It can be controlled in

the healthy way by nourishing and stimulating the gut microbes in our body to act on the

brain which increases the release of neurotransmitters to help relieve the effects of stress

Nutrient supplements referred to as nutraceuticals has been introduced to influence the brain

activity and protect it from the negative impact of stress hormones These nutraceuticals help

to enhance the quality of life by modulating the gut health They prevent the alteration of

microbiome during stress Extensive research has been conducted in the field of gut microbes

and nutraceuticals and their efficacy towards alleviating stress has been proved We are

moving towards the direction of exploring psych biotics as a mode of treatment for anxiety

15

depression and various psychiatric issues However it is a recently introduced term and

research and is still on-going whether it has proven benefits or not Dietary interventions with

food supplements designed to modulate responses to stress that can be administered

effectively Managing stress in the natural way is proven to be the most favorable method

Acknowledgements

The authors are thankful to Chettinad Academy of Research and Education (CARE) for the

support

Conflicts of interest

We declare no conflict of interest All co-authors have agreed to transfer the copyright to the

publisher if it is accepted for publication This study was partially financially supported by

Chettinad Hospital amp Research Institute (CHRI) Chettinad Academy of Research and

Education (CARE) Kelambakkam Chennai-603103 India

16

References

Anderson JW Baird P Davis RH Ferreri S Knutdson M Koraym A Waters V

Williams CL (2009) Health benefits of dietary fibre Nutrition Reviews 67188-205

Andres RH Ducray AD Schlattner U Wallimann T Widmer HR (2008) Functions

and effects of creatine in the central nervous system Brain Research Bulletin 76(4)329-43

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged blueberry-fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2)111-20

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged-blueberry fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2) 111-20

Barrett E Ross RP OToole PW Fitzgerald GF Stanton C (2012) gamma-

Aminobutyric acid production by culturable bacteria from the human intestine Journal of

applied microbiology 113411ndash417

Bazan NG (2005) Lipid signaling in neural plasticity brain repair and neuroprotection

Molecular Neurobiology 32(1)89-103

Bercik P Denou E Collins J Jackson W Lu J Jury J Deng Y Blennerhassett P

Macri J McCoy KD Verdu EF Collins SM (2011) The intestinal microbiota affect

central levels of brain-derived neurotropic factor and behavior in mice Gastroenterology

141599-609

Borre YE OKeeffe GW Clarke G Stanton C Dinan TG Cryan JF (2014)

Microbiota and neurodevelopmental windows implications for brain disorders Trends in

Molecular Medicine 20509-518

Bravo JA Forsythe P Chew MV (2011) Ingestion of Lactobacillus strain regulates

emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

17

Abstract

Human brain is the control system of body which helps in coordinating the function of every

organ and maintaining homeostasis A functioning brain receives information from the body

and interprets information guiding the bodyrsquos response to it There is found to be an

interaction between the brain and the intestinal flora of the body Apart from known benefits

of microbes such as digestion and host defense the gut microbiome also impacts mental

health Stress is being the major cause of occurrence of various mental health problems

Neuroinflammation and neurodegeneration are the pathophysiological implications of stress

as it disturbs the generation of neurons Gut microbes have been found to help ease the effects

of stress such as anxiety depression but there is a negative consequence of their composition

being altered in case of chronic stress or emotional trauma Specific food supplements

maintain the gut population as well as protects the brain from stress induced debilitating

effects Nutraceuticals synthesized to nutrify the microbiome and influence cognitive

functions and development of brain can be referred as neuro-nutraceuticals This review aims

to highlight the multi-targeted action of nutraceuticals and gut-microbiota upon brain during

stress and their specific effects on normal brain functioning and development

2

INTRODUCTION

Gut Microbiome

Every individual being is host to a diverse population of microbial organisms with varying

complexity About a 100 trillion (1014) microbes is present which is equivalent to 1011-

1012 cellsg colonic content with a biomass of gt1 kg This includes close to over 500 different

species (Eckburg et al 2005) These microbes are in a symbiotic relationship of mutualism

with the host and maintain a state of homeostasis with the hostrsquos immune system The gut

microbe is distinct for each individual depending on age geographic location diet

medication host related factors They are also found to differ within the same individual

according to the body niche Predominantly anaerobes make up the population of microbes

in the host The oral cavity contains a complex population of anaerobes such as

Bifidobacteria Bacteroides Leptotrichia Propionibacteria Fusobacteria Veillonella and

Peptostreptococci Anaerobes like Propionibacteria along with aerobes such as

Staphylococci and Coryne bacteria reside on the skin The stomach region has gram positive

aerobes like Lactobacillus Helicobacter pylori and Streptococci Likewise the composition

varies for the intestinal regions and vagina The microflora acquire nutrients like dietary

fibres starch oligosaccharides sugars lipids proteins from the host intestinal tract and

endogenous mucins sloughed epithelial enterocyte tissues bile acids and cholesterol

Experimental studies using germ-free mice have demonstrated the relevance of commensal

microbial organisms in normal physiological and metabolic activities Deregulation in the

gut microbial communities has resulted in various health implications Human gut

microbiome is the focal point of research impacting the functional aspects of the human

body and can be exploited for their potential therapeutic effects (Ravinder Nagpal et

al2014)Change in the diet can bring about a major transformation in the gut microbiota

The various other disruptive factors which impact the hostrsquos normal flora include use of

3

antibiotics immune suppression stress pathological condition and surgery (Figure 1)

Microbiome characteristics

The functions performed by the microbiota are referred to as microflora associated

characteristics (MAC) by various researchers (Collinder et al 1998) Among several

functions the important ones include digestion of metabolite substrates vitamin K and B

production drug metabolism mucosal cell development stimulation of immune system

protection against pathogenic organisms where it has been found to induce antimicrobial

proteins such as cathelicidins C-type lectins and (pro) defensins The microbial gene

products impact the metabolism and health status of the host Recent research findings on the

interaction of gut microbiome and the brain have paved the way for more in-depth studies on

understanding the impact of these simple microbes on the complex distant organ the brain

thereby transforming neurosciences opening frontiers for therapeutic strategies for

neurodevelopment disorders

Gut-brain signalling

There is increasing evidence of the critical role played by gut microflora in neuro and

immune modulatory functions during development and adulthood The normal microbiota is

responsible for synaptogenesis to occur and its absence denotes behavioral and

histopathological abnormalities (Cryan et al 2012) A homeostatic communication is

maintained between the brain and the gut intraluminal milieu through various signals

including neural hormonal and immunological A more recent observation has been the

pathogenesis of several Central nervous system disorders correlated with a perturbed gut-

microbiota population (Catanzaro R et al2015)During infancy there are innumerable

synaptic connections which provide the essential substrate for functional brain activities such

as cognition perception and action A study shows that the commensal microbiota is

necessary for the development of brain (Heijtz et al 2011) The authors hypothesized that

4

gut microbiota modulates synaptogenesis Intestinal microorganisms are also critical for

activation of systemic immunity They regulate the function of macrophages that reside in the

lamina propria of the intestine The pathways that link the intestinal flora to the brain are (1)

Via the activation of the vagus nerve from mature enteric nervous system (ENS) to central

nervous system (CNS) (Forsythe et al 2014) (2) Through circulatory system various

metabolites pass through intestine barriers and then across the blood brain barrier to regulate

neurological function (3) Via immune cells- Microbe associated molecular pattern

(MAMPPAMPs) such as bacterial lipoprotein lipopolysaccharide and polysaccharide A

Signals are sent to brain through cytokines like dendritic cells macrophages T cells and B

cells

Microbiota mediated alterations in behaviour and mood

The intestinal microbes send signals affecting the hypothalamic-pituitary-adrenal axis (HPA)

which reveals a bidirectional communication system between the host gut and brain (Figure

2) There are a high proportion of neurotransmitters in the gut which have the potential to

modulate activity of vagus nerve which is the primary nerve connecting enteric nervous

system to CNS and subsequently influence brain function (Bravo et al 2011) During fetal

development the microbiota plays a crucial role in programming the phenotype they

influence the levels of serotonin (5-HT 5 hydroxy tryptamine) BDNF (Brain derived

neurotropic factor) in regions of Amygdala and Hippocampus These factors play a regulatory

role in neurogenesis and synaptic plasticity

BDNF is a protein encoded by BDNF gene important for long term memory helps support

survival of existing neurons and encourage growth and differentiation of new neurons

generation of synapses The symbiotic organisms residing in the GI tract largely affect the

production and regulation of its function Reduced levels of BDNF are seen in neurological

5

conditions like schizophrenia depression Alzheimerrsquos mood disorders like anxiety and

epilepsy (Foster et al 2013)

Serotonin is a monoamine neurotransmitter acquired from the amino acid tryptophan It is

responsible for the well-being regulation of mood sleep and cognitive functions Deficit of

serotonin causes depression 5-HT synthesis requires tryptophan and this is generated by the

intestinal microbiota which can cross the blood brain barrier for the synthesis

Neurophysiology can be changed by actions of the microbiome such as by altering the

permeability of blood brain barrier allowing flux of metabolites into and out of the brain

(Bercik et al 2014) In absence of microbes there is a decreased level of neurotransmitters

such as dopamine and GABA Specific intestinal bacteria produce small molecules such as

serotonin dopamine epinephrine and norepinephrine (Wall et al 2014 Lyte et al 2013)

Mechanism of action

The microbes send signals to enterochromaffin cells which produce neurotransmitters and

enteric neurons glia The decarboxylation of the amino acid tryptophan by neurotransmitter

tryptamine is initiated by specific microbes residing in the namely Clostridium sporogenes

and Ruminococccus gnavus (Williams et al 2014) In the brain tryptamine a monoamine

alkaloid is a non-selective serotonin receptor agonist which plays an inhibitory role in the

response to serotonin and modulate mood and appetite (Zucchi et al 2006) while in the gut

tryptamine can also induce enterochromaffin cells to release 5-HT The gut microbiota is also

responsible for release of another neuromodulator tyramine which has higher affinity for

TAAR1 receptor found in the brain Lactic acid bacteria such as Lbrevis and enterococcus

species act locally via vagus nerve via the periphery (Barett et al 2012)

Studies have shown that microbiota derived signals can induce non-inflammatory cytokine

pathways For instance the plasma G-CSF can cross the blood brain barrier and acts to

6

stimulate neurogenesis in the brain (Zhao et al 2007) Through G-CSF production the

microbiota influences the rate of neurogenesis

With the knowledge of the important role played by microbes in neurological activities

research studies and findings progress towards maintaining this rich microbiota and

stimulating them to contribute to the host a positive effect Dietary macronutrients have a

great effect on the gut microbiome Bacteroidetes Firmicutes Actinobacteria are 3 major

phyla that inhabit the large intestine The diet can significantly change the composition of the

microbiota From birth the diet is involved in the development of microbial communities in

GI tract

Stress and its effects on brain

Human beings are susceptible to stress factors at some point of time irrespective of age

gender economic status As a matter of fact all organisms have some form of exposure to

stress It weakens the physiological functioning of the entire body and fails to maintain

homeostasis Stress has been known to cause many unfavorable effects in the body the first

among them equals derangement of gut mucosa permeability and compromised intestinal

morphology which indirectly impacts the brain leading to increased inflammation in

conditions like depression A symbiotic composition of Saccharomyces boulardii lysate has

been investigated to impede the stress induced gut hyper-permeability and other related

parameters were monitored (Takadanohara H et al 2012) It also triggers a chemical change

in the brain that modifies the synapses thereby disturbing the neuronal connectivity During

the period of exposure to stress there is elevated levels of cortisol commonly referred to as

ldquostress hormonerdquo is the bodyrsquos natural response to stress Response to stress is an essential

part of survival However while enabling the body to manage the effects of stress this

hormone has devastating effects on the brain The high levels of glucocorticoid activity are

associated with reduced neurogenic activity (Gould et al 1997a 1999b Lagace DC et al

7

2010) The hypothalamic-pituitary-adrenal axis (HPA) is considered as the central response

system in the body it reticulates the central nervous system and endocrine system and

coordinates a defective response to stress factors HPA axis is responsible for the prominent

increase in behaviour altering chemicals including glucocorticoids catecholamines and

mineralocorticoids Its activity is regulated by afferent nerve fibres of the parasympathetic

system such as vagus nerves oculomotor nerves limbic system which includes hippocampus

amygdala basal ganglia and sympathetic systems

The hippocampus is a horse shaped region near to the amygdala in the midbrain Our

experiences emotions memory retention rely entirely on the hippocampus to function

correctly Neuroscientists have confirmed that chronic stress can damage the brain severely

and have a long-term effect involving changes in brain structure such as shrinking the

hippocampus volume loss of memory retention neuroinflammation suppressing the neural

activity and increasing the size of amygdala which heightens flightfight response The

maintenance of stability in the brain is disturbed due to continual exposure of stress Raised

levels of cortisol is involved in the synthesis of neurotransmitter glutamate which is a

chemical used to transmit signals to other nerve cells This excitatory neurotransmitter when

released in high amounts has neurotoxic effects by generating free radicals Cortisol also

damages the receptors of the neurotransmitters serotonin and dopamine which are regulators

of mood pleasure happiness and motivation Prolonged stress is known to alter the blood

brain barrier permitting the entry of pathogens heavy metal toxins which damage the brain

cells (Figure 3) There is an immense loss of neurons and brain cells due to inhibitory action

of cortisol on the brain derived neurotropic factor (BDNF) which is a protein used to

maintain healthy brain cells and for synthesis of new cells in the brain

8

Role of nutraceuticals

The term ldquonutraceuticalrdquo was coined by Stephen L Defelice in 1979 According to Defelice

it is defined as food or parts of food that dispense medicalhealth benefits including

prevention and treatment It is a composite of nutrition and pharmaceutical which helps to

maintain the physiological functions of the body These nutrient factors provide sufficient

nutrients to meet the fundamental nutritional requirements for quality living balance and

growth (Maddi et al 2007) They are also referred to as medical foods and designer foods

These products are derived from food sources with additional health benefits besides

providing the basic nutritional value in foods (Rishi et al 2006) Nutraceutical compounds

specifically targeting the neurodevelopment processes are referred to ldquoneuro-nutraceuticalsrdquo

a term that has been recently introduced These supplements are chemically identified

molecules that beneficially affect the brain at molecular level Their actions are directed to

aid in improvement of cognition improve memory positively impact the production of

neurotransmitters reduce inflammations and ageing of brain management of

neurodegenerative and neuropsychiatric disorders (Malik et al 2008) In line with the

subject they also are known to enhance the gut microbes and influence their activities A

healthy gut impacts the brain development and signalling mechanisms It helps to lower the

stress levels and maintain a good mood Foods can infuse our brains with energy to make us

think faster and better Nutraceuticals range from isolated nutrients such as vitamins

minerals fatty acids probiotics prebiotics antioxidants polyaminoacids polysaccharides

herbal products genetically engineered foods and phytochemicals which include

(Carotenoids- fruits vegetables and egg yolk Flavonoid polyphenolics- berries fruits

vegetables legumes are potent antioxidants Non-flavonoid polyphenolics- dark grapes

raisins berries peanuts turmeric roots)

9

Effects of nutrients on gut and brain

The diverse composition of gut microbiota in humans depends on dietary habits The key

mechanisms to maintain gut health are considered to increase the intake of high fibre diet

polysaccharides polyunsaturated fatty acids antioxidants and phytochemicals High-fibre

rich foods stimulate fermentation which proliferates the bacteria and increase biomass

Fermentation causes carbohydrates to undergo chemical changes which result in organic

acids that provide energy for the microbes Short chain fatty acids (SCFA) are the end

products of carbohydrate fermentation which help to inhibit the growth of pathogenic

microorganisms The intake of short-chain non-digestible carbohydrates which include

inulin-type fructans fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS) are

source of prebiotics that typically target growth of bacterial groups such as

Bifidobacterium and Lactobacillus These prebiotic fibres help to ease anxiety depression

restore healthy sleep patterns and protect beneficial gut bacteria Dietary saturated fats may

increase the number of existing pro-inflammatory gut microbes by stimulating formation of

taurine conjugated bile acids that promotes growth of these microbes (Devkota et al 2012)

Polyphenol containing berries metabolized by resident microbiota results in bioactive

products which impacts the health (Duthie et al 2003) Any gut malfunction has a negative

impact on human health therefore it is highly essential to incorporate foods that enhance the

microflora of the gut Artichokes have a strong probiotic potential the high content of inulin

which is insoluble fibre ferments into healthy microflora (Gibson et al 1995) Adequate

administration of probiotics is recognized to have balanced immunoregulatory activities

Investigations on a particular probiotic strain Lactobacillus Pentosus has been shown to

enhance the cytokine production especially IL-10 which is responsible for maintaining the

host immunity by normalizing the T regulatory cells (M Kimura et al2017) Lately a

fascinating finding has been that cocoa or chocolate the most craved food across the globe

10

may modulate the gut commensal population They are found to contain flavonoids including

procyanidins like catechin and epicatechin oligomers which enhance the action of the

neurotransmitters in the brain A Homayouni Rad and his colleagues formulated chocolate as

a potential carrier of probiotic culture strains including lactobacilluscasei and paracasei

positively sustaining the intestinal microbiota population and also releasing stress busting

endorphins Another notable strain is the lactic acid bacteria Streptococcus thermophilus

widely used in the commercial production of fermented dairy products Because of its

inability to survive in the healthy gastric pH of the stomach it has not been suggested as a

ideal probiotic candidate Nonetheless Xiaohong Kangaan and colleagues conducted an

intriguing study on the health promoting effects of milk fermented by Streptococcus

thermophilus in mice the fermented milk was found to have an enhanced cell-mediated

response and positive immunostimulatory effects (M Kimura et al2017) Bananas restore

health of the bacterial community and reduce inflammation It is found to maintain harmony

between the different phyla present in the gut Polenta is a corn-based complex carbohydrate

which has fermentable components that fosters healthy microbiota because of its high fiber

(Anderson et al 2009) Broccoli kale cauliflower cabbage consist of sulfur containing

metabolites namely glucosinolates which are fragmented by the microbes to release

substances that reduce inflammation (Li et al 2008)

Benefits of berry fruit polyphenols

Oxidative stress is a serious threat triggering widespread increase in the occurrence of major

diseases such as Alzheimerrsquos Parkinsonrsquos other neurodegenerative disorders and ageing

Foods rich in antioxidant activity help to prevent age-related changes (Figure 4) Berry fruit

polyphenols can neutralize the negative effects of free-radicals the harmful by-products of

cellular metabolism which contribute to age related diseases They also possess a multiplicity

of actions aside from antioxidant activity They stimulate brain activity neuronal

11

communication cognitive skills calcium buffering ability improve movement control and

prevent memory loss Supplements derived from berry fruits like blueberry cranberry

strawberry have been reported to be effective in reversing motor and behavioral deficits and

control sensory inputs These tiny fruits laden with healing properties are referred to as brain

protective fruits berries are rich in bioflavonoids such as anthocyanins and proanthocyanins

both of which are scavengers of free radicals Active phytochemicals present in the blueberry

confer the benefit of being able to cross the blood-brain-barrier Anthocyanins have been

shown to penetrate the brain and their concentrations correspond to appropriate cognitive

performances (Lacueva et al 2005) They upregulate TNF α IL-1β NF-κB and

consequently suppress ageing and improve blood flow to the brain Blueberries are

responsible for reducing expression of stress signals and results in increasing protective

signals and impact cell signalling molecule expression (Shukitt-Hale et al 2008) The

anthocyanins elevate the level of BDNF (Brain derived neurotropic factor) which is crucial to

boost neuronal communication influencing cognitive function Heat shock proteins are

known to fight free radicals and inflammation inducing agents to support healthy brain

tissues The ability to generate heat shock proteins declines with age dramatically However

researchers have found that consumption of blueberries could restore heat shock protein

response and help protect against neurodegeneration processes associated with ageing

Blueberries play an essential role in reducing the toxicity of kainic acid on hippocampal cells

Kainic acid is an amino acid which is naturally abundant in seaweeds and can be neurotoxic

because of its potent ability to stimulate neurons by activating receptors for glutamate This

aminoacid can be induced in laboratory animal models to study various neurodegenerative

disorders

12

PUFAs

Polyunsaturated fatty acids (PUFAs) are critical components of neuronal cell membranes and

are involved in neurotransmitter communication within the neural networks They are

responsible for maintaining membrane fluidity essential synaptic vesicle fusion and serve as

precursors for lipid messengers which participate in signalling processes to promote neuronal

protection (Bazan et al 2005) Flaxseeds fish soybeans walnuts are rich in PUFA

specifically omega- 6 fatty acid linoleic acid omega-3 α linolenic acid

Intake of PUFA supplements for improve cognitive function

In most neurological conditions inflammation manifests in the nervous tissue and this

inflammation is a therapeutic target by the pharmaceutical industries During high levels of

stress the body cannot regulate an inflammatory response which leads to a greater risk of

development of other diseases Anti-inflammatory agents containing nutraceuticals is the

focus of development Oxymatrine derived from the root of a Chinese herb Sophora

flavescens has been reported to have anti-inflammatory actions and decreases damage

observed after hypoxic- ischaemic brain injury in neonatal rat models (Zhao et al 2015)

Apocynin obtained from the root of Picrorhiza kurroa is also believed to have anti-

inflammatory properties and attenuate the cholesterol oxidation product induced apoptosis in

neuronal cells by preventing production of reactive oxygen species (Simonyi et al 2012)

Quercetin known to be found in vegetables fruits have antioxidant effects regulate proteins

transcription factors and kinase dependent signalling pathways Nutraceutical additive actions

of quercetin expedite optimal delivery and improve brain activity Naturally occurring 7 8-

dihydroxyflavone rescues cognition deficits and serve as a novel treatment for autism and

schizophrenia Trans-resveratrol and pterostilbene are plant derived synergistic phytonutrients

improving brain health and having diverse actions against oxidative stress (Poulose et al

2015) Creatine is a natural substance when taken as supplements in recommended dose is

13

beneficial to enhance brain function and improve cognitive function (Wallimann 2008) (Table

1)

Management of stress

Nutrient supplements have the potential to overcome the debilitating effects of stress They

act as prophylactic and therapeutic agents and are more efficient and safe in comparison to

pharmaceutical drugs (Pandey et al 2010) Botanically derived ingredients are used to treat

mild depression anxiety improve sleep patterns and maintain good health Since a persistent

level of cortisol in circulation is the chief cause of depression and stress naturally derived

products target this hormone to annihilate the stress factors and boost mental health and

cognition Researchers have studied the effects of probiotics against stress in a zebrafish

model by introducing the bacterial strain Lactobacillus plantarum into the tank (Davis et al

2016) The objective is to bring the body back to homeostasis maintaining a balanced level

of cortisol The actions of gut microbes and nutraceuticals work interdependently to help

reduce the dangerous outcomes of stress upon the body Experiments with germ free mice

have been used to probe the role of microbiota in adult hippocampal neurogenesis Also

disruptions of gut microbiome induced mice behaviour resulted in anxiety depression and

even autism Gut microbes are the key modulators of brain plasticity cognitive functions and

help to optimize the bodyrsquos response to stress by regulating their synthesis of

neurotransmitters like serotonin to lower the cortisol level Studies have shown that during

stress there is an increased population of certain bacterial strains in the gut such as

Enterobacteriaceae Proteobacteria Actinobacteria and this can be controlled by increasing

the administration of probiotics containing Lactobacillus and Bifidobacterium species

Experiments have been conducted with Bifidobacterium longum and results showed that this

strain was able to reverse hippocampal and BDNF abnormalities

14

CONCLUSION

In today lsquos ambitious world so much importance is being given to performance perfection

competition that it leads to an insidious increase in stress depression anxiety Stress is a

psychological issue which predisposes a person to various other ailments It is inevitable in

the life of any individual but the duration and intensity differs According to Hans Selye who

coined the term stress in 1936 it is the non- specific response of the body to any demand for

change Stress levels are rising worldwide it is a top health concern The damages that can be

caused by stress are often underestimated It primarily affects the nervous system but

prolonged exposure leads to cardiovascular musculoskeletal diseases and even affects the

reproductive system Claude Bernard (1865-1961) observed that the maintenance of life is

essentially dependent on keeping our internal milieu constant in the face of a changing

environment Thus sustaining a state of homeostasis is vital for a healthy life Workplace

stress and depression is on the rise it is the health epidemic of 21 st century a frequently

reported problem According to WHO depression is among the leading causes of disability

globally There is a compelling need to confront the ameliorating and deleterious effects of

stress inflicted on an individual These health risks can be prevented or managed A multi

targeted approach is required to tackle a problem as severe as stress It can be controlled in

the healthy way by nourishing and stimulating the gut microbes in our body to act on the

brain which increases the release of neurotransmitters to help relieve the effects of stress

Nutrient supplements referred to as nutraceuticals has been introduced to influence the brain

activity and protect it from the negative impact of stress hormones These nutraceuticals help

to enhance the quality of life by modulating the gut health They prevent the alteration of

microbiome during stress Extensive research has been conducted in the field of gut microbes

and nutraceuticals and their efficacy towards alleviating stress has been proved We are

moving towards the direction of exploring psych biotics as a mode of treatment for anxiety

15

depression and various psychiatric issues However it is a recently introduced term and

research and is still on-going whether it has proven benefits or not Dietary interventions with

food supplements designed to modulate responses to stress that can be administered

effectively Managing stress in the natural way is proven to be the most favorable method

Acknowledgements

The authors are thankful to Chettinad Academy of Research and Education (CARE) for the

support

Conflicts of interest

We declare no conflict of interest All co-authors have agreed to transfer the copyright to the

publisher if it is accepted for publication This study was partially financially supported by

Chettinad Hospital amp Research Institute (CHRI) Chettinad Academy of Research and

Education (CARE) Kelambakkam Chennai-603103 India

16

References

Anderson JW Baird P Davis RH Ferreri S Knutdson M Koraym A Waters V

Williams CL (2009) Health benefits of dietary fibre Nutrition Reviews 67188-205

Andres RH Ducray AD Schlattner U Wallimann T Widmer HR (2008) Functions

and effects of creatine in the central nervous system Brain Research Bulletin 76(4)329-43

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged blueberry-fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2)111-20

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged-blueberry fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2) 111-20

Barrett E Ross RP OToole PW Fitzgerald GF Stanton C (2012) gamma-

Aminobutyric acid production by culturable bacteria from the human intestine Journal of

applied microbiology 113411ndash417

Bazan NG (2005) Lipid signaling in neural plasticity brain repair and neuroprotection

Molecular Neurobiology 32(1)89-103

Bercik P Denou E Collins J Jackson W Lu J Jury J Deng Y Blennerhassett P

Macri J McCoy KD Verdu EF Collins SM (2011) The intestinal microbiota affect

central levels of brain-derived neurotropic factor and behavior in mice Gastroenterology

141599-609

Borre YE OKeeffe GW Clarke G Stanton C Dinan TG Cryan JF (2014)

Microbiota and neurodevelopmental windows implications for brain disorders Trends in

Molecular Medicine 20509-518

Bravo JA Forsythe P Chew MV (2011) Ingestion of Lactobacillus strain regulates

emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

17

INTRODUCTION

Gut Microbiome

Every individual being is host to a diverse population of microbial organisms with varying

complexity About a 100 trillion (1014) microbes is present which is equivalent to 1011-

1012 cellsg colonic content with a biomass of gt1 kg This includes close to over 500 different

species (Eckburg et al 2005) These microbes are in a symbiotic relationship of mutualism

with the host and maintain a state of homeostasis with the hostrsquos immune system The gut

microbe is distinct for each individual depending on age geographic location diet

medication host related factors They are also found to differ within the same individual

according to the body niche Predominantly anaerobes make up the population of microbes

in the host The oral cavity contains a complex population of anaerobes such as

Bifidobacteria Bacteroides Leptotrichia Propionibacteria Fusobacteria Veillonella and

Peptostreptococci Anaerobes like Propionibacteria along with aerobes such as

Staphylococci and Coryne bacteria reside on the skin The stomach region has gram positive

aerobes like Lactobacillus Helicobacter pylori and Streptococci Likewise the composition

varies for the intestinal regions and vagina The microflora acquire nutrients like dietary

fibres starch oligosaccharides sugars lipids proteins from the host intestinal tract and

endogenous mucins sloughed epithelial enterocyte tissues bile acids and cholesterol

Experimental studies using germ-free mice have demonstrated the relevance of commensal

microbial organisms in normal physiological and metabolic activities Deregulation in the

gut microbial communities has resulted in various health implications Human gut

microbiome is the focal point of research impacting the functional aspects of the human

body and can be exploited for their potential therapeutic effects (Ravinder Nagpal et

al2014)Change in the diet can bring about a major transformation in the gut microbiota

The various other disruptive factors which impact the hostrsquos normal flora include use of

3

antibiotics immune suppression stress pathological condition and surgery (Figure 1)

Microbiome characteristics

The functions performed by the microbiota are referred to as microflora associated

characteristics (MAC) by various researchers (Collinder et al 1998) Among several

functions the important ones include digestion of metabolite substrates vitamin K and B

production drug metabolism mucosal cell development stimulation of immune system

protection against pathogenic organisms where it has been found to induce antimicrobial

proteins such as cathelicidins C-type lectins and (pro) defensins The microbial gene

products impact the metabolism and health status of the host Recent research findings on the

interaction of gut microbiome and the brain have paved the way for more in-depth studies on

understanding the impact of these simple microbes on the complex distant organ the brain

thereby transforming neurosciences opening frontiers for therapeutic strategies for

neurodevelopment disorders

Gut-brain signalling

There is increasing evidence of the critical role played by gut microflora in neuro and

immune modulatory functions during development and adulthood The normal microbiota is

responsible for synaptogenesis to occur and its absence denotes behavioral and

histopathological abnormalities (Cryan et al 2012) A homeostatic communication is

maintained between the brain and the gut intraluminal milieu through various signals

including neural hormonal and immunological A more recent observation has been the

pathogenesis of several Central nervous system disorders correlated with a perturbed gut-

microbiota population (Catanzaro R et al2015)During infancy there are innumerable

synaptic connections which provide the essential substrate for functional brain activities such

as cognition perception and action A study shows that the commensal microbiota is

necessary for the development of brain (Heijtz et al 2011) The authors hypothesized that

4

gut microbiota modulates synaptogenesis Intestinal microorganisms are also critical for

activation of systemic immunity They regulate the function of macrophages that reside in the

lamina propria of the intestine The pathways that link the intestinal flora to the brain are (1)

Via the activation of the vagus nerve from mature enteric nervous system (ENS) to central

nervous system (CNS) (Forsythe et al 2014) (2) Through circulatory system various

metabolites pass through intestine barriers and then across the blood brain barrier to regulate

neurological function (3) Via immune cells- Microbe associated molecular pattern

(MAMPPAMPs) such as bacterial lipoprotein lipopolysaccharide and polysaccharide A

Signals are sent to brain through cytokines like dendritic cells macrophages T cells and B

cells

Microbiota mediated alterations in behaviour and mood

The intestinal microbes send signals affecting the hypothalamic-pituitary-adrenal axis (HPA)

which reveals a bidirectional communication system between the host gut and brain (Figure

2) There are a high proportion of neurotransmitters in the gut which have the potential to

modulate activity of vagus nerve which is the primary nerve connecting enteric nervous

system to CNS and subsequently influence brain function (Bravo et al 2011) During fetal

development the microbiota plays a crucial role in programming the phenotype they

influence the levels of serotonin (5-HT 5 hydroxy tryptamine) BDNF (Brain derived

neurotropic factor) in regions of Amygdala and Hippocampus These factors play a regulatory

role in neurogenesis and synaptic plasticity

BDNF is a protein encoded by BDNF gene important for long term memory helps support

survival of existing neurons and encourage growth and differentiation of new neurons

generation of synapses The symbiotic organisms residing in the GI tract largely affect the

production and regulation of its function Reduced levels of BDNF are seen in neurological

5

conditions like schizophrenia depression Alzheimerrsquos mood disorders like anxiety and

epilepsy (Foster et al 2013)

Serotonin is a monoamine neurotransmitter acquired from the amino acid tryptophan It is

responsible for the well-being regulation of mood sleep and cognitive functions Deficit of

serotonin causes depression 5-HT synthesis requires tryptophan and this is generated by the

intestinal microbiota which can cross the blood brain barrier for the synthesis

Neurophysiology can be changed by actions of the microbiome such as by altering the

permeability of blood brain barrier allowing flux of metabolites into and out of the brain

(Bercik et al 2014) In absence of microbes there is a decreased level of neurotransmitters

such as dopamine and GABA Specific intestinal bacteria produce small molecules such as

serotonin dopamine epinephrine and norepinephrine (Wall et al 2014 Lyte et al 2013)

Mechanism of action

The microbes send signals to enterochromaffin cells which produce neurotransmitters and

enteric neurons glia The decarboxylation of the amino acid tryptophan by neurotransmitter

tryptamine is initiated by specific microbes residing in the namely Clostridium sporogenes

and Ruminococccus gnavus (Williams et al 2014) In the brain tryptamine a monoamine

alkaloid is a non-selective serotonin receptor agonist which plays an inhibitory role in the

response to serotonin and modulate mood and appetite (Zucchi et al 2006) while in the gut

tryptamine can also induce enterochromaffin cells to release 5-HT The gut microbiota is also

responsible for release of another neuromodulator tyramine which has higher affinity for

TAAR1 receptor found in the brain Lactic acid bacteria such as Lbrevis and enterococcus

species act locally via vagus nerve via the periphery (Barett et al 2012)

Studies have shown that microbiota derived signals can induce non-inflammatory cytokine

pathways For instance the plasma G-CSF can cross the blood brain barrier and acts to

6

stimulate neurogenesis in the brain (Zhao et al 2007) Through G-CSF production the

microbiota influences the rate of neurogenesis

With the knowledge of the important role played by microbes in neurological activities

research studies and findings progress towards maintaining this rich microbiota and

stimulating them to contribute to the host a positive effect Dietary macronutrients have a

great effect on the gut microbiome Bacteroidetes Firmicutes Actinobacteria are 3 major

phyla that inhabit the large intestine The diet can significantly change the composition of the

microbiota From birth the diet is involved in the development of microbial communities in

GI tract

Stress and its effects on brain

Human beings are susceptible to stress factors at some point of time irrespective of age

gender economic status As a matter of fact all organisms have some form of exposure to

stress It weakens the physiological functioning of the entire body and fails to maintain

homeostasis Stress has been known to cause many unfavorable effects in the body the first

among them equals derangement of gut mucosa permeability and compromised intestinal

morphology which indirectly impacts the brain leading to increased inflammation in

conditions like depression A symbiotic composition of Saccharomyces boulardii lysate has

been investigated to impede the stress induced gut hyper-permeability and other related

parameters were monitored (Takadanohara H et al 2012) It also triggers a chemical change

in the brain that modifies the synapses thereby disturbing the neuronal connectivity During

the period of exposure to stress there is elevated levels of cortisol commonly referred to as

ldquostress hormonerdquo is the bodyrsquos natural response to stress Response to stress is an essential

part of survival However while enabling the body to manage the effects of stress this

hormone has devastating effects on the brain The high levels of glucocorticoid activity are

associated with reduced neurogenic activity (Gould et al 1997a 1999b Lagace DC et al

7

2010) The hypothalamic-pituitary-adrenal axis (HPA) is considered as the central response

system in the body it reticulates the central nervous system and endocrine system and

coordinates a defective response to stress factors HPA axis is responsible for the prominent

increase in behaviour altering chemicals including glucocorticoids catecholamines and

mineralocorticoids Its activity is regulated by afferent nerve fibres of the parasympathetic

system such as vagus nerves oculomotor nerves limbic system which includes hippocampus

amygdala basal ganglia and sympathetic systems

The hippocampus is a horse shaped region near to the amygdala in the midbrain Our

experiences emotions memory retention rely entirely on the hippocampus to function

correctly Neuroscientists have confirmed that chronic stress can damage the brain severely

and have a long-term effect involving changes in brain structure such as shrinking the

hippocampus volume loss of memory retention neuroinflammation suppressing the neural

activity and increasing the size of amygdala which heightens flightfight response The

maintenance of stability in the brain is disturbed due to continual exposure of stress Raised

levels of cortisol is involved in the synthesis of neurotransmitter glutamate which is a

chemical used to transmit signals to other nerve cells This excitatory neurotransmitter when

released in high amounts has neurotoxic effects by generating free radicals Cortisol also

damages the receptors of the neurotransmitters serotonin and dopamine which are regulators

of mood pleasure happiness and motivation Prolonged stress is known to alter the blood

brain barrier permitting the entry of pathogens heavy metal toxins which damage the brain

cells (Figure 3) There is an immense loss of neurons and brain cells due to inhibitory action

of cortisol on the brain derived neurotropic factor (BDNF) which is a protein used to

maintain healthy brain cells and for synthesis of new cells in the brain

8

Role of nutraceuticals

The term ldquonutraceuticalrdquo was coined by Stephen L Defelice in 1979 According to Defelice

it is defined as food or parts of food that dispense medicalhealth benefits including

prevention and treatment It is a composite of nutrition and pharmaceutical which helps to

maintain the physiological functions of the body These nutrient factors provide sufficient

nutrients to meet the fundamental nutritional requirements for quality living balance and

growth (Maddi et al 2007) They are also referred to as medical foods and designer foods

These products are derived from food sources with additional health benefits besides

providing the basic nutritional value in foods (Rishi et al 2006) Nutraceutical compounds

specifically targeting the neurodevelopment processes are referred to ldquoneuro-nutraceuticalsrdquo

a term that has been recently introduced These supplements are chemically identified

molecules that beneficially affect the brain at molecular level Their actions are directed to

aid in improvement of cognition improve memory positively impact the production of

neurotransmitters reduce inflammations and ageing of brain management of

neurodegenerative and neuropsychiatric disorders (Malik et al 2008) In line with the

subject they also are known to enhance the gut microbes and influence their activities A

healthy gut impacts the brain development and signalling mechanisms It helps to lower the

stress levels and maintain a good mood Foods can infuse our brains with energy to make us

think faster and better Nutraceuticals range from isolated nutrients such as vitamins

minerals fatty acids probiotics prebiotics antioxidants polyaminoacids polysaccharides

herbal products genetically engineered foods and phytochemicals which include

(Carotenoids- fruits vegetables and egg yolk Flavonoid polyphenolics- berries fruits

vegetables legumes are potent antioxidants Non-flavonoid polyphenolics- dark grapes

raisins berries peanuts turmeric roots)

9

Effects of nutrients on gut and brain

The diverse composition of gut microbiota in humans depends on dietary habits The key

mechanisms to maintain gut health are considered to increase the intake of high fibre diet

polysaccharides polyunsaturated fatty acids antioxidants and phytochemicals High-fibre

rich foods stimulate fermentation which proliferates the bacteria and increase biomass

Fermentation causes carbohydrates to undergo chemical changes which result in organic

acids that provide energy for the microbes Short chain fatty acids (SCFA) are the end

products of carbohydrate fermentation which help to inhibit the growth of pathogenic

microorganisms The intake of short-chain non-digestible carbohydrates which include

inulin-type fructans fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS) are

source of prebiotics that typically target growth of bacterial groups such as

Bifidobacterium and Lactobacillus These prebiotic fibres help to ease anxiety depression

restore healthy sleep patterns and protect beneficial gut bacteria Dietary saturated fats may

increase the number of existing pro-inflammatory gut microbes by stimulating formation of

taurine conjugated bile acids that promotes growth of these microbes (Devkota et al 2012)

Polyphenol containing berries metabolized by resident microbiota results in bioactive

products which impacts the health (Duthie et al 2003) Any gut malfunction has a negative

impact on human health therefore it is highly essential to incorporate foods that enhance the

microflora of the gut Artichokes have a strong probiotic potential the high content of inulin

which is insoluble fibre ferments into healthy microflora (Gibson et al 1995) Adequate

administration of probiotics is recognized to have balanced immunoregulatory activities

Investigations on a particular probiotic strain Lactobacillus Pentosus has been shown to

enhance the cytokine production especially IL-10 which is responsible for maintaining the

host immunity by normalizing the T regulatory cells (M Kimura et al2017) Lately a

fascinating finding has been that cocoa or chocolate the most craved food across the globe

10

may modulate the gut commensal population They are found to contain flavonoids including

procyanidins like catechin and epicatechin oligomers which enhance the action of the

neurotransmitters in the brain A Homayouni Rad and his colleagues formulated chocolate as

a potential carrier of probiotic culture strains including lactobacilluscasei and paracasei

positively sustaining the intestinal microbiota population and also releasing stress busting

endorphins Another notable strain is the lactic acid bacteria Streptococcus thermophilus

widely used in the commercial production of fermented dairy products Because of its

inability to survive in the healthy gastric pH of the stomach it has not been suggested as a

ideal probiotic candidate Nonetheless Xiaohong Kangaan and colleagues conducted an

intriguing study on the health promoting effects of milk fermented by Streptococcus

thermophilus in mice the fermented milk was found to have an enhanced cell-mediated

response and positive immunostimulatory effects (M Kimura et al2017) Bananas restore

health of the bacterial community and reduce inflammation It is found to maintain harmony

between the different phyla present in the gut Polenta is a corn-based complex carbohydrate

which has fermentable components that fosters healthy microbiota because of its high fiber

(Anderson et al 2009) Broccoli kale cauliflower cabbage consist of sulfur containing

metabolites namely glucosinolates which are fragmented by the microbes to release

substances that reduce inflammation (Li et al 2008)

Benefits of berry fruit polyphenols

Oxidative stress is a serious threat triggering widespread increase in the occurrence of major

diseases such as Alzheimerrsquos Parkinsonrsquos other neurodegenerative disorders and ageing

Foods rich in antioxidant activity help to prevent age-related changes (Figure 4) Berry fruit

polyphenols can neutralize the negative effects of free-radicals the harmful by-products of

cellular metabolism which contribute to age related diseases They also possess a multiplicity

of actions aside from antioxidant activity They stimulate brain activity neuronal

11

communication cognitive skills calcium buffering ability improve movement control and

prevent memory loss Supplements derived from berry fruits like blueberry cranberry

strawberry have been reported to be effective in reversing motor and behavioral deficits and

control sensory inputs These tiny fruits laden with healing properties are referred to as brain

protective fruits berries are rich in bioflavonoids such as anthocyanins and proanthocyanins

both of which are scavengers of free radicals Active phytochemicals present in the blueberry

confer the benefit of being able to cross the blood-brain-barrier Anthocyanins have been

shown to penetrate the brain and their concentrations correspond to appropriate cognitive

performances (Lacueva et al 2005) They upregulate TNF α IL-1β NF-κB and

consequently suppress ageing and improve blood flow to the brain Blueberries are

responsible for reducing expression of stress signals and results in increasing protective

signals and impact cell signalling molecule expression (Shukitt-Hale et al 2008) The

anthocyanins elevate the level of BDNF (Brain derived neurotropic factor) which is crucial to

boost neuronal communication influencing cognitive function Heat shock proteins are

known to fight free radicals and inflammation inducing agents to support healthy brain

tissues The ability to generate heat shock proteins declines with age dramatically However

researchers have found that consumption of blueberries could restore heat shock protein

response and help protect against neurodegeneration processes associated with ageing

Blueberries play an essential role in reducing the toxicity of kainic acid on hippocampal cells

Kainic acid is an amino acid which is naturally abundant in seaweeds and can be neurotoxic

because of its potent ability to stimulate neurons by activating receptors for glutamate This

aminoacid can be induced in laboratory animal models to study various neurodegenerative

disorders

12

PUFAs

Polyunsaturated fatty acids (PUFAs) are critical components of neuronal cell membranes and

are involved in neurotransmitter communication within the neural networks They are

responsible for maintaining membrane fluidity essential synaptic vesicle fusion and serve as

precursors for lipid messengers which participate in signalling processes to promote neuronal

protection (Bazan et al 2005) Flaxseeds fish soybeans walnuts are rich in PUFA

specifically omega- 6 fatty acid linoleic acid omega-3 α linolenic acid

Intake of PUFA supplements for improve cognitive function

In most neurological conditions inflammation manifests in the nervous tissue and this

inflammation is a therapeutic target by the pharmaceutical industries During high levels of

stress the body cannot regulate an inflammatory response which leads to a greater risk of

development of other diseases Anti-inflammatory agents containing nutraceuticals is the

focus of development Oxymatrine derived from the root of a Chinese herb Sophora

flavescens has been reported to have anti-inflammatory actions and decreases damage

observed after hypoxic- ischaemic brain injury in neonatal rat models (Zhao et al 2015)

Apocynin obtained from the root of Picrorhiza kurroa is also believed to have anti-

inflammatory properties and attenuate the cholesterol oxidation product induced apoptosis in

neuronal cells by preventing production of reactive oxygen species (Simonyi et al 2012)

Quercetin known to be found in vegetables fruits have antioxidant effects regulate proteins

transcription factors and kinase dependent signalling pathways Nutraceutical additive actions

of quercetin expedite optimal delivery and improve brain activity Naturally occurring 7 8-

dihydroxyflavone rescues cognition deficits and serve as a novel treatment for autism and

schizophrenia Trans-resveratrol and pterostilbene are plant derived synergistic phytonutrients

improving brain health and having diverse actions against oxidative stress (Poulose et al

2015) Creatine is a natural substance when taken as supplements in recommended dose is

13

beneficial to enhance brain function and improve cognitive function (Wallimann 2008) (Table

1)

Management of stress

Nutrient supplements have the potential to overcome the debilitating effects of stress They

act as prophylactic and therapeutic agents and are more efficient and safe in comparison to

pharmaceutical drugs (Pandey et al 2010) Botanically derived ingredients are used to treat

mild depression anxiety improve sleep patterns and maintain good health Since a persistent

level of cortisol in circulation is the chief cause of depression and stress naturally derived

products target this hormone to annihilate the stress factors and boost mental health and

cognition Researchers have studied the effects of probiotics against stress in a zebrafish

model by introducing the bacterial strain Lactobacillus plantarum into the tank (Davis et al

2016) The objective is to bring the body back to homeostasis maintaining a balanced level

of cortisol The actions of gut microbes and nutraceuticals work interdependently to help

reduce the dangerous outcomes of stress upon the body Experiments with germ free mice

have been used to probe the role of microbiota in adult hippocampal neurogenesis Also

disruptions of gut microbiome induced mice behaviour resulted in anxiety depression and

even autism Gut microbes are the key modulators of brain plasticity cognitive functions and

help to optimize the bodyrsquos response to stress by regulating their synthesis of

neurotransmitters like serotonin to lower the cortisol level Studies have shown that during

stress there is an increased population of certain bacterial strains in the gut such as

Enterobacteriaceae Proteobacteria Actinobacteria and this can be controlled by increasing

the administration of probiotics containing Lactobacillus and Bifidobacterium species

Experiments have been conducted with Bifidobacterium longum and results showed that this

strain was able to reverse hippocampal and BDNF abnormalities

14

CONCLUSION

In today lsquos ambitious world so much importance is being given to performance perfection

competition that it leads to an insidious increase in stress depression anxiety Stress is a

psychological issue which predisposes a person to various other ailments It is inevitable in

the life of any individual but the duration and intensity differs According to Hans Selye who

coined the term stress in 1936 it is the non- specific response of the body to any demand for

change Stress levels are rising worldwide it is a top health concern The damages that can be

caused by stress are often underestimated It primarily affects the nervous system but

prolonged exposure leads to cardiovascular musculoskeletal diseases and even affects the

reproductive system Claude Bernard (1865-1961) observed that the maintenance of life is

essentially dependent on keeping our internal milieu constant in the face of a changing

environment Thus sustaining a state of homeostasis is vital for a healthy life Workplace

stress and depression is on the rise it is the health epidemic of 21 st century a frequently

reported problem According to WHO depression is among the leading causes of disability

globally There is a compelling need to confront the ameliorating and deleterious effects of

stress inflicted on an individual These health risks can be prevented or managed A multi

targeted approach is required to tackle a problem as severe as stress It can be controlled in

the healthy way by nourishing and stimulating the gut microbes in our body to act on the

brain which increases the release of neurotransmitters to help relieve the effects of stress

Nutrient supplements referred to as nutraceuticals has been introduced to influence the brain

activity and protect it from the negative impact of stress hormones These nutraceuticals help

to enhance the quality of life by modulating the gut health They prevent the alteration of

microbiome during stress Extensive research has been conducted in the field of gut microbes

and nutraceuticals and their efficacy towards alleviating stress has been proved We are

moving towards the direction of exploring psych biotics as a mode of treatment for anxiety

15

depression and various psychiatric issues However it is a recently introduced term and

research and is still on-going whether it has proven benefits or not Dietary interventions with

food supplements designed to modulate responses to stress that can be administered

effectively Managing stress in the natural way is proven to be the most favorable method

Acknowledgements

The authors are thankful to Chettinad Academy of Research and Education (CARE) for the

support

Conflicts of interest

We declare no conflict of interest All co-authors have agreed to transfer the copyright to the

publisher if it is accepted for publication This study was partially financially supported by

Chettinad Hospital amp Research Institute (CHRI) Chettinad Academy of Research and

Education (CARE) Kelambakkam Chennai-603103 India

16

References

Anderson JW Baird P Davis RH Ferreri S Knutdson M Koraym A Waters V

Williams CL (2009) Health benefits of dietary fibre Nutrition Reviews 67188-205

Andres RH Ducray AD Schlattner U Wallimann T Widmer HR (2008) Functions

and effects of creatine in the central nervous system Brain Research Bulletin 76(4)329-43

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged blueberry-fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2)111-20

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged-blueberry fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2) 111-20

Barrett E Ross RP OToole PW Fitzgerald GF Stanton C (2012) gamma-

Aminobutyric acid production by culturable bacteria from the human intestine Journal of

applied microbiology 113411ndash417

Bazan NG (2005) Lipid signaling in neural plasticity brain repair and neuroprotection

Molecular Neurobiology 32(1)89-103

Bercik P Denou E Collins J Jackson W Lu J Jury J Deng Y Blennerhassett P

Macri J McCoy KD Verdu EF Collins SM (2011) The intestinal microbiota affect

central levels of brain-derived neurotropic factor and behavior in mice Gastroenterology

141599-609

Borre YE OKeeffe GW Clarke G Stanton C Dinan TG Cryan JF (2014)

Microbiota and neurodevelopmental windows implications for brain disorders Trends in

Molecular Medicine 20509-518

Bravo JA Forsythe P Chew MV (2011) Ingestion of Lactobacillus strain regulates

emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

17

antibiotics immune suppression stress pathological condition and surgery (Figure 1)

Microbiome characteristics

The functions performed by the microbiota are referred to as microflora associated

characteristics (MAC) by various researchers (Collinder et al 1998) Among several

functions the important ones include digestion of metabolite substrates vitamin K and B

production drug metabolism mucosal cell development stimulation of immune system

protection against pathogenic organisms where it has been found to induce antimicrobial

proteins such as cathelicidins C-type lectins and (pro) defensins The microbial gene

products impact the metabolism and health status of the host Recent research findings on the

interaction of gut microbiome and the brain have paved the way for more in-depth studies on

understanding the impact of these simple microbes on the complex distant organ the brain

thereby transforming neurosciences opening frontiers for therapeutic strategies for

neurodevelopment disorders

Gut-brain signalling

There is increasing evidence of the critical role played by gut microflora in neuro and

immune modulatory functions during development and adulthood The normal microbiota is

responsible for synaptogenesis to occur and its absence denotes behavioral and

histopathological abnormalities (Cryan et al 2012) A homeostatic communication is

maintained between the brain and the gut intraluminal milieu through various signals

including neural hormonal and immunological A more recent observation has been the

pathogenesis of several Central nervous system disorders correlated with a perturbed gut-

microbiota population (Catanzaro R et al2015)During infancy there are innumerable

synaptic connections which provide the essential substrate for functional brain activities such

as cognition perception and action A study shows that the commensal microbiota is

necessary for the development of brain (Heijtz et al 2011) The authors hypothesized that

4

gut microbiota modulates synaptogenesis Intestinal microorganisms are also critical for

activation of systemic immunity They regulate the function of macrophages that reside in the

lamina propria of the intestine The pathways that link the intestinal flora to the brain are (1)

Via the activation of the vagus nerve from mature enteric nervous system (ENS) to central

nervous system (CNS) (Forsythe et al 2014) (2) Through circulatory system various

metabolites pass through intestine barriers and then across the blood brain barrier to regulate

neurological function (3) Via immune cells- Microbe associated molecular pattern

(MAMPPAMPs) such as bacterial lipoprotein lipopolysaccharide and polysaccharide A

Signals are sent to brain through cytokines like dendritic cells macrophages T cells and B

cells

Microbiota mediated alterations in behaviour and mood

The intestinal microbes send signals affecting the hypothalamic-pituitary-adrenal axis (HPA)

which reveals a bidirectional communication system between the host gut and brain (Figure

2) There are a high proportion of neurotransmitters in the gut which have the potential to

modulate activity of vagus nerve which is the primary nerve connecting enteric nervous

system to CNS and subsequently influence brain function (Bravo et al 2011) During fetal

development the microbiota plays a crucial role in programming the phenotype they

influence the levels of serotonin (5-HT 5 hydroxy tryptamine) BDNF (Brain derived

neurotropic factor) in regions of Amygdala and Hippocampus These factors play a regulatory

role in neurogenesis and synaptic plasticity

BDNF is a protein encoded by BDNF gene important for long term memory helps support

survival of existing neurons and encourage growth and differentiation of new neurons

generation of synapses The symbiotic organisms residing in the GI tract largely affect the

production and regulation of its function Reduced levels of BDNF are seen in neurological

5

conditions like schizophrenia depression Alzheimerrsquos mood disorders like anxiety and

epilepsy (Foster et al 2013)

Serotonin is a monoamine neurotransmitter acquired from the amino acid tryptophan It is

responsible for the well-being regulation of mood sleep and cognitive functions Deficit of

serotonin causes depression 5-HT synthesis requires tryptophan and this is generated by the

intestinal microbiota which can cross the blood brain barrier for the synthesis

Neurophysiology can be changed by actions of the microbiome such as by altering the

permeability of blood brain barrier allowing flux of metabolites into and out of the brain

(Bercik et al 2014) In absence of microbes there is a decreased level of neurotransmitters

such as dopamine and GABA Specific intestinal bacteria produce small molecules such as

serotonin dopamine epinephrine and norepinephrine (Wall et al 2014 Lyte et al 2013)

Mechanism of action

The microbes send signals to enterochromaffin cells which produce neurotransmitters and

enteric neurons glia The decarboxylation of the amino acid tryptophan by neurotransmitter

tryptamine is initiated by specific microbes residing in the namely Clostridium sporogenes

and Ruminococccus gnavus (Williams et al 2014) In the brain tryptamine a monoamine

alkaloid is a non-selective serotonin receptor agonist which plays an inhibitory role in the

response to serotonin and modulate mood and appetite (Zucchi et al 2006) while in the gut

tryptamine can also induce enterochromaffin cells to release 5-HT The gut microbiota is also

responsible for release of another neuromodulator tyramine which has higher affinity for

TAAR1 receptor found in the brain Lactic acid bacteria such as Lbrevis and enterococcus

species act locally via vagus nerve via the periphery (Barett et al 2012)

Studies have shown that microbiota derived signals can induce non-inflammatory cytokine

pathways For instance the plasma G-CSF can cross the blood brain barrier and acts to

6

stimulate neurogenesis in the brain (Zhao et al 2007) Through G-CSF production the

microbiota influences the rate of neurogenesis

With the knowledge of the important role played by microbes in neurological activities

research studies and findings progress towards maintaining this rich microbiota and

stimulating them to contribute to the host a positive effect Dietary macronutrients have a

great effect on the gut microbiome Bacteroidetes Firmicutes Actinobacteria are 3 major

phyla that inhabit the large intestine The diet can significantly change the composition of the

microbiota From birth the diet is involved in the development of microbial communities in

GI tract

Stress and its effects on brain

Human beings are susceptible to stress factors at some point of time irrespective of age

gender economic status As a matter of fact all organisms have some form of exposure to

stress It weakens the physiological functioning of the entire body and fails to maintain

homeostasis Stress has been known to cause many unfavorable effects in the body the first

among them equals derangement of gut mucosa permeability and compromised intestinal

morphology which indirectly impacts the brain leading to increased inflammation in

conditions like depression A symbiotic composition of Saccharomyces boulardii lysate has

been investigated to impede the stress induced gut hyper-permeability and other related

parameters were monitored (Takadanohara H et al 2012) It also triggers a chemical change

in the brain that modifies the synapses thereby disturbing the neuronal connectivity During

the period of exposure to stress there is elevated levels of cortisol commonly referred to as

ldquostress hormonerdquo is the bodyrsquos natural response to stress Response to stress is an essential

part of survival However while enabling the body to manage the effects of stress this

hormone has devastating effects on the brain The high levels of glucocorticoid activity are

associated with reduced neurogenic activity (Gould et al 1997a 1999b Lagace DC et al

7

2010) The hypothalamic-pituitary-adrenal axis (HPA) is considered as the central response

system in the body it reticulates the central nervous system and endocrine system and

coordinates a defective response to stress factors HPA axis is responsible for the prominent

increase in behaviour altering chemicals including glucocorticoids catecholamines and

mineralocorticoids Its activity is regulated by afferent nerve fibres of the parasympathetic

system such as vagus nerves oculomotor nerves limbic system which includes hippocampus

amygdala basal ganglia and sympathetic systems

The hippocampus is a horse shaped region near to the amygdala in the midbrain Our

experiences emotions memory retention rely entirely on the hippocampus to function

correctly Neuroscientists have confirmed that chronic stress can damage the brain severely

and have a long-term effect involving changes in brain structure such as shrinking the

hippocampus volume loss of memory retention neuroinflammation suppressing the neural

activity and increasing the size of amygdala which heightens flightfight response The

maintenance of stability in the brain is disturbed due to continual exposure of stress Raised

levels of cortisol is involved in the synthesis of neurotransmitter glutamate which is a

chemical used to transmit signals to other nerve cells This excitatory neurotransmitter when

released in high amounts has neurotoxic effects by generating free radicals Cortisol also

damages the receptors of the neurotransmitters serotonin and dopamine which are regulators

of mood pleasure happiness and motivation Prolonged stress is known to alter the blood

brain barrier permitting the entry of pathogens heavy metal toxins which damage the brain

cells (Figure 3) There is an immense loss of neurons and brain cells due to inhibitory action

of cortisol on the brain derived neurotropic factor (BDNF) which is a protein used to

maintain healthy brain cells and for synthesis of new cells in the brain

8

Role of nutraceuticals

The term ldquonutraceuticalrdquo was coined by Stephen L Defelice in 1979 According to Defelice

it is defined as food or parts of food that dispense medicalhealth benefits including

prevention and treatment It is a composite of nutrition and pharmaceutical which helps to

maintain the physiological functions of the body These nutrient factors provide sufficient

nutrients to meet the fundamental nutritional requirements for quality living balance and

growth (Maddi et al 2007) They are also referred to as medical foods and designer foods

These products are derived from food sources with additional health benefits besides

providing the basic nutritional value in foods (Rishi et al 2006) Nutraceutical compounds

specifically targeting the neurodevelopment processes are referred to ldquoneuro-nutraceuticalsrdquo

a term that has been recently introduced These supplements are chemically identified

molecules that beneficially affect the brain at molecular level Their actions are directed to

aid in improvement of cognition improve memory positively impact the production of

neurotransmitters reduce inflammations and ageing of brain management of

neurodegenerative and neuropsychiatric disorders (Malik et al 2008) In line with the

subject they also are known to enhance the gut microbes and influence their activities A

healthy gut impacts the brain development and signalling mechanisms It helps to lower the

stress levels and maintain a good mood Foods can infuse our brains with energy to make us

think faster and better Nutraceuticals range from isolated nutrients such as vitamins

minerals fatty acids probiotics prebiotics antioxidants polyaminoacids polysaccharides

herbal products genetically engineered foods and phytochemicals which include

(Carotenoids- fruits vegetables and egg yolk Flavonoid polyphenolics- berries fruits

vegetables legumes are potent antioxidants Non-flavonoid polyphenolics- dark grapes

raisins berries peanuts turmeric roots)

9

Effects of nutrients on gut and brain

The diverse composition of gut microbiota in humans depends on dietary habits The key

mechanisms to maintain gut health are considered to increase the intake of high fibre diet

polysaccharides polyunsaturated fatty acids antioxidants and phytochemicals High-fibre

rich foods stimulate fermentation which proliferates the bacteria and increase biomass

Fermentation causes carbohydrates to undergo chemical changes which result in organic

acids that provide energy for the microbes Short chain fatty acids (SCFA) are the end

products of carbohydrate fermentation which help to inhibit the growth of pathogenic

microorganisms The intake of short-chain non-digestible carbohydrates which include

inulin-type fructans fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS) are

source of prebiotics that typically target growth of bacterial groups such as

Bifidobacterium and Lactobacillus These prebiotic fibres help to ease anxiety depression

restore healthy sleep patterns and protect beneficial gut bacteria Dietary saturated fats may

increase the number of existing pro-inflammatory gut microbes by stimulating formation of

taurine conjugated bile acids that promotes growth of these microbes (Devkota et al 2012)

Polyphenol containing berries metabolized by resident microbiota results in bioactive

products which impacts the health (Duthie et al 2003) Any gut malfunction has a negative

impact on human health therefore it is highly essential to incorporate foods that enhance the

microflora of the gut Artichokes have a strong probiotic potential the high content of inulin

which is insoluble fibre ferments into healthy microflora (Gibson et al 1995) Adequate

administration of probiotics is recognized to have balanced immunoregulatory activities

Investigations on a particular probiotic strain Lactobacillus Pentosus has been shown to

enhance the cytokine production especially IL-10 which is responsible for maintaining the

host immunity by normalizing the T regulatory cells (M Kimura et al2017) Lately a

fascinating finding has been that cocoa or chocolate the most craved food across the globe

10

may modulate the gut commensal population They are found to contain flavonoids including

procyanidins like catechin and epicatechin oligomers which enhance the action of the

neurotransmitters in the brain A Homayouni Rad and his colleagues formulated chocolate as

a potential carrier of probiotic culture strains including lactobacilluscasei and paracasei

positively sustaining the intestinal microbiota population and also releasing stress busting

endorphins Another notable strain is the lactic acid bacteria Streptococcus thermophilus

widely used in the commercial production of fermented dairy products Because of its

inability to survive in the healthy gastric pH of the stomach it has not been suggested as a

ideal probiotic candidate Nonetheless Xiaohong Kangaan and colleagues conducted an

intriguing study on the health promoting effects of milk fermented by Streptococcus

thermophilus in mice the fermented milk was found to have an enhanced cell-mediated

response and positive immunostimulatory effects (M Kimura et al2017) Bananas restore

health of the bacterial community and reduce inflammation It is found to maintain harmony

between the different phyla present in the gut Polenta is a corn-based complex carbohydrate

which has fermentable components that fosters healthy microbiota because of its high fiber

(Anderson et al 2009) Broccoli kale cauliflower cabbage consist of sulfur containing

metabolites namely glucosinolates which are fragmented by the microbes to release

substances that reduce inflammation (Li et al 2008)

Benefits of berry fruit polyphenols

Oxidative stress is a serious threat triggering widespread increase in the occurrence of major

diseases such as Alzheimerrsquos Parkinsonrsquos other neurodegenerative disorders and ageing

Foods rich in antioxidant activity help to prevent age-related changes (Figure 4) Berry fruit

polyphenols can neutralize the negative effects of free-radicals the harmful by-products of

cellular metabolism which contribute to age related diseases They also possess a multiplicity

of actions aside from antioxidant activity They stimulate brain activity neuronal

11

communication cognitive skills calcium buffering ability improve movement control and

prevent memory loss Supplements derived from berry fruits like blueberry cranberry

strawberry have been reported to be effective in reversing motor and behavioral deficits and

control sensory inputs These tiny fruits laden with healing properties are referred to as brain

protective fruits berries are rich in bioflavonoids such as anthocyanins and proanthocyanins

both of which are scavengers of free radicals Active phytochemicals present in the blueberry

confer the benefit of being able to cross the blood-brain-barrier Anthocyanins have been

shown to penetrate the brain and their concentrations correspond to appropriate cognitive

performances (Lacueva et al 2005) They upregulate TNF α IL-1β NF-κB and

consequently suppress ageing and improve blood flow to the brain Blueberries are

responsible for reducing expression of stress signals and results in increasing protective

signals and impact cell signalling molecule expression (Shukitt-Hale et al 2008) The

anthocyanins elevate the level of BDNF (Brain derived neurotropic factor) which is crucial to

boost neuronal communication influencing cognitive function Heat shock proteins are

known to fight free radicals and inflammation inducing agents to support healthy brain

tissues The ability to generate heat shock proteins declines with age dramatically However

researchers have found that consumption of blueberries could restore heat shock protein

response and help protect against neurodegeneration processes associated with ageing

Blueberries play an essential role in reducing the toxicity of kainic acid on hippocampal cells

Kainic acid is an amino acid which is naturally abundant in seaweeds and can be neurotoxic

because of its potent ability to stimulate neurons by activating receptors for glutamate This

aminoacid can be induced in laboratory animal models to study various neurodegenerative

disorders

12

PUFAs

Polyunsaturated fatty acids (PUFAs) are critical components of neuronal cell membranes and

are involved in neurotransmitter communication within the neural networks They are

responsible for maintaining membrane fluidity essential synaptic vesicle fusion and serve as

precursors for lipid messengers which participate in signalling processes to promote neuronal

protection (Bazan et al 2005) Flaxseeds fish soybeans walnuts are rich in PUFA

specifically omega- 6 fatty acid linoleic acid omega-3 α linolenic acid

Intake of PUFA supplements for improve cognitive function

In most neurological conditions inflammation manifests in the nervous tissue and this

inflammation is a therapeutic target by the pharmaceutical industries During high levels of

stress the body cannot regulate an inflammatory response which leads to a greater risk of

development of other diseases Anti-inflammatory agents containing nutraceuticals is the

focus of development Oxymatrine derived from the root of a Chinese herb Sophora

flavescens has been reported to have anti-inflammatory actions and decreases damage

observed after hypoxic- ischaemic brain injury in neonatal rat models (Zhao et al 2015)

Apocynin obtained from the root of Picrorhiza kurroa is also believed to have anti-

inflammatory properties and attenuate the cholesterol oxidation product induced apoptosis in

neuronal cells by preventing production of reactive oxygen species (Simonyi et al 2012)

Quercetin known to be found in vegetables fruits have antioxidant effects regulate proteins

transcription factors and kinase dependent signalling pathways Nutraceutical additive actions

of quercetin expedite optimal delivery and improve brain activity Naturally occurring 7 8-

dihydroxyflavone rescues cognition deficits and serve as a novel treatment for autism and

schizophrenia Trans-resveratrol and pterostilbene are plant derived synergistic phytonutrients

improving brain health and having diverse actions against oxidative stress (Poulose et al

2015) Creatine is a natural substance when taken as supplements in recommended dose is

13

beneficial to enhance brain function and improve cognitive function (Wallimann 2008) (Table

1)

Management of stress

Nutrient supplements have the potential to overcome the debilitating effects of stress They

act as prophylactic and therapeutic agents and are more efficient and safe in comparison to

pharmaceutical drugs (Pandey et al 2010) Botanically derived ingredients are used to treat

mild depression anxiety improve sleep patterns and maintain good health Since a persistent

level of cortisol in circulation is the chief cause of depression and stress naturally derived

products target this hormone to annihilate the stress factors and boost mental health and

cognition Researchers have studied the effects of probiotics against stress in a zebrafish

model by introducing the bacterial strain Lactobacillus plantarum into the tank (Davis et al

2016) The objective is to bring the body back to homeostasis maintaining a balanced level

of cortisol The actions of gut microbes and nutraceuticals work interdependently to help

reduce the dangerous outcomes of stress upon the body Experiments with germ free mice

have been used to probe the role of microbiota in adult hippocampal neurogenesis Also

disruptions of gut microbiome induced mice behaviour resulted in anxiety depression and

even autism Gut microbes are the key modulators of brain plasticity cognitive functions and

help to optimize the bodyrsquos response to stress by regulating their synthesis of

neurotransmitters like serotonin to lower the cortisol level Studies have shown that during

stress there is an increased population of certain bacterial strains in the gut such as

Enterobacteriaceae Proteobacteria Actinobacteria and this can be controlled by increasing

the administration of probiotics containing Lactobacillus and Bifidobacterium species

Experiments have been conducted with Bifidobacterium longum and results showed that this

strain was able to reverse hippocampal and BDNF abnormalities

14

CONCLUSION

In today lsquos ambitious world so much importance is being given to performance perfection

competition that it leads to an insidious increase in stress depression anxiety Stress is a

psychological issue which predisposes a person to various other ailments It is inevitable in

the life of any individual but the duration and intensity differs According to Hans Selye who

coined the term stress in 1936 it is the non- specific response of the body to any demand for

change Stress levels are rising worldwide it is a top health concern The damages that can be

caused by stress are often underestimated It primarily affects the nervous system but

prolonged exposure leads to cardiovascular musculoskeletal diseases and even affects the

reproductive system Claude Bernard (1865-1961) observed that the maintenance of life is

essentially dependent on keeping our internal milieu constant in the face of a changing

environment Thus sustaining a state of homeostasis is vital for a healthy life Workplace

stress and depression is on the rise it is the health epidemic of 21 st century a frequently

reported problem According to WHO depression is among the leading causes of disability

globally There is a compelling need to confront the ameliorating and deleterious effects of

stress inflicted on an individual These health risks can be prevented or managed A multi

targeted approach is required to tackle a problem as severe as stress It can be controlled in

the healthy way by nourishing and stimulating the gut microbes in our body to act on the

brain which increases the release of neurotransmitters to help relieve the effects of stress

Nutrient supplements referred to as nutraceuticals has been introduced to influence the brain

activity and protect it from the negative impact of stress hormones These nutraceuticals help

to enhance the quality of life by modulating the gut health They prevent the alteration of

microbiome during stress Extensive research has been conducted in the field of gut microbes

and nutraceuticals and their efficacy towards alleviating stress has been proved We are

moving towards the direction of exploring psych biotics as a mode of treatment for anxiety

15

depression and various psychiatric issues However it is a recently introduced term and

research and is still on-going whether it has proven benefits or not Dietary interventions with

food supplements designed to modulate responses to stress that can be administered

effectively Managing stress in the natural way is proven to be the most favorable method

Acknowledgements

The authors are thankful to Chettinad Academy of Research and Education (CARE) for the

support

Conflicts of interest

We declare no conflict of interest All co-authors have agreed to transfer the copyright to the

publisher if it is accepted for publication This study was partially financially supported by

Chettinad Hospital amp Research Institute (CHRI) Chettinad Academy of Research and

Education (CARE) Kelambakkam Chennai-603103 India

16

References

Anderson JW Baird P Davis RH Ferreri S Knutdson M Koraym A Waters V

Williams CL (2009) Health benefits of dietary fibre Nutrition Reviews 67188-205

Andres RH Ducray AD Schlattner U Wallimann T Widmer HR (2008) Functions

and effects of creatine in the central nervous system Brain Research Bulletin 76(4)329-43

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged blueberry-fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2)111-20

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged-blueberry fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2) 111-20

Barrett E Ross RP OToole PW Fitzgerald GF Stanton C (2012) gamma-

Aminobutyric acid production by culturable bacteria from the human intestine Journal of

applied microbiology 113411ndash417

Bazan NG (2005) Lipid signaling in neural plasticity brain repair and neuroprotection

Molecular Neurobiology 32(1)89-103

Bercik P Denou E Collins J Jackson W Lu J Jury J Deng Y Blennerhassett P

Macri J McCoy KD Verdu EF Collins SM (2011) The intestinal microbiota affect

central levels of brain-derived neurotropic factor and behavior in mice Gastroenterology

141599-609

Borre YE OKeeffe GW Clarke G Stanton C Dinan TG Cryan JF (2014)

Microbiota and neurodevelopmental windows implications for brain disorders Trends in

Molecular Medicine 20509-518

Bravo JA Forsythe P Chew MV (2011) Ingestion of Lactobacillus strain regulates

emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

17

gut microbiota modulates synaptogenesis Intestinal microorganisms are also critical for

activation of systemic immunity They regulate the function of macrophages that reside in the

lamina propria of the intestine The pathways that link the intestinal flora to the brain are (1)

Via the activation of the vagus nerve from mature enteric nervous system (ENS) to central

nervous system (CNS) (Forsythe et al 2014) (2) Through circulatory system various

metabolites pass through intestine barriers and then across the blood brain barrier to regulate

neurological function (3) Via immune cells- Microbe associated molecular pattern

(MAMPPAMPs) such as bacterial lipoprotein lipopolysaccharide and polysaccharide A

Signals are sent to brain through cytokines like dendritic cells macrophages T cells and B

cells

Microbiota mediated alterations in behaviour and mood

The intestinal microbes send signals affecting the hypothalamic-pituitary-adrenal axis (HPA)

which reveals a bidirectional communication system between the host gut and brain (Figure

2) There are a high proportion of neurotransmitters in the gut which have the potential to

modulate activity of vagus nerve which is the primary nerve connecting enteric nervous

system to CNS and subsequently influence brain function (Bravo et al 2011) During fetal

development the microbiota plays a crucial role in programming the phenotype they

influence the levels of serotonin (5-HT 5 hydroxy tryptamine) BDNF (Brain derived

neurotropic factor) in regions of Amygdala and Hippocampus These factors play a regulatory

role in neurogenesis and synaptic plasticity

BDNF is a protein encoded by BDNF gene important for long term memory helps support

survival of existing neurons and encourage growth and differentiation of new neurons

generation of synapses The symbiotic organisms residing in the GI tract largely affect the

production and regulation of its function Reduced levels of BDNF are seen in neurological

5

conditions like schizophrenia depression Alzheimerrsquos mood disorders like anxiety and

epilepsy (Foster et al 2013)

Serotonin is a monoamine neurotransmitter acquired from the amino acid tryptophan It is

responsible for the well-being regulation of mood sleep and cognitive functions Deficit of

serotonin causes depression 5-HT synthesis requires tryptophan and this is generated by the

intestinal microbiota which can cross the blood brain barrier for the synthesis

Neurophysiology can be changed by actions of the microbiome such as by altering the

permeability of blood brain barrier allowing flux of metabolites into and out of the brain

(Bercik et al 2014) In absence of microbes there is a decreased level of neurotransmitters

such as dopamine and GABA Specific intestinal bacteria produce small molecules such as

serotonin dopamine epinephrine and norepinephrine (Wall et al 2014 Lyte et al 2013)

Mechanism of action

The microbes send signals to enterochromaffin cells which produce neurotransmitters and

enteric neurons glia The decarboxylation of the amino acid tryptophan by neurotransmitter

tryptamine is initiated by specific microbes residing in the namely Clostridium sporogenes

and Ruminococccus gnavus (Williams et al 2014) In the brain tryptamine a monoamine

alkaloid is a non-selective serotonin receptor agonist which plays an inhibitory role in the

response to serotonin and modulate mood and appetite (Zucchi et al 2006) while in the gut

tryptamine can also induce enterochromaffin cells to release 5-HT The gut microbiota is also

responsible for release of another neuromodulator tyramine which has higher affinity for

TAAR1 receptor found in the brain Lactic acid bacteria such as Lbrevis and enterococcus

species act locally via vagus nerve via the periphery (Barett et al 2012)

Studies have shown that microbiota derived signals can induce non-inflammatory cytokine

pathways For instance the plasma G-CSF can cross the blood brain barrier and acts to

6

stimulate neurogenesis in the brain (Zhao et al 2007) Through G-CSF production the

microbiota influences the rate of neurogenesis

With the knowledge of the important role played by microbes in neurological activities

research studies and findings progress towards maintaining this rich microbiota and

stimulating them to contribute to the host a positive effect Dietary macronutrients have a

great effect on the gut microbiome Bacteroidetes Firmicutes Actinobacteria are 3 major

phyla that inhabit the large intestine The diet can significantly change the composition of the

microbiota From birth the diet is involved in the development of microbial communities in

GI tract

Stress and its effects on brain

Human beings are susceptible to stress factors at some point of time irrespective of age

gender economic status As a matter of fact all organisms have some form of exposure to

stress It weakens the physiological functioning of the entire body and fails to maintain

homeostasis Stress has been known to cause many unfavorable effects in the body the first

among them equals derangement of gut mucosa permeability and compromised intestinal

morphology which indirectly impacts the brain leading to increased inflammation in

conditions like depression A symbiotic composition of Saccharomyces boulardii lysate has

been investigated to impede the stress induced gut hyper-permeability and other related

parameters were monitored (Takadanohara H et al 2012) It also triggers a chemical change

in the brain that modifies the synapses thereby disturbing the neuronal connectivity During

the period of exposure to stress there is elevated levels of cortisol commonly referred to as

ldquostress hormonerdquo is the bodyrsquos natural response to stress Response to stress is an essential

part of survival However while enabling the body to manage the effects of stress this

hormone has devastating effects on the brain The high levels of glucocorticoid activity are

associated with reduced neurogenic activity (Gould et al 1997a 1999b Lagace DC et al

7

2010) The hypothalamic-pituitary-adrenal axis (HPA) is considered as the central response

system in the body it reticulates the central nervous system and endocrine system and

coordinates a defective response to stress factors HPA axis is responsible for the prominent

increase in behaviour altering chemicals including glucocorticoids catecholamines and

mineralocorticoids Its activity is regulated by afferent nerve fibres of the parasympathetic

system such as vagus nerves oculomotor nerves limbic system which includes hippocampus

amygdala basal ganglia and sympathetic systems

The hippocampus is a horse shaped region near to the amygdala in the midbrain Our

experiences emotions memory retention rely entirely on the hippocampus to function

correctly Neuroscientists have confirmed that chronic stress can damage the brain severely

and have a long-term effect involving changes in brain structure such as shrinking the

hippocampus volume loss of memory retention neuroinflammation suppressing the neural

activity and increasing the size of amygdala which heightens flightfight response The

maintenance of stability in the brain is disturbed due to continual exposure of stress Raised

levels of cortisol is involved in the synthesis of neurotransmitter glutamate which is a

chemical used to transmit signals to other nerve cells This excitatory neurotransmitter when

released in high amounts has neurotoxic effects by generating free radicals Cortisol also

damages the receptors of the neurotransmitters serotonin and dopamine which are regulators

of mood pleasure happiness and motivation Prolonged stress is known to alter the blood

brain barrier permitting the entry of pathogens heavy metal toxins which damage the brain

cells (Figure 3) There is an immense loss of neurons and brain cells due to inhibitory action

of cortisol on the brain derived neurotropic factor (BDNF) which is a protein used to

maintain healthy brain cells and for synthesis of new cells in the brain

8

Role of nutraceuticals

The term ldquonutraceuticalrdquo was coined by Stephen L Defelice in 1979 According to Defelice

it is defined as food or parts of food that dispense medicalhealth benefits including

prevention and treatment It is a composite of nutrition and pharmaceutical which helps to

maintain the physiological functions of the body These nutrient factors provide sufficient

nutrients to meet the fundamental nutritional requirements for quality living balance and

growth (Maddi et al 2007) They are also referred to as medical foods and designer foods

These products are derived from food sources with additional health benefits besides

providing the basic nutritional value in foods (Rishi et al 2006) Nutraceutical compounds

specifically targeting the neurodevelopment processes are referred to ldquoneuro-nutraceuticalsrdquo

a term that has been recently introduced These supplements are chemically identified

molecules that beneficially affect the brain at molecular level Their actions are directed to

aid in improvement of cognition improve memory positively impact the production of

neurotransmitters reduce inflammations and ageing of brain management of

neurodegenerative and neuropsychiatric disorders (Malik et al 2008) In line with the

subject they also are known to enhance the gut microbes and influence their activities A

healthy gut impacts the brain development and signalling mechanisms It helps to lower the

stress levels and maintain a good mood Foods can infuse our brains with energy to make us

think faster and better Nutraceuticals range from isolated nutrients such as vitamins

minerals fatty acids probiotics prebiotics antioxidants polyaminoacids polysaccharides

herbal products genetically engineered foods and phytochemicals which include

(Carotenoids- fruits vegetables and egg yolk Flavonoid polyphenolics- berries fruits

vegetables legumes are potent antioxidants Non-flavonoid polyphenolics- dark grapes

raisins berries peanuts turmeric roots)

9

Effects of nutrients on gut and brain

The diverse composition of gut microbiota in humans depends on dietary habits The key

mechanisms to maintain gut health are considered to increase the intake of high fibre diet

polysaccharides polyunsaturated fatty acids antioxidants and phytochemicals High-fibre

rich foods stimulate fermentation which proliferates the bacteria and increase biomass

Fermentation causes carbohydrates to undergo chemical changes which result in organic

acids that provide energy for the microbes Short chain fatty acids (SCFA) are the end

products of carbohydrate fermentation which help to inhibit the growth of pathogenic

microorganisms The intake of short-chain non-digestible carbohydrates which include

inulin-type fructans fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS) are

source of prebiotics that typically target growth of bacterial groups such as

Bifidobacterium and Lactobacillus These prebiotic fibres help to ease anxiety depression

restore healthy sleep patterns and protect beneficial gut bacteria Dietary saturated fats may

increase the number of existing pro-inflammatory gut microbes by stimulating formation of

taurine conjugated bile acids that promotes growth of these microbes (Devkota et al 2012)

Polyphenol containing berries metabolized by resident microbiota results in bioactive

products which impacts the health (Duthie et al 2003) Any gut malfunction has a negative

impact on human health therefore it is highly essential to incorporate foods that enhance the

microflora of the gut Artichokes have a strong probiotic potential the high content of inulin

which is insoluble fibre ferments into healthy microflora (Gibson et al 1995) Adequate

administration of probiotics is recognized to have balanced immunoregulatory activities

Investigations on a particular probiotic strain Lactobacillus Pentosus has been shown to

enhance the cytokine production especially IL-10 which is responsible for maintaining the

host immunity by normalizing the T regulatory cells (M Kimura et al2017) Lately a

fascinating finding has been that cocoa or chocolate the most craved food across the globe

10

may modulate the gut commensal population They are found to contain flavonoids including

procyanidins like catechin and epicatechin oligomers which enhance the action of the

neurotransmitters in the brain A Homayouni Rad and his colleagues formulated chocolate as

a potential carrier of probiotic culture strains including lactobacilluscasei and paracasei

positively sustaining the intestinal microbiota population and also releasing stress busting

endorphins Another notable strain is the lactic acid bacteria Streptococcus thermophilus

widely used in the commercial production of fermented dairy products Because of its

inability to survive in the healthy gastric pH of the stomach it has not been suggested as a

ideal probiotic candidate Nonetheless Xiaohong Kangaan and colleagues conducted an

intriguing study on the health promoting effects of milk fermented by Streptococcus

thermophilus in mice the fermented milk was found to have an enhanced cell-mediated

response and positive immunostimulatory effects (M Kimura et al2017) Bananas restore

health of the bacterial community and reduce inflammation It is found to maintain harmony

between the different phyla present in the gut Polenta is a corn-based complex carbohydrate

which has fermentable components that fosters healthy microbiota because of its high fiber

(Anderson et al 2009) Broccoli kale cauliflower cabbage consist of sulfur containing

metabolites namely glucosinolates which are fragmented by the microbes to release

substances that reduce inflammation (Li et al 2008)

Benefits of berry fruit polyphenols

Oxidative stress is a serious threat triggering widespread increase in the occurrence of major

diseases such as Alzheimerrsquos Parkinsonrsquos other neurodegenerative disorders and ageing

Foods rich in antioxidant activity help to prevent age-related changes (Figure 4) Berry fruit

polyphenols can neutralize the negative effects of free-radicals the harmful by-products of

cellular metabolism which contribute to age related diseases They also possess a multiplicity

of actions aside from antioxidant activity They stimulate brain activity neuronal

11

communication cognitive skills calcium buffering ability improve movement control and

prevent memory loss Supplements derived from berry fruits like blueberry cranberry

strawberry have been reported to be effective in reversing motor and behavioral deficits and

control sensory inputs These tiny fruits laden with healing properties are referred to as brain

protective fruits berries are rich in bioflavonoids such as anthocyanins and proanthocyanins

both of which are scavengers of free radicals Active phytochemicals present in the blueberry

confer the benefit of being able to cross the blood-brain-barrier Anthocyanins have been

shown to penetrate the brain and their concentrations correspond to appropriate cognitive

performances (Lacueva et al 2005) They upregulate TNF α IL-1β NF-κB and

consequently suppress ageing and improve blood flow to the brain Blueberries are

responsible for reducing expression of stress signals and results in increasing protective

signals and impact cell signalling molecule expression (Shukitt-Hale et al 2008) The

anthocyanins elevate the level of BDNF (Brain derived neurotropic factor) which is crucial to

boost neuronal communication influencing cognitive function Heat shock proteins are

known to fight free radicals and inflammation inducing agents to support healthy brain

tissues The ability to generate heat shock proteins declines with age dramatically However

researchers have found that consumption of blueberries could restore heat shock protein

response and help protect against neurodegeneration processes associated with ageing

Blueberries play an essential role in reducing the toxicity of kainic acid on hippocampal cells

Kainic acid is an amino acid which is naturally abundant in seaweeds and can be neurotoxic

because of its potent ability to stimulate neurons by activating receptors for glutamate This

aminoacid can be induced in laboratory animal models to study various neurodegenerative

disorders

12

PUFAs

Polyunsaturated fatty acids (PUFAs) are critical components of neuronal cell membranes and

are involved in neurotransmitter communication within the neural networks They are

responsible for maintaining membrane fluidity essential synaptic vesicle fusion and serve as

precursors for lipid messengers which participate in signalling processes to promote neuronal

protection (Bazan et al 2005) Flaxseeds fish soybeans walnuts are rich in PUFA

specifically omega- 6 fatty acid linoleic acid omega-3 α linolenic acid

Intake of PUFA supplements for improve cognitive function

In most neurological conditions inflammation manifests in the nervous tissue and this

inflammation is a therapeutic target by the pharmaceutical industries During high levels of

stress the body cannot regulate an inflammatory response which leads to a greater risk of

development of other diseases Anti-inflammatory agents containing nutraceuticals is the

focus of development Oxymatrine derived from the root of a Chinese herb Sophora

flavescens has been reported to have anti-inflammatory actions and decreases damage

observed after hypoxic- ischaemic brain injury in neonatal rat models (Zhao et al 2015)

Apocynin obtained from the root of Picrorhiza kurroa is also believed to have anti-

inflammatory properties and attenuate the cholesterol oxidation product induced apoptosis in

neuronal cells by preventing production of reactive oxygen species (Simonyi et al 2012)

Quercetin known to be found in vegetables fruits have antioxidant effects regulate proteins

transcription factors and kinase dependent signalling pathways Nutraceutical additive actions

of quercetin expedite optimal delivery and improve brain activity Naturally occurring 7 8-

dihydroxyflavone rescues cognition deficits and serve as a novel treatment for autism and

schizophrenia Trans-resveratrol and pterostilbene are plant derived synergistic phytonutrients

improving brain health and having diverse actions against oxidative stress (Poulose et al

2015) Creatine is a natural substance when taken as supplements in recommended dose is

13

beneficial to enhance brain function and improve cognitive function (Wallimann 2008) (Table

1)

Management of stress

Nutrient supplements have the potential to overcome the debilitating effects of stress They

act as prophylactic and therapeutic agents and are more efficient and safe in comparison to

pharmaceutical drugs (Pandey et al 2010) Botanically derived ingredients are used to treat

mild depression anxiety improve sleep patterns and maintain good health Since a persistent

level of cortisol in circulation is the chief cause of depression and stress naturally derived

products target this hormone to annihilate the stress factors and boost mental health and

cognition Researchers have studied the effects of probiotics against stress in a zebrafish

model by introducing the bacterial strain Lactobacillus plantarum into the tank (Davis et al

2016) The objective is to bring the body back to homeostasis maintaining a balanced level

of cortisol The actions of gut microbes and nutraceuticals work interdependently to help

reduce the dangerous outcomes of stress upon the body Experiments with germ free mice

have been used to probe the role of microbiota in adult hippocampal neurogenesis Also

disruptions of gut microbiome induced mice behaviour resulted in anxiety depression and

even autism Gut microbes are the key modulators of brain plasticity cognitive functions and

help to optimize the bodyrsquos response to stress by regulating their synthesis of

neurotransmitters like serotonin to lower the cortisol level Studies have shown that during

stress there is an increased population of certain bacterial strains in the gut such as

Enterobacteriaceae Proteobacteria Actinobacteria and this can be controlled by increasing

the administration of probiotics containing Lactobacillus and Bifidobacterium species

Experiments have been conducted with Bifidobacterium longum and results showed that this

strain was able to reverse hippocampal and BDNF abnormalities

14

CONCLUSION

In today lsquos ambitious world so much importance is being given to performance perfection

competition that it leads to an insidious increase in stress depression anxiety Stress is a

psychological issue which predisposes a person to various other ailments It is inevitable in

the life of any individual but the duration and intensity differs According to Hans Selye who

coined the term stress in 1936 it is the non- specific response of the body to any demand for

change Stress levels are rising worldwide it is a top health concern The damages that can be

caused by stress are often underestimated It primarily affects the nervous system but

prolonged exposure leads to cardiovascular musculoskeletal diseases and even affects the

reproductive system Claude Bernard (1865-1961) observed that the maintenance of life is

essentially dependent on keeping our internal milieu constant in the face of a changing

environment Thus sustaining a state of homeostasis is vital for a healthy life Workplace

stress and depression is on the rise it is the health epidemic of 21 st century a frequently

reported problem According to WHO depression is among the leading causes of disability

globally There is a compelling need to confront the ameliorating and deleterious effects of

stress inflicted on an individual These health risks can be prevented or managed A multi

targeted approach is required to tackle a problem as severe as stress It can be controlled in

the healthy way by nourishing and stimulating the gut microbes in our body to act on the

brain which increases the release of neurotransmitters to help relieve the effects of stress

Nutrient supplements referred to as nutraceuticals has been introduced to influence the brain

activity and protect it from the negative impact of stress hormones These nutraceuticals help

to enhance the quality of life by modulating the gut health They prevent the alteration of

microbiome during stress Extensive research has been conducted in the field of gut microbes

and nutraceuticals and their efficacy towards alleviating stress has been proved We are

moving towards the direction of exploring psych biotics as a mode of treatment for anxiety

15

depression and various psychiatric issues However it is a recently introduced term and

research and is still on-going whether it has proven benefits or not Dietary interventions with

food supplements designed to modulate responses to stress that can be administered

effectively Managing stress in the natural way is proven to be the most favorable method

Acknowledgements

The authors are thankful to Chettinad Academy of Research and Education (CARE) for the

support

Conflicts of interest

We declare no conflict of interest All co-authors have agreed to transfer the copyright to the

publisher if it is accepted for publication This study was partially financially supported by

Chettinad Hospital amp Research Institute (CHRI) Chettinad Academy of Research and

Education (CARE) Kelambakkam Chennai-603103 India

16

References

Anderson JW Baird P Davis RH Ferreri S Knutdson M Koraym A Waters V

Williams CL (2009) Health benefits of dietary fibre Nutrition Reviews 67188-205

Andres RH Ducray AD Schlattner U Wallimann T Widmer HR (2008) Functions

and effects of creatine in the central nervous system Brain Research Bulletin 76(4)329-43

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged blueberry-fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2)111-20

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged-blueberry fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2) 111-20

Barrett E Ross RP OToole PW Fitzgerald GF Stanton C (2012) gamma-

Aminobutyric acid production by culturable bacteria from the human intestine Journal of

applied microbiology 113411ndash417

Bazan NG (2005) Lipid signaling in neural plasticity brain repair and neuroprotection

Molecular Neurobiology 32(1)89-103

Bercik P Denou E Collins J Jackson W Lu J Jury J Deng Y Blennerhassett P

Macri J McCoy KD Verdu EF Collins SM (2011) The intestinal microbiota affect

central levels of brain-derived neurotropic factor and behavior in mice Gastroenterology

141599-609

Borre YE OKeeffe GW Clarke G Stanton C Dinan TG Cryan JF (2014)

Microbiota and neurodevelopmental windows implications for brain disorders Trends in

Molecular Medicine 20509-518

Bravo JA Forsythe P Chew MV (2011) Ingestion of Lactobacillus strain regulates

emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

17

conditions like schizophrenia depression Alzheimerrsquos mood disorders like anxiety and

epilepsy (Foster et al 2013)

Serotonin is a monoamine neurotransmitter acquired from the amino acid tryptophan It is

responsible for the well-being regulation of mood sleep and cognitive functions Deficit of

serotonin causes depression 5-HT synthesis requires tryptophan and this is generated by the

intestinal microbiota which can cross the blood brain barrier for the synthesis

Neurophysiology can be changed by actions of the microbiome such as by altering the

permeability of blood brain barrier allowing flux of metabolites into and out of the brain

(Bercik et al 2014) In absence of microbes there is a decreased level of neurotransmitters

such as dopamine and GABA Specific intestinal bacteria produce small molecules such as

serotonin dopamine epinephrine and norepinephrine (Wall et al 2014 Lyte et al 2013)

Mechanism of action

The microbes send signals to enterochromaffin cells which produce neurotransmitters and

enteric neurons glia The decarboxylation of the amino acid tryptophan by neurotransmitter

tryptamine is initiated by specific microbes residing in the namely Clostridium sporogenes

and Ruminococccus gnavus (Williams et al 2014) In the brain tryptamine a monoamine

alkaloid is a non-selective serotonin receptor agonist which plays an inhibitory role in the

response to serotonin and modulate mood and appetite (Zucchi et al 2006) while in the gut

tryptamine can also induce enterochromaffin cells to release 5-HT The gut microbiota is also

responsible for release of another neuromodulator tyramine which has higher affinity for

TAAR1 receptor found in the brain Lactic acid bacteria such as Lbrevis and enterococcus

species act locally via vagus nerve via the periphery (Barett et al 2012)

Studies have shown that microbiota derived signals can induce non-inflammatory cytokine

pathways For instance the plasma G-CSF can cross the blood brain barrier and acts to

6

stimulate neurogenesis in the brain (Zhao et al 2007) Through G-CSF production the

microbiota influences the rate of neurogenesis

With the knowledge of the important role played by microbes in neurological activities

research studies and findings progress towards maintaining this rich microbiota and

stimulating them to contribute to the host a positive effect Dietary macronutrients have a

great effect on the gut microbiome Bacteroidetes Firmicutes Actinobacteria are 3 major

phyla that inhabit the large intestine The diet can significantly change the composition of the

microbiota From birth the diet is involved in the development of microbial communities in

GI tract

Stress and its effects on brain

Human beings are susceptible to stress factors at some point of time irrespective of age

gender economic status As a matter of fact all organisms have some form of exposure to

stress It weakens the physiological functioning of the entire body and fails to maintain

homeostasis Stress has been known to cause many unfavorable effects in the body the first

among them equals derangement of gut mucosa permeability and compromised intestinal

morphology which indirectly impacts the brain leading to increased inflammation in

conditions like depression A symbiotic composition of Saccharomyces boulardii lysate has

been investigated to impede the stress induced gut hyper-permeability and other related

parameters were monitored (Takadanohara H et al 2012) It also triggers a chemical change

in the brain that modifies the synapses thereby disturbing the neuronal connectivity During

the period of exposure to stress there is elevated levels of cortisol commonly referred to as

ldquostress hormonerdquo is the bodyrsquos natural response to stress Response to stress is an essential

part of survival However while enabling the body to manage the effects of stress this

hormone has devastating effects on the brain The high levels of glucocorticoid activity are

associated with reduced neurogenic activity (Gould et al 1997a 1999b Lagace DC et al

7

2010) The hypothalamic-pituitary-adrenal axis (HPA) is considered as the central response

system in the body it reticulates the central nervous system and endocrine system and

coordinates a defective response to stress factors HPA axis is responsible for the prominent

increase in behaviour altering chemicals including glucocorticoids catecholamines and

mineralocorticoids Its activity is regulated by afferent nerve fibres of the parasympathetic

system such as vagus nerves oculomotor nerves limbic system which includes hippocampus

amygdala basal ganglia and sympathetic systems

The hippocampus is a horse shaped region near to the amygdala in the midbrain Our

experiences emotions memory retention rely entirely on the hippocampus to function

correctly Neuroscientists have confirmed that chronic stress can damage the brain severely

and have a long-term effect involving changes in brain structure such as shrinking the

hippocampus volume loss of memory retention neuroinflammation suppressing the neural

activity and increasing the size of amygdala which heightens flightfight response The

maintenance of stability in the brain is disturbed due to continual exposure of stress Raised

levels of cortisol is involved in the synthesis of neurotransmitter glutamate which is a

chemical used to transmit signals to other nerve cells This excitatory neurotransmitter when

released in high amounts has neurotoxic effects by generating free radicals Cortisol also

damages the receptors of the neurotransmitters serotonin and dopamine which are regulators

of mood pleasure happiness and motivation Prolonged stress is known to alter the blood

brain barrier permitting the entry of pathogens heavy metal toxins which damage the brain

cells (Figure 3) There is an immense loss of neurons and brain cells due to inhibitory action

of cortisol on the brain derived neurotropic factor (BDNF) which is a protein used to

maintain healthy brain cells and for synthesis of new cells in the brain

8

Role of nutraceuticals

The term ldquonutraceuticalrdquo was coined by Stephen L Defelice in 1979 According to Defelice

it is defined as food or parts of food that dispense medicalhealth benefits including

prevention and treatment It is a composite of nutrition and pharmaceutical which helps to

maintain the physiological functions of the body These nutrient factors provide sufficient

nutrients to meet the fundamental nutritional requirements for quality living balance and

growth (Maddi et al 2007) They are also referred to as medical foods and designer foods

These products are derived from food sources with additional health benefits besides

providing the basic nutritional value in foods (Rishi et al 2006) Nutraceutical compounds

specifically targeting the neurodevelopment processes are referred to ldquoneuro-nutraceuticalsrdquo

a term that has been recently introduced These supplements are chemically identified

molecules that beneficially affect the brain at molecular level Their actions are directed to

aid in improvement of cognition improve memory positively impact the production of

neurotransmitters reduce inflammations and ageing of brain management of

neurodegenerative and neuropsychiatric disorders (Malik et al 2008) In line with the

subject they also are known to enhance the gut microbes and influence their activities A

healthy gut impacts the brain development and signalling mechanisms It helps to lower the

stress levels and maintain a good mood Foods can infuse our brains with energy to make us

think faster and better Nutraceuticals range from isolated nutrients such as vitamins

minerals fatty acids probiotics prebiotics antioxidants polyaminoacids polysaccharides

herbal products genetically engineered foods and phytochemicals which include

(Carotenoids- fruits vegetables and egg yolk Flavonoid polyphenolics- berries fruits

vegetables legumes are potent antioxidants Non-flavonoid polyphenolics- dark grapes

raisins berries peanuts turmeric roots)

9

Effects of nutrients on gut and brain

The diverse composition of gut microbiota in humans depends on dietary habits The key

mechanisms to maintain gut health are considered to increase the intake of high fibre diet

polysaccharides polyunsaturated fatty acids antioxidants and phytochemicals High-fibre

rich foods stimulate fermentation which proliferates the bacteria and increase biomass

Fermentation causes carbohydrates to undergo chemical changes which result in organic

acids that provide energy for the microbes Short chain fatty acids (SCFA) are the end

products of carbohydrate fermentation which help to inhibit the growth of pathogenic

microorganisms The intake of short-chain non-digestible carbohydrates which include

inulin-type fructans fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS) are

source of prebiotics that typically target growth of bacterial groups such as

Bifidobacterium and Lactobacillus These prebiotic fibres help to ease anxiety depression

restore healthy sleep patterns and protect beneficial gut bacteria Dietary saturated fats may

increase the number of existing pro-inflammatory gut microbes by stimulating formation of

taurine conjugated bile acids that promotes growth of these microbes (Devkota et al 2012)

Polyphenol containing berries metabolized by resident microbiota results in bioactive

products which impacts the health (Duthie et al 2003) Any gut malfunction has a negative

impact on human health therefore it is highly essential to incorporate foods that enhance the

microflora of the gut Artichokes have a strong probiotic potential the high content of inulin

which is insoluble fibre ferments into healthy microflora (Gibson et al 1995) Adequate

administration of probiotics is recognized to have balanced immunoregulatory activities

Investigations on a particular probiotic strain Lactobacillus Pentosus has been shown to

enhance the cytokine production especially IL-10 which is responsible for maintaining the

host immunity by normalizing the T regulatory cells (M Kimura et al2017) Lately a

fascinating finding has been that cocoa or chocolate the most craved food across the globe

10

may modulate the gut commensal population They are found to contain flavonoids including

procyanidins like catechin and epicatechin oligomers which enhance the action of the

neurotransmitters in the brain A Homayouni Rad and his colleagues formulated chocolate as

a potential carrier of probiotic culture strains including lactobacilluscasei and paracasei

positively sustaining the intestinal microbiota population and also releasing stress busting

endorphins Another notable strain is the lactic acid bacteria Streptococcus thermophilus

widely used in the commercial production of fermented dairy products Because of its

inability to survive in the healthy gastric pH of the stomach it has not been suggested as a

ideal probiotic candidate Nonetheless Xiaohong Kangaan and colleagues conducted an

intriguing study on the health promoting effects of milk fermented by Streptococcus

thermophilus in mice the fermented milk was found to have an enhanced cell-mediated

response and positive immunostimulatory effects (M Kimura et al2017) Bananas restore

health of the bacterial community and reduce inflammation It is found to maintain harmony

between the different phyla present in the gut Polenta is a corn-based complex carbohydrate

which has fermentable components that fosters healthy microbiota because of its high fiber

(Anderson et al 2009) Broccoli kale cauliflower cabbage consist of sulfur containing

metabolites namely glucosinolates which are fragmented by the microbes to release

substances that reduce inflammation (Li et al 2008)

Benefits of berry fruit polyphenols

Oxidative stress is a serious threat triggering widespread increase in the occurrence of major

diseases such as Alzheimerrsquos Parkinsonrsquos other neurodegenerative disorders and ageing

Foods rich in antioxidant activity help to prevent age-related changes (Figure 4) Berry fruit

polyphenols can neutralize the negative effects of free-radicals the harmful by-products of

cellular metabolism which contribute to age related diseases They also possess a multiplicity

of actions aside from antioxidant activity They stimulate brain activity neuronal

11

communication cognitive skills calcium buffering ability improve movement control and

prevent memory loss Supplements derived from berry fruits like blueberry cranberry

strawberry have been reported to be effective in reversing motor and behavioral deficits and

control sensory inputs These tiny fruits laden with healing properties are referred to as brain

protective fruits berries are rich in bioflavonoids such as anthocyanins and proanthocyanins

both of which are scavengers of free radicals Active phytochemicals present in the blueberry

confer the benefit of being able to cross the blood-brain-barrier Anthocyanins have been

shown to penetrate the brain and their concentrations correspond to appropriate cognitive

performances (Lacueva et al 2005) They upregulate TNF α IL-1β NF-κB and

consequently suppress ageing and improve blood flow to the brain Blueberries are

responsible for reducing expression of stress signals and results in increasing protective

signals and impact cell signalling molecule expression (Shukitt-Hale et al 2008) The

anthocyanins elevate the level of BDNF (Brain derived neurotropic factor) which is crucial to

boost neuronal communication influencing cognitive function Heat shock proteins are

known to fight free radicals and inflammation inducing agents to support healthy brain

tissues The ability to generate heat shock proteins declines with age dramatically However

researchers have found that consumption of blueberries could restore heat shock protein

response and help protect against neurodegeneration processes associated with ageing

Blueberries play an essential role in reducing the toxicity of kainic acid on hippocampal cells

Kainic acid is an amino acid which is naturally abundant in seaweeds and can be neurotoxic

because of its potent ability to stimulate neurons by activating receptors for glutamate This

aminoacid can be induced in laboratory animal models to study various neurodegenerative

disorders

12

PUFAs

Polyunsaturated fatty acids (PUFAs) are critical components of neuronal cell membranes and

are involved in neurotransmitter communication within the neural networks They are

responsible for maintaining membrane fluidity essential synaptic vesicle fusion and serve as

precursors for lipid messengers which participate in signalling processes to promote neuronal

protection (Bazan et al 2005) Flaxseeds fish soybeans walnuts are rich in PUFA

specifically omega- 6 fatty acid linoleic acid omega-3 α linolenic acid

Intake of PUFA supplements for improve cognitive function

In most neurological conditions inflammation manifests in the nervous tissue and this

inflammation is a therapeutic target by the pharmaceutical industries During high levels of

stress the body cannot regulate an inflammatory response which leads to a greater risk of

development of other diseases Anti-inflammatory agents containing nutraceuticals is the

focus of development Oxymatrine derived from the root of a Chinese herb Sophora

flavescens has been reported to have anti-inflammatory actions and decreases damage

observed after hypoxic- ischaemic brain injury in neonatal rat models (Zhao et al 2015)

Apocynin obtained from the root of Picrorhiza kurroa is also believed to have anti-

inflammatory properties and attenuate the cholesterol oxidation product induced apoptosis in

neuronal cells by preventing production of reactive oxygen species (Simonyi et al 2012)

Quercetin known to be found in vegetables fruits have antioxidant effects regulate proteins

transcription factors and kinase dependent signalling pathways Nutraceutical additive actions

of quercetin expedite optimal delivery and improve brain activity Naturally occurring 7 8-

dihydroxyflavone rescues cognition deficits and serve as a novel treatment for autism and

schizophrenia Trans-resveratrol and pterostilbene are plant derived synergistic phytonutrients

improving brain health and having diverse actions against oxidative stress (Poulose et al

2015) Creatine is a natural substance when taken as supplements in recommended dose is

13

beneficial to enhance brain function and improve cognitive function (Wallimann 2008) (Table

1)

Management of stress

Nutrient supplements have the potential to overcome the debilitating effects of stress They

act as prophylactic and therapeutic agents and are more efficient and safe in comparison to

pharmaceutical drugs (Pandey et al 2010) Botanically derived ingredients are used to treat

mild depression anxiety improve sleep patterns and maintain good health Since a persistent

level of cortisol in circulation is the chief cause of depression and stress naturally derived

products target this hormone to annihilate the stress factors and boost mental health and

cognition Researchers have studied the effects of probiotics against stress in a zebrafish

model by introducing the bacterial strain Lactobacillus plantarum into the tank (Davis et al

2016) The objective is to bring the body back to homeostasis maintaining a balanced level

of cortisol The actions of gut microbes and nutraceuticals work interdependently to help

reduce the dangerous outcomes of stress upon the body Experiments with germ free mice

have been used to probe the role of microbiota in adult hippocampal neurogenesis Also

disruptions of gut microbiome induced mice behaviour resulted in anxiety depression and

even autism Gut microbes are the key modulators of brain plasticity cognitive functions and

help to optimize the bodyrsquos response to stress by regulating their synthesis of

neurotransmitters like serotonin to lower the cortisol level Studies have shown that during

stress there is an increased population of certain bacterial strains in the gut such as

Enterobacteriaceae Proteobacteria Actinobacteria and this can be controlled by increasing

the administration of probiotics containing Lactobacillus and Bifidobacterium species

Experiments have been conducted with Bifidobacterium longum and results showed that this

strain was able to reverse hippocampal and BDNF abnormalities

14

CONCLUSION

In today lsquos ambitious world so much importance is being given to performance perfection

competition that it leads to an insidious increase in stress depression anxiety Stress is a

psychological issue which predisposes a person to various other ailments It is inevitable in

the life of any individual but the duration and intensity differs According to Hans Selye who

coined the term stress in 1936 it is the non- specific response of the body to any demand for

change Stress levels are rising worldwide it is a top health concern The damages that can be

caused by stress are often underestimated It primarily affects the nervous system but

prolonged exposure leads to cardiovascular musculoskeletal diseases and even affects the

reproductive system Claude Bernard (1865-1961) observed that the maintenance of life is

essentially dependent on keeping our internal milieu constant in the face of a changing

environment Thus sustaining a state of homeostasis is vital for a healthy life Workplace

stress and depression is on the rise it is the health epidemic of 21 st century a frequently

reported problem According to WHO depression is among the leading causes of disability

globally There is a compelling need to confront the ameliorating and deleterious effects of

stress inflicted on an individual These health risks can be prevented or managed A multi

targeted approach is required to tackle a problem as severe as stress It can be controlled in

the healthy way by nourishing and stimulating the gut microbes in our body to act on the

brain which increases the release of neurotransmitters to help relieve the effects of stress

Nutrient supplements referred to as nutraceuticals has been introduced to influence the brain

activity and protect it from the negative impact of stress hormones These nutraceuticals help

to enhance the quality of life by modulating the gut health They prevent the alteration of

microbiome during stress Extensive research has been conducted in the field of gut microbes

and nutraceuticals and their efficacy towards alleviating stress has been proved We are

moving towards the direction of exploring psych biotics as a mode of treatment for anxiety

15

depression and various psychiatric issues However it is a recently introduced term and

research and is still on-going whether it has proven benefits or not Dietary interventions with

food supplements designed to modulate responses to stress that can be administered

effectively Managing stress in the natural way is proven to be the most favorable method

Acknowledgements

The authors are thankful to Chettinad Academy of Research and Education (CARE) for the

support

Conflicts of interest

We declare no conflict of interest All co-authors have agreed to transfer the copyright to the

publisher if it is accepted for publication This study was partially financially supported by

Chettinad Hospital amp Research Institute (CHRI) Chettinad Academy of Research and

Education (CARE) Kelambakkam Chennai-603103 India

16

References

Anderson JW Baird P Davis RH Ferreri S Knutdson M Koraym A Waters V

Williams CL (2009) Health benefits of dietary fibre Nutrition Reviews 67188-205

Andres RH Ducray AD Schlattner U Wallimann T Widmer HR (2008) Functions

and effects of creatine in the central nervous system Brain Research Bulletin 76(4)329-43

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged blueberry-fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2)111-20

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged-blueberry fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2) 111-20

Barrett E Ross RP OToole PW Fitzgerald GF Stanton C (2012) gamma-

Aminobutyric acid production by culturable bacteria from the human intestine Journal of

applied microbiology 113411ndash417

Bazan NG (2005) Lipid signaling in neural plasticity brain repair and neuroprotection

Molecular Neurobiology 32(1)89-103

Bercik P Denou E Collins J Jackson W Lu J Jury J Deng Y Blennerhassett P

Macri J McCoy KD Verdu EF Collins SM (2011) The intestinal microbiota affect

central levels of brain-derived neurotropic factor and behavior in mice Gastroenterology

141599-609

Borre YE OKeeffe GW Clarke G Stanton C Dinan TG Cryan JF (2014)

Microbiota and neurodevelopmental windows implications for brain disorders Trends in

Molecular Medicine 20509-518

Bravo JA Forsythe P Chew MV (2011) Ingestion of Lactobacillus strain regulates

emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

17

stimulate neurogenesis in the brain (Zhao et al 2007) Through G-CSF production the

microbiota influences the rate of neurogenesis

With the knowledge of the important role played by microbes in neurological activities

research studies and findings progress towards maintaining this rich microbiota and

stimulating them to contribute to the host a positive effect Dietary macronutrients have a

great effect on the gut microbiome Bacteroidetes Firmicutes Actinobacteria are 3 major

phyla that inhabit the large intestine The diet can significantly change the composition of the

microbiota From birth the diet is involved in the development of microbial communities in

GI tract

Stress and its effects on brain

Human beings are susceptible to stress factors at some point of time irrespective of age

gender economic status As a matter of fact all organisms have some form of exposure to

stress It weakens the physiological functioning of the entire body and fails to maintain

homeostasis Stress has been known to cause many unfavorable effects in the body the first

among them equals derangement of gut mucosa permeability and compromised intestinal

morphology which indirectly impacts the brain leading to increased inflammation in

conditions like depression A symbiotic composition of Saccharomyces boulardii lysate has

been investigated to impede the stress induced gut hyper-permeability and other related

parameters were monitored (Takadanohara H et al 2012) It also triggers a chemical change

in the brain that modifies the synapses thereby disturbing the neuronal connectivity During

the period of exposure to stress there is elevated levels of cortisol commonly referred to as

ldquostress hormonerdquo is the bodyrsquos natural response to stress Response to stress is an essential

part of survival However while enabling the body to manage the effects of stress this

hormone has devastating effects on the brain The high levels of glucocorticoid activity are

associated with reduced neurogenic activity (Gould et al 1997a 1999b Lagace DC et al

7

2010) The hypothalamic-pituitary-adrenal axis (HPA) is considered as the central response

system in the body it reticulates the central nervous system and endocrine system and

coordinates a defective response to stress factors HPA axis is responsible for the prominent

increase in behaviour altering chemicals including glucocorticoids catecholamines and

mineralocorticoids Its activity is regulated by afferent nerve fibres of the parasympathetic

system such as vagus nerves oculomotor nerves limbic system which includes hippocampus

amygdala basal ganglia and sympathetic systems

The hippocampus is a horse shaped region near to the amygdala in the midbrain Our

experiences emotions memory retention rely entirely on the hippocampus to function

correctly Neuroscientists have confirmed that chronic stress can damage the brain severely

and have a long-term effect involving changes in brain structure such as shrinking the

hippocampus volume loss of memory retention neuroinflammation suppressing the neural

activity and increasing the size of amygdala which heightens flightfight response The

maintenance of stability in the brain is disturbed due to continual exposure of stress Raised

levels of cortisol is involved in the synthesis of neurotransmitter glutamate which is a

chemical used to transmit signals to other nerve cells This excitatory neurotransmitter when

released in high amounts has neurotoxic effects by generating free radicals Cortisol also

damages the receptors of the neurotransmitters serotonin and dopamine which are regulators

of mood pleasure happiness and motivation Prolonged stress is known to alter the blood

brain barrier permitting the entry of pathogens heavy metal toxins which damage the brain

cells (Figure 3) There is an immense loss of neurons and brain cells due to inhibitory action

of cortisol on the brain derived neurotropic factor (BDNF) which is a protein used to

maintain healthy brain cells and for synthesis of new cells in the brain

8

Role of nutraceuticals

The term ldquonutraceuticalrdquo was coined by Stephen L Defelice in 1979 According to Defelice

it is defined as food or parts of food that dispense medicalhealth benefits including

prevention and treatment It is a composite of nutrition and pharmaceutical which helps to

maintain the physiological functions of the body These nutrient factors provide sufficient

nutrients to meet the fundamental nutritional requirements for quality living balance and

growth (Maddi et al 2007) They are also referred to as medical foods and designer foods

These products are derived from food sources with additional health benefits besides

providing the basic nutritional value in foods (Rishi et al 2006) Nutraceutical compounds

specifically targeting the neurodevelopment processes are referred to ldquoneuro-nutraceuticalsrdquo

a term that has been recently introduced These supplements are chemically identified

molecules that beneficially affect the brain at molecular level Their actions are directed to

aid in improvement of cognition improve memory positively impact the production of

neurotransmitters reduce inflammations and ageing of brain management of

neurodegenerative and neuropsychiatric disorders (Malik et al 2008) In line with the

subject they also are known to enhance the gut microbes and influence their activities A

healthy gut impacts the brain development and signalling mechanisms It helps to lower the

stress levels and maintain a good mood Foods can infuse our brains with energy to make us

think faster and better Nutraceuticals range from isolated nutrients such as vitamins

minerals fatty acids probiotics prebiotics antioxidants polyaminoacids polysaccharides

herbal products genetically engineered foods and phytochemicals which include

(Carotenoids- fruits vegetables and egg yolk Flavonoid polyphenolics- berries fruits

vegetables legumes are potent antioxidants Non-flavonoid polyphenolics- dark grapes

raisins berries peanuts turmeric roots)

9

Effects of nutrients on gut and brain

The diverse composition of gut microbiota in humans depends on dietary habits The key

mechanisms to maintain gut health are considered to increase the intake of high fibre diet

polysaccharides polyunsaturated fatty acids antioxidants and phytochemicals High-fibre

rich foods stimulate fermentation which proliferates the bacteria and increase biomass

Fermentation causes carbohydrates to undergo chemical changes which result in organic

acids that provide energy for the microbes Short chain fatty acids (SCFA) are the end

products of carbohydrate fermentation which help to inhibit the growth of pathogenic

microorganisms The intake of short-chain non-digestible carbohydrates which include

inulin-type fructans fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS) are

source of prebiotics that typically target growth of bacterial groups such as

Bifidobacterium and Lactobacillus These prebiotic fibres help to ease anxiety depression

restore healthy sleep patterns and protect beneficial gut bacteria Dietary saturated fats may

increase the number of existing pro-inflammatory gut microbes by stimulating formation of

taurine conjugated bile acids that promotes growth of these microbes (Devkota et al 2012)

Polyphenol containing berries metabolized by resident microbiota results in bioactive

products which impacts the health (Duthie et al 2003) Any gut malfunction has a negative

impact on human health therefore it is highly essential to incorporate foods that enhance the

microflora of the gut Artichokes have a strong probiotic potential the high content of inulin

which is insoluble fibre ferments into healthy microflora (Gibson et al 1995) Adequate

administration of probiotics is recognized to have balanced immunoregulatory activities

Investigations on a particular probiotic strain Lactobacillus Pentosus has been shown to

enhance the cytokine production especially IL-10 which is responsible for maintaining the

host immunity by normalizing the T regulatory cells (M Kimura et al2017) Lately a

fascinating finding has been that cocoa or chocolate the most craved food across the globe

10

may modulate the gut commensal population They are found to contain flavonoids including

procyanidins like catechin and epicatechin oligomers which enhance the action of the

neurotransmitters in the brain A Homayouni Rad and his colleagues formulated chocolate as

a potential carrier of probiotic culture strains including lactobacilluscasei and paracasei

positively sustaining the intestinal microbiota population and also releasing stress busting

endorphins Another notable strain is the lactic acid bacteria Streptococcus thermophilus

widely used in the commercial production of fermented dairy products Because of its

inability to survive in the healthy gastric pH of the stomach it has not been suggested as a

ideal probiotic candidate Nonetheless Xiaohong Kangaan and colleagues conducted an

intriguing study on the health promoting effects of milk fermented by Streptococcus

thermophilus in mice the fermented milk was found to have an enhanced cell-mediated

response and positive immunostimulatory effects (M Kimura et al2017) Bananas restore

health of the bacterial community and reduce inflammation It is found to maintain harmony

between the different phyla present in the gut Polenta is a corn-based complex carbohydrate

which has fermentable components that fosters healthy microbiota because of its high fiber

(Anderson et al 2009) Broccoli kale cauliflower cabbage consist of sulfur containing

metabolites namely glucosinolates which are fragmented by the microbes to release

substances that reduce inflammation (Li et al 2008)

Benefits of berry fruit polyphenols

Oxidative stress is a serious threat triggering widespread increase in the occurrence of major

diseases such as Alzheimerrsquos Parkinsonrsquos other neurodegenerative disorders and ageing

Foods rich in antioxidant activity help to prevent age-related changes (Figure 4) Berry fruit

polyphenols can neutralize the negative effects of free-radicals the harmful by-products of

cellular metabolism which contribute to age related diseases They also possess a multiplicity

of actions aside from antioxidant activity They stimulate brain activity neuronal

11

communication cognitive skills calcium buffering ability improve movement control and

prevent memory loss Supplements derived from berry fruits like blueberry cranberry

strawberry have been reported to be effective in reversing motor and behavioral deficits and

control sensory inputs These tiny fruits laden with healing properties are referred to as brain

protective fruits berries are rich in bioflavonoids such as anthocyanins and proanthocyanins

both of which are scavengers of free radicals Active phytochemicals present in the blueberry

confer the benefit of being able to cross the blood-brain-barrier Anthocyanins have been

shown to penetrate the brain and their concentrations correspond to appropriate cognitive

performances (Lacueva et al 2005) They upregulate TNF α IL-1β NF-κB and

consequently suppress ageing and improve blood flow to the brain Blueberries are

responsible for reducing expression of stress signals and results in increasing protective

signals and impact cell signalling molecule expression (Shukitt-Hale et al 2008) The

anthocyanins elevate the level of BDNF (Brain derived neurotropic factor) which is crucial to

boost neuronal communication influencing cognitive function Heat shock proteins are

known to fight free radicals and inflammation inducing agents to support healthy brain

tissues The ability to generate heat shock proteins declines with age dramatically However

researchers have found that consumption of blueberries could restore heat shock protein

response and help protect against neurodegeneration processes associated with ageing

Blueberries play an essential role in reducing the toxicity of kainic acid on hippocampal cells

Kainic acid is an amino acid which is naturally abundant in seaweeds and can be neurotoxic

because of its potent ability to stimulate neurons by activating receptors for glutamate This

aminoacid can be induced in laboratory animal models to study various neurodegenerative

disorders

12

PUFAs

Polyunsaturated fatty acids (PUFAs) are critical components of neuronal cell membranes and

are involved in neurotransmitter communication within the neural networks They are

responsible for maintaining membrane fluidity essential synaptic vesicle fusion and serve as

precursors for lipid messengers which participate in signalling processes to promote neuronal

protection (Bazan et al 2005) Flaxseeds fish soybeans walnuts are rich in PUFA

specifically omega- 6 fatty acid linoleic acid omega-3 α linolenic acid

Intake of PUFA supplements for improve cognitive function

In most neurological conditions inflammation manifests in the nervous tissue and this

inflammation is a therapeutic target by the pharmaceutical industries During high levels of

stress the body cannot regulate an inflammatory response which leads to a greater risk of

development of other diseases Anti-inflammatory agents containing nutraceuticals is the

focus of development Oxymatrine derived from the root of a Chinese herb Sophora

flavescens has been reported to have anti-inflammatory actions and decreases damage

observed after hypoxic- ischaemic brain injury in neonatal rat models (Zhao et al 2015)

Apocynin obtained from the root of Picrorhiza kurroa is also believed to have anti-

inflammatory properties and attenuate the cholesterol oxidation product induced apoptosis in

neuronal cells by preventing production of reactive oxygen species (Simonyi et al 2012)

Quercetin known to be found in vegetables fruits have antioxidant effects regulate proteins

transcription factors and kinase dependent signalling pathways Nutraceutical additive actions

of quercetin expedite optimal delivery and improve brain activity Naturally occurring 7 8-

dihydroxyflavone rescues cognition deficits and serve as a novel treatment for autism and

schizophrenia Trans-resveratrol and pterostilbene are plant derived synergistic phytonutrients

improving brain health and having diverse actions against oxidative stress (Poulose et al

2015) Creatine is a natural substance when taken as supplements in recommended dose is

13

beneficial to enhance brain function and improve cognitive function (Wallimann 2008) (Table

1)

Management of stress

Nutrient supplements have the potential to overcome the debilitating effects of stress They

act as prophylactic and therapeutic agents and are more efficient and safe in comparison to

pharmaceutical drugs (Pandey et al 2010) Botanically derived ingredients are used to treat

mild depression anxiety improve sleep patterns and maintain good health Since a persistent

level of cortisol in circulation is the chief cause of depression and stress naturally derived

products target this hormone to annihilate the stress factors and boost mental health and

cognition Researchers have studied the effects of probiotics against stress in a zebrafish

model by introducing the bacterial strain Lactobacillus plantarum into the tank (Davis et al

2016) The objective is to bring the body back to homeostasis maintaining a balanced level

of cortisol The actions of gut microbes and nutraceuticals work interdependently to help

reduce the dangerous outcomes of stress upon the body Experiments with germ free mice

have been used to probe the role of microbiota in adult hippocampal neurogenesis Also

disruptions of gut microbiome induced mice behaviour resulted in anxiety depression and

even autism Gut microbes are the key modulators of brain plasticity cognitive functions and

help to optimize the bodyrsquos response to stress by regulating their synthesis of

neurotransmitters like serotonin to lower the cortisol level Studies have shown that during

stress there is an increased population of certain bacterial strains in the gut such as

Enterobacteriaceae Proteobacteria Actinobacteria and this can be controlled by increasing

the administration of probiotics containing Lactobacillus and Bifidobacterium species

Experiments have been conducted with Bifidobacterium longum and results showed that this

strain was able to reverse hippocampal and BDNF abnormalities

14

CONCLUSION

In today lsquos ambitious world so much importance is being given to performance perfection

competition that it leads to an insidious increase in stress depression anxiety Stress is a

psychological issue which predisposes a person to various other ailments It is inevitable in

the life of any individual but the duration and intensity differs According to Hans Selye who

coined the term stress in 1936 it is the non- specific response of the body to any demand for

change Stress levels are rising worldwide it is a top health concern The damages that can be

caused by stress are often underestimated It primarily affects the nervous system but

prolonged exposure leads to cardiovascular musculoskeletal diseases and even affects the

reproductive system Claude Bernard (1865-1961) observed that the maintenance of life is

essentially dependent on keeping our internal milieu constant in the face of a changing

environment Thus sustaining a state of homeostasis is vital for a healthy life Workplace

stress and depression is on the rise it is the health epidemic of 21 st century a frequently

reported problem According to WHO depression is among the leading causes of disability

globally There is a compelling need to confront the ameliorating and deleterious effects of

stress inflicted on an individual These health risks can be prevented or managed A multi

targeted approach is required to tackle a problem as severe as stress It can be controlled in

the healthy way by nourishing and stimulating the gut microbes in our body to act on the

brain which increases the release of neurotransmitters to help relieve the effects of stress

Nutrient supplements referred to as nutraceuticals has been introduced to influence the brain

activity and protect it from the negative impact of stress hormones These nutraceuticals help

to enhance the quality of life by modulating the gut health They prevent the alteration of

microbiome during stress Extensive research has been conducted in the field of gut microbes

and nutraceuticals and their efficacy towards alleviating stress has been proved We are

moving towards the direction of exploring psych biotics as a mode of treatment for anxiety

15

depression and various psychiatric issues However it is a recently introduced term and

research and is still on-going whether it has proven benefits or not Dietary interventions with

food supplements designed to modulate responses to stress that can be administered

effectively Managing stress in the natural way is proven to be the most favorable method

Acknowledgements

The authors are thankful to Chettinad Academy of Research and Education (CARE) for the

support

Conflicts of interest

We declare no conflict of interest All co-authors have agreed to transfer the copyright to the

publisher if it is accepted for publication This study was partially financially supported by

Chettinad Hospital amp Research Institute (CHRI) Chettinad Academy of Research and

Education (CARE) Kelambakkam Chennai-603103 India

16

References

Anderson JW Baird P Davis RH Ferreri S Knutdson M Koraym A Waters V

Williams CL (2009) Health benefits of dietary fibre Nutrition Reviews 67188-205

Andres RH Ducray AD Schlattner U Wallimann T Widmer HR (2008) Functions

and effects of creatine in the central nervous system Brain Research Bulletin 76(4)329-43

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged blueberry-fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2)111-20

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged-blueberry fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2) 111-20

Barrett E Ross RP OToole PW Fitzgerald GF Stanton C (2012) gamma-

Aminobutyric acid production by culturable bacteria from the human intestine Journal of

applied microbiology 113411ndash417

Bazan NG (2005) Lipid signaling in neural plasticity brain repair and neuroprotection

Molecular Neurobiology 32(1)89-103

Bercik P Denou E Collins J Jackson W Lu J Jury J Deng Y Blennerhassett P

Macri J McCoy KD Verdu EF Collins SM (2011) The intestinal microbiota affect

central levels of brain-derived neurotropic factor and behavior in mice Gastroenterology

141599-609

Borre YE OKeeffe GW Clarke G Stanton C Dinan TG Cryan JF (2014)

Microbiota and neurodevelopmental windows implications for brain disorders Trends in

Molecular Medicine 20509-518

Bravo JA Forsythe P Chew MV (2011) Ingestion of Lactobacillus strain regulates

emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

17

2010) The hypothalamic-pituitary-adrenal axis (HPA) is considered as the central response

system in the body it reticulates the central nervous system and endocrine system and

coordinates a defective response to stress factors HPA axis is responsible for the prominent

increase in behaviour altering chemicals including glucocorticoids catecholamines and

mineralocorticoids Its activity is regulated by afferent nerve fibres of the parasympathetic

system such as vagus nerves oculomotor nerves limbic system which includes hippocampus

amygdala basal ganglia and sympathetic systems

The hippocampus is a horse shaped region near to the amygdala in the midbrain Our

experiences emotions memory retention rely entirely on the hippocampus to function

correctly Neuroscientists have confirmed that chronic stress can damage the brain severely

and have a long-term effect involving changes in brain structure such as shrinking the

hippocampus volume loss of memory retention neuroinflammation suppressing the neural

activity and increasing the size of amygdala which heightens flightfight response The

maintenance of stability in the brain is disturbed due to continual exposure of stress Raised

levels of cortisol is involved in the synthesis of neurotransmitter glutamate which is a

chemical used to transmit signals to other nerve cells This excitatory neurotransmitter when

released in high amounts has neurotoxic effects by generating free radicals Cortisol also

damages the receptors of the neurotransmitters serotonin and dopamine which are regulators

of mood pleasure happiness and motivation Prolonged stress is known to alter the blood

brain barrier permitting the entry of pathogens heavy metal toxins which damage the brain

cells (Figure 3) There is an immense loss of neurons and brain cells due to inhibitory action

of cortisol on the brain derived neurotropic factor (BDNF) which is a protein used to

maintain healthy brain cells and for synthesis of new cells in the brain

8

Role of nutraceuticals

The term ldquonutraceuticalrdquo was coined by Stephen L Defelice in 1979 According to Defelice

it is defined as food or parts of food that dispense medicalhealth benefits including

prevention and treatment It is a composite of nutrition and pharmaceutical which helps to

maintain the physiological functions of the body These nutrient factors provide sufficient

nutrients to meet the fundamental nutritional requirements for quality living balance and

growth (Maddi et al 2007) They are also referred to as medical foods and designer foods

These products are derived from food sources with additional health benefits besides

providing the basic nutritional value in foods (Rishi et al 2006) Nutraceutical compounds

specifically targeting the neurodevelopment processes are referred to ldquoneuro-nutraceuticalsrdquo

a term that has been recently introduced These supplements are chemically identified

molecules that beneficially affect the brain at molecular level Their actions are directed to

aid in improvement of cognition improve memory positively impact the production of

neurotransmitters reduce inflammations and ageing of brain management of

neurodegenerative and neuropsychiatric disorders (Malik et al 2008) In line with the

subject they also are known to enhance the gut microbes and influence their activities A

healthy gut impacts the brain development and signalling mechanisms It helps to lower the

stress levels and maintain a good mood Foods can infuse our brains with energy to make us

think faster and better Nutraceuticals range from isolated nutrients such as vitamins

minerals fatty acids probiotics prebiotics antioxidants polyaminoacids polysaccharides

herbal products genetically engineered foods and phytochemicals which include

(Carotenoids- fruits vegetables and egg yolk Flavonoid polyphenolics- berries fruits

vegetables legumes are potent antioxidants Non-flavonoid polyphenolics- dark grapes

raisins berries peanuts turmeric roots)

9

Effects of nutrients on gut and brain

The diverse composition of gut microbiota in humans depends on dietary habits The key

mechanisms to maintain gut health are considered to increase the intake of high fibre diet

polysaccharides polyunsaturated fatty acids antioxidants and phytochemicals High-fibre

rich foods stimulate fermentation which proliferates the bacteria and increase biomass

Fermentation causes carbohydrates to undergo chemical changes which result in organic

acids that provide energy for the microbes Short chain fatty acids (SCFA) are the end

products of carbohydrate fermentation which help to inhibit the growth of pathogenic

microorganisms The intake of short-chain non-digestible carbohydrates which include

inulin-type fructans fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS) are

source of prebiotics that typically target growth of bacterial groups such as

Bifidobacterium and Lactobacillus These prebiotic fibres help to ease anxiety depression

restore healthy sleep patterns and protect beneficial gut bacteria Dietary saturated fats may

increase the number of existing pro-inflammatory gut microbes by stimulating formation of

taurine conjugated bile acids that promotes growth of these microbes (Devkota et al 2012)

Polyphenol containing berries metabolized by resident microbiota results in bioactive

products which impacts the health (Duthie et al 2003) Any gut malfunction has a negative

impact on human health therefore it is highly essential to incorporate foods that enhance the

microflora of the gut Artichokes have a strong probiotic potential the high content of inulin

which is insoluble fibre ferments into healthy microflora (Gibson et al 1995) Adequate

administration of probiotics is recognized to have balanced immunoregulatory activities

Investigations on a particular probiotic strain Lactobacillus Pentosus has been shown to

enhance the cytokine production especially IL-10 which is responsible for maintaining the

host immunity by normalizing the T regulatory cells (M Kimura et al2017) Lately a

fascinating finding has been that cocoa or chocolate the most craved food across the globe

10

may modulate the gut commensal population They are found to contain flavonoids including

procyanidins like catechin and epicatechin oligomers which enhance the action of the

neurotransmitters in the brain A Homayouni Rad and his colleagues formulated chocolate as

a potential carrier of probiotic culture strains including lactobacilluscasei and paracasei

positively sustaining the intestinal microbiota population and also releasing stress busting

endorphins Another notable strain is the lactic acid bacteria Streptococcus thermophilus

widely used in the commercial production of fermented dairy products Because of its

inability to survive in the healthy gastric pH of the stomach it has not been suggested as a

ideal probiotic candidate Nonetheless Xiaohong Kangaan and colleagues conducted an

intriguing study on the health promoting effects of milk fermented by Streptococcus

thermophilus in mice the fermented milk was found to have an enhanced cell-mediated

response and positive immunostimulatory effects (M Kimura et al2017) Bananas restore

health of the bacterial community and reduce inflammation It is found to maintain harmony

between the different phyla present in the gut Polenta is a corn-based complex carbohydrate

which has fermentable components that fosters healthy microbiota because of its high fiber

(Anderson et al 2009) Broccoli kale cauliflower cabbage consist of sulfur containing

metabolites namely glucosinolates which are fragmented by the microbes to release

substances that reduce inflammation (Li et al 2008)

Benefits of berry fruit polyphenols

Oxidative stress is a serious threat triggering widespread increase in the occurrence of major

diseases such as Alzheimerrsquos Parkinsonrsquos other neurodegenerative disorders and ageing

Foods rich in antioxidant activity help to prevent age-related changes (Figure 4) Berry fruit

polyphenols can neutralize the negative effects of free-radicals the harmful by-products of

cellular metabolism which contribute to age related diseases They also possess a multiplicity

of actions aside from antioxidant activity They stimulate brain activity neuronal

11

communication cognitive skills calcium buffering ability improve movement control and

prevent memory loss Supplements derived from berry fruits like blueberry cranberry

strawberry have been reported to be effective in reversing motor and behavioral deficits and

control sensory inputs These tiny fruits laden with healing properties are referred to as brain

protective fruits berries are rich in bioflavonoids such as anthocyanins and proanthocyanins

both of which are scavengers of free radicals Active phytochemicals present in the blueberry

confer the benefit of being able to cross the blood-brain-barrier Anthocyanins have been

shown to penetrate the brain and their concentrations correspond to appropriate cognitive

performances (Lacueva et al 2005) They upregulate TNF α IL-1β NF-κB and

consequently suppress ageing and improve blood flow to the brain Blueberries are

responsible for reducing expression of stress signals and results in increasing protective

signals and impact cell signalling molecule expression (Shukitt-Hale et al 2008) The

anthocyanins elevate the level of BDNF (Brain derived neurotropic factor) which is crucial to

boost neuronal communication influencing cognitive function Heat shock proteins are

known to fight free radicals and inflammation inducing agents to support healthy brain

tissues The ability to generate heat shock proteins declines with age dramatically However

researchers have found that consumption of blueberries could restore heat shock protein

response and help protect against neurodegeneration processes associated with ageing

Blueberries play an essential role in reducing the toxicity of kainic acid on hippocampal cells

Kainic acid is an amino acid which is naturally abundant in seaweeds and can be neurotoxic

because of its potent ability to stimulate neurons by activating receptors for glutamate This

aminoacid can be induced in laboratory animal models to study various neurodegenerative

disorders

12

PUFAs

Polyunsaturated fatty acids (PUFAs) are critical components of neuronal cell membranes and

are involved in neurotransmitter communication within the neural networks They are

responsible for maintaining membrane fluidity essential synaptic vesicle fusion and serve as

precursors for lipid messengers which participate in signalling processes to promote neuronal

protection (Bazan et al 2005) Flaxseeds fish soybeans walnuts are rich in PUFA

specifically omega- 6 fatty acid linoleic acid omega-3 α linolenic acid

Intake of PUFA supplements for improve cognitive function

In most neurological conditions inflammation manifests in the nervous tissue and this

inflammation is a therapeutic target by the pharmaceutical industries During high levels of

stress the body cannot regulate an inflammatory response which leads to a greater risk of

development of other diseases Anti-inflammatory agents containing nutraceuticals is the

focus of development Oxymatrine derived from the root of a Chinese herb Sophora

flavescens has been reported to have anti-inflammatory actions and decreases damage

observed after hypoxic- ischaemic brain injury in neonatal rat models (Zhao et al 2015)

Apocynin obtained from the root of Picrorhiza kurroa is also believed to have anti-

inflammatory properties and attenuate the cholesterol oxidation product induced apoptosis in

neuronal cells by preventing production of reactive oxygen species (Simonyi et al 2012)

Quercetin known to be found in vegetables fruits have antioxidant effects regulate proteins

transcription factors and kinase dependent signalling pathways Nutraceutical additive actions

of quercetin expedite optimal delivery and improve brain activity Naturally occurring 7 8-

dihydroxyflavone rescues cognition deficits and serve as a novel treatment for autism and

schizophrenia Trans-resveratrol and pterostilbene are plant derived synergistic phytonutrients

improving brain health and having diverse actions against oxidative stress (Poulose et al

2015) Creatine is a natural substance when taken as supplements in recommended dose is

13

beneficial to enhance brain function and improve cognitive function (Wallimann 2008) (Table

1)

Management of stress

Nutrient supplements have the potential to overcome the debilitating effects of stress They

act as prophylactic and therapeutic agents and are more efficient and safe in comparison to

pharmaceutical drugs (Pandey et al 2010) Botanically derived ingredients are used to treat

mild depression anxiety improve sleep patterns and maintain good health Since a persistent

level of cortisol in circulation is the chief cause of depression and stress naturally derived

products target this hormone to annihilate the stress factors and boost mental health and

cognition Researchers have studied the effects of probiotics against stress in a zebrafish

model by introducing the bacterial strain Lactobacillus plantarum into the tank (Davis et al

2016) The objective is to bring the body back to homeostasis maintaining a balanced level

of cortisol The actions of gut microbes and nutraceuticals work interdependently to help

reduce the dangerous outcomes of stress upon the body Experiments with germ free mice

have been used to probe the role of microbiota in adult hippocampal neurogenesis Also

disruptions of gut microbiome induced mice behaviour resulted in anxiety depression and

even autism Gut microbes are the key modulators of brain plasticity cognitive functions and

help to optimize the bodyrsquos response to stress by regulating their synthesis of

neurotransmitters like serotonin to lower the cortisol level Studies have shown that during

stress there is an increased population of certain bacterial strains in the gut such as

Enterobacteriaceae Proteobacteria Actinobacteria and this can be controlled by increasing

the administration of probiotics containing Lactobacillus and Bifidobacterium species

Experiments have been conducted with Bifidobacterium longum and results showed that this

strain was able to reverse hippocampal and BDNF abnormalities

14

CONCLUSION

In today lsquos ambitious world so much importance is being given to performance perfection

competition that it leads to an insidious increase in stress depression anxiety Stress is a

psychological issue which predisposes a person to various other ailments It is inevitable in

the life of any individual but the duration and intensity differs According to Hans Selye who

coined the term stress in 1936 it is the non- specific response of the body to any demand for

change Stress levels are rising worldwide it is a top health concern The damages that can be

caused by stress are often underestimated It primarily affects the nervous system but

prolonged exposure leads to cardiovascular musculoskeletal diseases and even affects the

reproductive system Claude Bernard (1865-1961) observed that the maintenance of life is

essentially dependent on keeping our internal milieu constant in the face of a changing

environment Thus sustaining a state of homeostasis is vital for a healthy life Workplace

stress and depression is on the rise it is the health epidemic of 21 st century a frequently

reported problem According to WHO depression is among the leading causes of disability

globally There is a compelling need to confront the ameliorating and deleterious effects of

stress inflicted on an individual These health risks can be prevented or managed A multi

targeted approach is required to tackle a problem as severe as stress It can be controlled in

the healthy way by nourishing and stimulating the gut microbes in our body to act on the

brain which increases the release of neurotransmitters to help relieve the effects of stress

Nutrient supplements referred to as nutraceuticals has been introduced to influence the brain

activity and protect it from the negative impact of stress hormones These nutraceuticals help

to enhance the quality of life by modulating the gut health They prevent the alteration of

microbiome during stress Extensive research has been conducted in the field of gut microbes

and nutraceuticals and their efficacy towards alleviating stress has been proved We are

moving towards the direction of exploring psych biotics as a mode of treatment for anxiety

15

depression and various psychiatric issues However it is a recently introduced term and

research and is still on-going whether it has proven benefits or not Dietary interventions with

food supplements designed to modulate responses to stress that can be administered

effectively Managing stress in the natural way is proven to be the most favorable method

Acknowledgements

The authors are thankful to Chettinad Academy of Research and Education (CARE) for the

support

Conflicts of interest

We declare no conflict of interest All co-authors have agreed to transfer the copyright to the

publisher if it is accepted for publication This study was partially financially supported by

Chettinad Hospital amp Research Institute (CHRI) Chettinad Academy of Research and

Education (CARE) Kelambakkam Chennai-603103 India

16

References

Anderson JW Baird P Davis RH Ferreri S Knutdson M Koraym A Waters V

Williams CL (2009) Health benefits of dietary fibre Nutrition Reviews 67188-205

Andres RH Ducray AD Schlattner U Wallimann T Widmer HR (2008) Functions

and effects of creatine in the central nervous system Brain Research Bulletin 76(4)329-43

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged blueberry-fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2)111-20

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged-blueberry fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2) 111-20

Barrett E Ross RP OToole PW Fitzgerald GF Stanton C (2012) gamma-

Aminobutyric acid production by culturable bacteria from the human intestine Journal of

applied microbiology 113411ndash417

Bazan NG (2005) Lipid signaling in neural plasticity brain repair and neuroprotection

Molecular Neurobiology 32(1)89-103

Bercik P Denou E Collins J Jackson W Lu J Jury J Deng Y Blennerhassett P

Macri J McCoy KD Verdu EF Collins SM (2011) The intestinal microbiota affect

central levels of brain-derived neurotropic factor and behavior in mice Gastroenterology

141599-609

Borre YE OKeeffe GW Clarke G Stanton C Dinan TG Cryan JF (2014)

Microbiota and neurodevelopmental windows implications for brain disorders Trends in

Molecular Medicine 20509-518

Bravo JA Forsythe P Chew MV (2011) Ingestion of Lactobacillus strain regulates

emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

17

Role of nutraceuticals

The term ldquonutraceuticalrdquo was coined by Stephen L Defelice in 1979 According to Defelice

it is defined as food or parts of food that dispense medicalhealth benefits including

prevention and treatment It is a composite of nutrition and pharmaceutical which helps to

maintain the physiological functions of the body These nutrient factors provide sufficient

nutrients to meet the fundamental nutritional requirements for quality living balance and

growth (Maddi et al 2007) They are also referred to as medical foods and designer foods

These products are derived from food sources with additional health benefits besides

providing the basic nutritional value in foods (Rishi et al 2006) Nutraceutical compounds

specifically targeting the neurodevelopment processes are referred to ldquoneuro-nutraceuticalsrdquo

a term that has been recently introduced These supplements are chemically identified

molecules that beneficially affect the brain at molecular level Their actions are directed to

aid in improvement of cognition improve memory positively impact the production of

neurotransmitters reduce inflammations and ageing of brain management of

neurodegenerative and neuropsychiatric disorders (Malik et al 2008) In line with the

subject they also are known to enhance the gut microbes and influence their activities A

healthy gut impacts the brain development and signalling mechanisms It helps to lower the

stress levels and maintain a good mood Foods can infuse our brains with energy to make us

think faster and better Nutraceuticals range from isolated nutrients such as vitamins

minerals fatty acids probiotics prebiotics antioxidants polyaminoacids polysaccharides

herbal products genetically engineered foods and phytochemicals which include

(Carotenoids- fruits vegetables and egg yolk Flavonoid polyphenolics- berries fruits

vegetables legumes are potent antioxidants Non-flavonoid polyphenolics- dark grapes

raisins berries peanuts turmeric roots)

9

Effects of nutrients on gut and brain

The diverse composition of gut microbiota in humans depends on dietary habits The key

mechanisms to maintain gut health are considered to increase the intake of high fibre diet

polysaccharides polyunsaturated fatty acids antioxidants and phytochemicals High-fibre

rich foods stimulate fermentation which proliferates the bacteria and increase biomass

Fermentation causes carbohydrates to undergo chemical changes which result in organic

acids that provide energy for the microbes Short chain fatty acids (SCFA) are the end

products of carbohydrate fermentation which help to inhibit the growth of pathogenic

microorganisms The intake of short-chain non-digestible carbohydrates which include

inulin-type fructans fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS) are

source of prebiotics that typically target growth of bacterial groups such as

Bifidobacterium and Lactobacillus These prebiotic fibres help to ease anxiety depression

restore healthy sleep patterns and protect beneficial gut bacteria Dietary saturated fats may

increase the number of existing pro-inflammatory gut microbes by stimulating formation of

taurine conjugated bile acids that promotes growth of these microbes (Devkota et al 2012)

Polyphenol containing berries metabolized by resident microbiota results in bioactive

products which impacts the health (Duthie et al 2003) Any gut malfunction has a negative

impact on human health therefore it is highly essential to incorporate foods that enhance the

microflora of the gut Artichokes have a strong probiotic potential the high content of inulin

which is insoluble fibre ferments into healthy microflora (Gibson et al 1995) Adequate

administration of probiotics is recognized to have balanced immunoregulatory activities

Investigations on a particular probiotic strain Lactobacillus Pentosus has been shown to

enhance the cytokine production especially IL-10 which is responsible for maintaining the

host immunity by normalizing the T regulatory cells (M Kimura et al2017) Lately a

fascinating finding has been that cocoa or chocolate the most craved food across the globe

10

may modulate the gut commensal population They are found to contain flavonoids including

procyanidins like catechin and epicatechin oligomers which enhance the action of the

neurotransmitters in the brain A Homayouni Rad and his colleagues formulated chocolate as

a potential carrier of probiotic culture strains including lactobacilluscasei and paracasei

positively sustaining the intestinal microbiota population and also releasing stress busting

endorphins Another notable strain is the lactic acid bacteria Streptococcus thermophilus

widely used in the commercial production of fermented dairy products Because of its

inability to survive in the healthy gastric pH of the stomach it has not been suggested as a

ideal probiotic candidate Nonetheless Xiaohong Kangaan and colleagues conducted an

intriguing study on the health promoting effects of milk fermented by Streptococcus

thermophilus in mice the fermented milk was found to have an enhanced cell-mediated

response and positive immunostimulatory effects (M Kimura et al2017) Bananas restore

health of the bacterial community and reduce inflammation It is found to maintain harmony

between the different phyla present in the gut Polenta is a corn-based complex carbohydrate

which has fermentable components that fosters healthy microbiota because of its high fiber

(Anderson et al 2009) Broccoli kale cauliflower cabbage consist of sulfur containing

metabolites namely glucosinolates which are fragmented by the microbes to release

substances that reduce inflammation (Li et al 2008)

Benefits of berry fruit polyphenols

Oxidative stress is a serious threat triggering widespread increase in the occurrence of major

diseases such as Alzheimerrsquos Parkinsonrsquos other neurodegenerative disorders and ageing

Foods rich in antioxidant activity help to prevent age-related changes (Figure 4) Berry fruit

polyphenols can neutralize the negative effects of free-radicals the harmful by-products of

cellular metabolism which contribute to age related diseases They also possess a multiplicity

of actions aside from antioxidant activity They stimulate brain activity neuronal

11

communication cognitive skills calcium buffering ability improve movement control and

prevent memory loss Supplements derived from berry fruits like blueberry cranberry

strawberry have been reported to be effective in reversing motor and behavioral deficits and

control sensory inputs These tiny fruits laden with healing properties are referred to as brain

protective fruits berries are rich in bioflavonoids such as anthocyanins and proanthocyanins

both of which are scavengers of free radicals Active phytochemicals present in the blueberry

confer the benefit of being able to cross the blood-brain-barrier Anthocyanins have been

shown to penetrate the brain and their concentrations correspond to appropriate cognitive

performances (Lacueva et al 2005) They upregulate TNF α IL-1β NF-κB and

consequently suppress ageing and improve blood flow to the brain Blueberries are

responsible for reducing expression of stress signals and results in increasing protective

signals and impact cell signalling molecule expression (Shukitt-Hale et al 2008) The

anthocyanins elevate the level of BDNF (Brain derived neurotropic factor) which is crucial to

boost neuronal communication influencing cognitive function Heat shock proteins are

known to fight free radicals and inflammation inducing agents to support healthy brain

tissues The ability to generate heat shock proteins declines with age dramatically However

researchers have found that consumption of blueberries could restore heat shock protein

response and help protect against neurodegeneration processes associated with ageing

Blueberries play an essential role in reducing the toxicity of kainic acid on hippocampal cells

Kainic acid is an amino acid which is naturally abundant in seaweeds and can be neurotoxic

because of its potent ability to stimulate neurons by activating receptors for glutamate This

aminoacid can be induced in laboratory animal models to study various neurodegenerative

disorders

12

PUFAs

Polyunsaturated fatty acids (PUFAs) are critical components of neuronal cell membranes and

are involved in neurotransmitter communication within the neural networks They are

responsible for maintaining membrane fluidity essential synaptic vesicle fusion and serve as

precursors for lipid messengers which participate in signalling processes to promote neuronal

protection (Bazan et al 2005) Flaxseeds fish soybeans walnuts are rich in PUFA

specifically omega- 6 fatty acid linoleic acid omega-3 α linolenic acid

Intake of PUFA supplements for improve cognitive function

In most neurological conditions inflammation manifests in the nervous tissue and this

inflammation is a therapeutic target by the pharmaceutical industries During high levels of

stress the body cannot regulate an inflammatory response which leads to a greater risk of

development of other diseases Anti-inflammatory agents containing nutraceuticals is the

focus of development Oxymatrine derived from the root of a Chinese herb Sophora

flavescens has been reported to have anti-inflammatory actions and decreases damage

observed after hypoxic- ischaemic brain injury in neonatal rat models (Zhao et al 2015)

Apocynin obtained from the root of Picrorhiza kurroa is also believed to have anti-

inflammatory properties and attenuate the cholesterol oxidation product induced apoptosis in

neuronal cells by preventing production of reactive oxygen species (Simonyi et al 2012)

Quercetin known to be found in vegetables fruits have antioxidant effects regulate proteins

transcription factors and kinase dependent signalling pathways Nutraceutical additive actions

of quercetin expedite optimal delivery and improve brain activity Naturally occurring 7 8-

dihydroxyflavone rescues cognition deficits and serve as a novel treatment for autism and

schizophrenia Trans-resveratrol and pterostilbene are plant derived synergistic phytonutrients

improving brain health and having diverse actions against oxidative stress (Poulose et al

2015) Creatine is a natural substance when taken as supplements in recommended dose is

13

beneficial to enhance brain function and improve cognitive function (Wallimann 2008) (Table

1)

Management of stress

Nutrient supplements have the potential to overcome the debilitating effects of stress They

act as prophylactic and therapeutic agents and are more efficient and safe in comparison to

pharmaceutical drugs (Pandey et al 2010) Botanically derived ingredients are used to treat

mild depression anxiety improve sleep patterns and maintain good health Since a persistent

level of cortisol in circulation is the chief cause of depression and stress naturally derived

products target this hormone to annihilate the stress factors and boost mental health and

cognition Researchers have studied the effects of probiotics against stress in a zebrafish

model by introducing the bacterial strain Lactobacillus plantarum into the tank (Davis et al

2016) The objective is to bring the body back to homeostasis maintaining a balanced level

of cortisol The actions of gut microbes and nutraceuticals work interdependently to help

reduce the dangerous outcomes of stress upon the body Experiments with germ free mice

have been used to probe the role of microbiota in adult hippocampal neurogenesis Also

disruptions of gut microbiome induced mice behaviour resulted in anxiety depression and

even autism Gut microbes are the key modulators of brain plasticity cognitive functions and

help to optimize the bodyrsquos response to stress by regulating their synthesis of

neurotransmitters like serotonin to lower the cortisol level Studies have shown that during

stress there is an increased population of certain bacterial strains in the gut such as

Enterobacteriaceae Proteobacteria Actinobacteria and this can be controlled by increasing

the administration of probiotics containing Lactobacillus and Bifidobacterium species

Experiments have been conducted with Bifidobacterium longum and results showed that this

strain was able to reverse hippocampal and BDNF abnormalities

14

CONCLUSION

In today lsquos ambitious world so much importance is being given to performance perfection

competition that it leads to an insidious increase in stress depression anxiety Stress is a

psychological issue which predisposes a person to various other ailments It is inevitable in

the life of any individual but the duration and intensity differs According to Hans Selye who

coined the term stress in 1936 it is the non- specific response of the body to any demand for

change Stress levels are rising worldwide it is a top health concern The damages that can be

caused by stress are often underestimated It primarily affects the nervous system but

prolonged exposure leads to cardiovascular musculoskeletal diseases and even affects the

reproductive system Claude Bernard (1865-1961) observed that the maintenance of life is

essentially dependent on keeping our internal milieu constant in the face of a changing

environment Thus sustaining a state of homeostasis is vital for a healthy life Workplace

stress and depression is on the rise it is the health epidemic of 21 st century a frequently

reported problem According to WHO depression is among the leading causes of disability

globally There is a compelling need to confront the ameliorating and deleterious effects of

stress inflicted on an individual These health risks can be prevented or managed A multi

targeted approach is required to tackle a problem as severe as stress It can be controlled in

the healthy way by nourishing and stimulating the gut microbes in our body to act on the

brain which increases the release of neurotransmitters to help relieve the effects of stress

Nutrient supplements referred to as nutraceuticals has been introduced to influence the brain

activity and protect it from the negative impact of stress hormones These nutraceuticals help

to enhance the quality of life by modulating the gut health They prevent the alteration of

microbiome during stress Extensive research has been conducted in the field of gut microbes

and nutraceuticals and their efficacy towards alleviating stress has been proved We are

moving towards the direction of exploring psych biotics as a mode of treatment for anxiety

15

depression and various psychiatric issues However it is a recently introduced term and

research and is still on-going whether it has proven benefits or not Dietary interventions with

food supplements designed to modulate responses to stress that can be administered

effectively Managing stress in the natural way is proven to be the most favorable method

Acknowledgements

The authors are thankful to Chettinad Academy of Research and Education (CARE) for the

support

Conflicts of interest

We declare no conflict of interest All co-authors have agreed to transfer the copyright to the

publisher if it is accepted for publication This study was partially financially supported by

Chettinad Hospital amp Research Institute (CHRI) Chettinad Academy of Research and

Education (CARE) Kelambakkam Chennai-603103 India

16

References

Anderson JW Baird P Davis RH Ferreri S Knutdson M Koraym A Waters V

Williams CL (2009) Health benefits of dietary fibre Nutrition Reviews 67188-205

Andres RH Ducray AD Schlattner U Wallimann T Widmer HR (2008) Functions

and effects of creatine in the central nervous system Brain Research Bulletin 76(4)329-43

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged blueberry-fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2)111-20

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged-blueberry fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2) 111-20

Barrett E Ross RP OToole PW Fitzgerald GF Stanton C (2012) gamma-

Aminobutyric acid production by culturable bacteria from the human intestine Journal of

applied microbiology 113411ndash417

Bazan NG (2005) Lipid signaling in neural plasticity brain repair and neuroprotection

Molecular Neurobiology 32(1)89-103

Bercik P Denou E Collins J Jackson W Lu J Jury J Deng Y Blennerhassett P

Macri J McCoy KD Verdu EF Collins SM (2011) The intestinal microbiota affect

central levels of brain-derived neurotropic factor and behavior in mice Gastroenterology

141599-609

Borre YE OKeeffe GW Clarke G Stanton C Dinan TG Cryan JF (2014)

Microbiota and neurodevelopmental windows implications for brain disorders Trends in

Molecular Medicine 20509-518

Bravo JA Forsythe P Chew MV (2011) Ingestion of Lactobacillus strain regulates

emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

17

Effects of nutrients on gut and brain

The diverse composition of gut microbiota in humans depends on dietary habits The key

mechanisms to maintain gut health are considered to increase the intake of high fibre diet

polysaccharides polyunsaturated fatty acids antioxidants and phytochemicals High-fibre

rich foods stimulate fermentation which proliferates the bacteria and increase biomass

Fermentation causes carbohydrates to undergo chemical changes which result in organic

acids that provide energy for the microbes Short chain fatty acids (SCFA) are the end

products of carbohydrate fermentation which help to inhibit the growth of pathogenic

microorganisms The intake of short-chain non-digestible carbohydrates which include

inulin-type fructans fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS) are

source of prebiotics that typically target growth of bacterial groups such as

Bifidobacterium and Lactobacillus These prebiotic fibres help to ease anxiety depression

restore healthy sleep patterns and protect beneficial gut bacteria Dietary saturated fats may

increase the number of existing pro-inflammatory gut microbes by stimulating formation of

taurine conjugated bile acids that promotes growth of these microbes (Devkota et al 2012)

Polyphenol containing berries metabolized by resident microbiota results in bioactive

products which impacts the health (Duthie et al 2003) Any gut malfunction has a negative

impact on human health therefore it is highly essential to incorporate foods that enhance the

microflora of the gut Artichokes have a strong probiotic potential the high content of inulin

which is insoluble fibre ferments into healthy microflora (Gibson et al 1995) Adequate

administration of probiotics is recognized to have balanced immunoregulatory activities

Investigations on a particular probiotic strain Lactobacillus Pentosus has been shown to

enhance the cytokine production especially IL-10 which is responsible for maintaining the

host immunity by normalizing the T regulatory cells (M Kimura et al2017) Lately a

fascinating finding has been that cocoa or chocolate the most craved food across the globe

10

may modulate the gut commensal population They are found to contain flavonoids including

procyanidins like catechin and epicatechin oligomers which enhance the action of the

neurotransmitters in the brain A Homayouni Rad and his colleagues formulated chocolate as

a potential carrier of probiotic culture strains including lactobacilluscasei and paracasei

positively sustaining the intestinal microbiota population and also releasing stress busting

endorphins Another notable strain is the lactic acid bacteria Streptococcus thermophilus

widely used in the commercial production of fermented dairy products Because of its

inability to survive in the healthy gastric pH of the stomach it has not been suggested as a

ideal probiotic candidate Nonetheless Xiaohong Kangaan and colleagues conducted an

intriguing study on the health promoting effects of milk fermented by Streptococcus

thermophilus in mice the fermented milk was found to have an enhanced cell-mediated

response and positive immunostimulatory effects (M Kimura et al2017) Bananas restore

health of the bacterial community and reduce inflammation It is found to maintain harmony

between the different phyla present in the gut Polenta is a corn-based complex carbohydrate

which has fermentable components that fosters healthy microbiota because of its high fiber

(Anderson et al 2009) Broccoli kale cauliflower cabbage consist of sulfur containing

metabolites namely glucosinolates which are fragmented by the microbes to release

substances that reduce inflammation (Li et al 2008)

Benefits of berry fruit polyphenols

Oxidative stress is a serious threat triggering widespread increase in the occurrence of major

diseases such as Alzheimerrsquos Parkinsonrsquos other neurodegenerative disorders and ageing

Foods rich in antioxidant activity help to prevent age-related changes (Figure 4) Berry fruit

polyphenols can neutralize the negative effects of free-radicals the harmful by-products of

cellular metabolism which contribute to age related diseases They also possess a multiplicity

of actions aside from antioxidant activity They stimulate brain activity neuronal

11

communication cognitive skills calcium buffering ability improve movement control and

prevent memory loss Supplements derived from berry fruits like blueberry cranberry

strawberry have been reported to be effective in reversing motor and behavioral deficits and

control sensory inputs These tiny fruits laden with healing properties are referred to as brain

protective fruits berries are rich in bioflavonoids such as anthocyanins and proanthocyanins

both of which are scavengers of free radicals Active phytochemicals present in the blueberry

confer the benefit of being able to cross the blood-brain-barrier Anthocyanins have been

shown to penetrate the brain and their concentrations correspond to appropriate cognitive

performances (Lacueva et al 2005) They upregulate TNF α IL-1β NF-κB and

consequently suppress ageing and improve blood flow to the brain Blueberries are

responsible for reducing expression of stress signals and results in increasing protective

signals and impact cell signalling molecule expression (Shukitt-Hale et al 2008) The

anthocyanins elevate the level of BDNF (Brain derived neurotropic factor) which is crucial to

boost neuronal communication influencing cognitive function Heat shock proteins are

known to fight free radicals and inflammation inducing agents to support healthy brain

tissues The ability to generate heat shock proteins declines with age dramatically However

researchers have found that consumption of blueberries could restore heat shock protein

response and help protect against neurodegeneration processes associated with ageing

Blueberries play an essential role in reducing the toxicity of kainic acid on hippocampal cells

Kainic acid is an amino acid which is naturally abundant in seaweeds and can be neurotoxic

because of its potent ability to stimulate neurons by activating receptors for glutamate This

aminoacid can be induced in laboratory animal models to study various neurodegenerative

disorders

12

PUFAs

Polyunsaturated fatty acids (PUFAs) are critical components of neuronal cell membranes and

are involved in neurotransmitter communication within the neural networks They are

responsible for maintaining membrane fluidity essential synaptic vesicle fusion and serve as

precursors for lipid messengers which participate in signalling processes to promote neuronal

protection (Bazan et al 2005) Flaxseeds fish soybeans walnuts are rich in PUFA

specifically omega- 6 fatty acid linoleic acid omega-3 α linolenic acid

Intake of PUFA supplements for improve cognitive function

In most neurological conditions inflammation manifests in the nervous tissue and this

inflammation is a therapeutic target by the pharmaceutical industries During high levels of

stress the body cannot regulate an inflammatory response which leads to a greater risk of

development of other diseases Anti-inflammatory agents containing nutraceuticals is the

focus of development Oxymatrine derived from the root of a Chinese herb Sophora

flavescens has been reported to have anti-inflammatory actions and decreases damage

observed after hypoxic- ischaemic brain injury in neonatal rat models (Zhao et al 2015)

Apocynin obtained from the root of Picrorhiza kurroa is also believed to have anti-

inflammatory properties and attenuate the cholesterol oxidation product induced apoptosis in

neuronal cells by preventing production of reactive oxygen species (Simonyi et al 2012)

Quercetin known to be found in vegetables fruits have antioxidant effects regulate proteins

transcription factors and kinase dependent signalling pathways Nutraceutical additive actions

of quercetin expedite optimal delivery and improve brain activity Naturally occurring 7 8-

dihydroxyflavone rescues cognition deficits and serve as a novel treatment for autism and

schizophrenia Trans-resveratrol and pterostilbene are plant derived synergistic phytonutrients

improving brain health and having diverse actions against oxidative stress (Poulose et al

2015) Creatine is a natural substance when taken as supplements in recommended dose is

13

beneficial to enhance brain function and improve cognitive function (Wallimann 2008) (Table

1)

Management of stress

Nutrient supplements have the potential to overcome the debilitating effects of stress They

act as prophylactic and therapeutic agents and are more efficient and safe in comparison to

pharmaceutical drugs (Pandey et al 2010) Botanically derived ingredients are used to treat

mild depression anxiety improve sleep patterns and maintain good health Since a persistent

level of cortisol in circulation is the chief cause of depression and stress naturally derived

products target this hormone to annihilate the stress factors and boost mental health and

cognition Researchers have studied the effects of probiotics against stress in a zebrafish

model by introducing the bacterial strain Lactobacillus plantarum into the tank (Davis et al

2016) The objective is to bring the body back to homeostasis maintaining a balanced level

of cortisol The actions of gut microbes and nutraceuticals work interdependently to help

reduce the dangerous outcomes of stress upon the body Experiments with germ free mice

have been used to probe the role of microbiota in adult hippocampal neurogenesis Also

disruptions of gut microbiome induced mice behaviour resulted in anxiety depression and

even autism Gut microbes are the key modulators of brain plasticity cognitive functions and

help to optimize the bodyrsquos response to stress by regulating their synthesis of

neurotransmitters like serotonin to lower the cortisol level Studies have shown that during

stress there is an increased population of certain bacterial strains in the gut such as

Enterobacteriaceae Proteobacteria Actinobacteria and this can be controlled by increasing

the administration of probiotics containing Lactobacillus and Bifidobacterium species

Experiments have been conducted with Bifidobacterium longum and results showed that this

strain was able to reverse hippocampal and BDNF abnormalities

14

CONCLUSION

In today lsquos ambitious world so much importance is being given to performance perfection

competition that it leads to an insidious increase in stress depression anxiety Stress is a

psychological issue which predisposes a person to various other ailments It is inevitable in

the life of any individual but the duration and intensity differs According to Hans Selye who

coined the term stress in 1936 it is the non- specific response of the body to any demand for

change Stress levels are rising worldwide it is a top health concern The damages that can be

caused by stress are often underestimated It primarily affects the nervous system but

prolonged exposure leads to cardiovascular musculoskeletal diseases and even affects the

reproductive system Claude Bernard (1865-1961) observed that the maintenance of life is

essentially dependent on keeping our internal milieu constant in the face of a changing

environment Thus sustaining a state of homeostasis is vital for a healthy life Workplace

stress and depression is on the rise it is the health epidemic of 21 st century a frequently

reported problem According to WHO depression is among the leading causes of disability

globally There is a compelling need to confront the ameliorating and deleterious effects of

stress inflicted on an individual These health risks can be prevented or managed A multi

targeted approach is required to tackle a problem as severe as stress It can be controlled in

the healthy way by nourishing and stimulating the gut microbes in our body to act on the

brain which increases the release of neurotransmitters to help relieve the effects of stress

Nutrient supplements referred to as nutraceuticals has been introduced to influence the brain

activity and protect it from the negative impact of stress hormones These nutraceuticals help

to enhance the quality of life by modulating the gut health They prevent the alteration of

microbiome during stress Extensive research has been conducted in the field of gut microbes

and nutraceuticals and their efficacy towards alleviating stress has been proved We are

moving towards the direction of exploring psych biotics as a mode of treatment for anxiety

15

depression and various psychiatric issues However it is a recently introduced term and

research and is still on-going whether it has proven benefits or not Dietary interventions with

food supplements designed to modulate responses to stress that can be administered

effectively Managing stress in the natural way is proven to be the most favorable method

Acknowledgements

The authors are thankful to Chettinad Academy of Research and Education (CARE) for the

support

Conflicts of interest

We declare no conflict of interest All co-authors have agreed to transfer the copyright to the

publisher if it is accepted for publication This study was partially financially supported by

Chettinad Hospital amp Research Institute (CHRI) Chettinad Academy of Research and

Education (CARE) Kelambakkam Chennai-603103 India

16

References

Anderson JW Baird P Davis RH Ferreri S Knutdson M Koraym A Waters V

Williams CL (2009) Health benefits of dietary fibre Nutrition Reviews 67188-205

Andres RH Ducray AD Schlattner U Wallimann T Widmer HR (2008) Functions

and effects of creatine in the central nervous system Brain Research Bulletin 76(4)329-43

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged blueberry-fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2)111-20

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged-blueberry fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2) 111-20

Barrett E Ross RP OToole PW Fitzgerald GF Stanton C (2012) gamma-

Aminobutyric acid production by culturable bacteria from the human intestine Journal of

applied microbiology 113411ndash417

Bazan NG (2005) Lipid signaling in neural plasticity brain repair and neuroprotection

Molecular Neurobiology 32(1)89-103

Bercik P Denou E Collins J Jackson W Lu J Jury J Deng Y Blennerhassett P

Macri J McCoy KD Verdu EF Collins SM (2011) The intestinal microbiota affect

central levels of brain-derived neurotropic factor and behavior in mice Gastroenterology

141599-609

Borre YE OKeeffe GW Clarke G Stanton C Dinan TG Cryan JF (2014)

Microbiota and neurodevelopmental windows implications for brain disorders Trends in

Molecular Medicine 20509-518

Bravo JA Forsythe P Chew MV (2011) Ingestion of Lactobacillus strain regulates

emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

17

may modulate the gut commensal population They are found to contain flavonoids including

procyanidins like catechin and epicatechin oligomers which enhance the action of the

neurotransmitters in the brain A Homayouni Rad and his colleagues formulated chocolate as

a potential carrier of probiotic culture strains including lactobacilluscasei and paracasei

positively sustaining the intestinal microbiota population and also releasing stress busting

endorphins Another notable strain is the lactic acid bacteria Streptococcus thermophilus

widely used in the commercial production of fermented dairy products Because of its

inability to survive in the healthy gastric pH of the stomach it has not been suggested as a

ideal probiotic candidate Nonetheless Xiaohong Kangaan and colleagues conducted an

intriguing study on the health promoting effects of milk fermented by Streptococcus

thermophilus in mice the fermented milk was found to have an enhanced cell-mediated

response and positive immunostimulatory effects (M Kimura et al2017) Bananas restore

health of the bacterial community and reduce inflammation It is found to maintain harmony

between the different phyla present in the gut Polenta is a corn-based complex carbohydrate

which has fermentable components that fosters healthy microbiota because of its high fiber

(Anderson et al 2009) Broccoli kale cauliflower cabbage consist of sulfur containing

metabolites namely glucosinolates which are fragmented by the microbes to release

substances that reduce inflammation (Li et al 2008)

Benefits of berry fruit polyphenols

Oxidative stress is a serious threat triggering widespread increase in the occurrence of major

diseases such as Alzheimerrsquos Parkinsonrsquos other neurodegenerative disorders and ageing

Foods rich in antioxidant activity help to prevent age-related changes (Figure 4) Berry fruit

polyphenols can neutralize the negative effects of free-radicals the harmful by-products of

cellular metabolism which contribute to age related diseases They also possess a multiplicity

of actions aside from antioxidant activity They stimulate brain activity neuronal

11

communication cognitive skills calcium buffering ability improve movement control and

prevent memory loss Supplements derived from berry fruits like blueberry cranberry

strawberry have been reported to be effective in reversing motor and behavioral deficits and

control sensory inputs These tiny fruits laden with healing properties are referred to as brain

protective fruits berries are rich in bioflavonoids such as anthocyanins and proanthocyanins

both of which are scavengers of free radicals Active phytochemicals present in the blueberry

confer the benefit of being able to cross the blood-brain-barrier Anthocyanins have been

shown to penetrate the brain and their concentrations correspond to appropriate cognitive

performances (Lacueva et al 2005) They upregulate TNF α IL-1β NF-κB and

consequently suppress ageing and improve blood flow to the brain Blueberries are

responsible for reducing expression of stress signals and results in increasing protective

signals and impact cell signalling molecule expression (Shukitt-Hale et al 2008) The

anthocyanins elevate the level of BDNF (Brain derived neurotropic factor) which is crucial to

boost neuronal communication influencing cognitive function Heat shock proteins are

known to fight free radicals and inflammation inducing agents to support healthy brain

tissues The ability to generate heat shock proteins declines with age dramatically However

researchers have found that consumption of blueberries could restore heat shock protein

response and help protect against neurodegeneration processes associated with ageing

Blueberries play an essential role in reducing the toxicity of kainic acid on hippocampal cells

Kainic acid is an amino acid which is naturally abundant in seaweeds and can be neurotoxic

because of its potent ability to stimulate neurons by activating receptors for glutamate This

aminoacid can be induced in laboratory animal models to study various neurodegenerative

disorders

12

PUFAs

Polyunsaturated fatty acids (PUFAs) are critical components of neuronal cell membranes and

are involved in neurotransmitter communication within the neural networks They are

responsible for maintaining membrane fluidity essential synaptic vesicle fusion and serve as

precursors for lipid messengers which participate in signalling processes to promote neuronal

protection (Bazan et al 2005) Flaxseeds fish soybeans walnuts are rich in PUFA

specifically omega- 6 fatty acid linoleic acid omega-3 α linolenic acid

Intake of PUFA supplements for improve cognitive function

In most neurological conditions inflammation manifests in the nervous tissue and this

inflammation is a therapeutic target by the pharmaceutical industries During high levels of

stress the body cannot regulate an inflammatory response which leads to a greater risk of

development of other diseases Anti-inflammatory agents containing nutraceuticals is the

focus of development Oxymatrine derived from the root of a Chinese herb Sophora

flavescens has been reported to have anti-inflammatory actions and decreases damage

observed after hypoxic- ischaemic brain injury in neonatal rat models (Zhao et al 2015)

Apocynin obtained from the root of Picrorhiza kurroa is also believed to have anti-

inflammatory properties and attenuate the cholesterol oxidation product induced apoptosis in

neuronal cells by preventing production of reactive oxygen species (Simonyi et al 2012)

Quercetin known to be found in vegetables fruits have antioxidant effects regulate proteins

transcription factors and kinase dependent signalling pathways Nutraceutical additive actions

of quercetin expedite optimal delivery and improve brain activity Naturally occurring 7 8-

dihydroxyflavone rescues cognition deficits and serve as a novel treatment for autism and

schizophrenia Trans-resveratrol and pterostilbene are plant derived synergistic phytonutrients

improving brain health and having diverse actions against oxidative stress (Poulose et al

2015) Creatine is a natural substance when taken as supplements in recommended dose is

13

beneficial to enhance brain function and improve cognitive function (Wallimann 2008) (Table

1)

Management of stress

Nutrient supplements have the potential to overcome the debilitating effects of stress They

act as prophylactic and therapeutic agents and are more efficient and safe in comparison to

pharmaceutical drugs (Pandey et al 2010) Botanically derived ingredients are used to treat

mild depression anxiety improve sleep patterns and maintain good health Since a persistent

level of cortisol in circulation is the chief cause of depression and stress naturally derived

products target this hormone to annihilate the stress factors and boost mental health and

cognition Researchers have studied the effects of probiotics against stress in a zebrafish

model by introducing the bacterial strain Lactobacillus plantarum into the tank (Davis et al

2016) The objective is to bring the body back to homeostasis maintaining a balanced level

of cortisol The actions of gut microbes and nutraceuticals work interdependently to help

reduce the dangerous outcomes of stress upon the body Experiments with germ free mice

have been used to probe the role of microbiota in adult hippocampal neurogenesis Also

disruptions of gut microbiome induced mice behaviour resulted in anxiety depression and

even autism Gut microbes are the key modulators of brain plasticity cognitive functions and

help to optimize the bodyrsquos response to stress by regulating their synthesis of

neurotransmitters like serotonin to lower the cortisol level Studies have shown that during

stress there is an increased population of certain bacterial strains in the gut such as

Enterobacteriaceae Proteobacteria Actinobacteria and this can be controlled by increasing

the administration of probiotics containing Lactobacillus and Bifidobacterium species

Experiments have been conducted with Bifidobacterium longum and results showed that this

strain was able to reverse hippocampal and BDNF abnormalities

14

CONCLUSION

In today lsquos ambitious world so much importance is being given to performance perfection

competition that it leads to an insidious increase in stress depression anxiety Stress is a

psychological issue which predisposes a person to various other ailments It is inevitable in

the life of any individual but the duration and intensity differs According to Hans Selye who

coined the term stress in 1936 it is the non- specific response of the body to any demand for

change Stress levels are rising worldwide it is a top health concern The damages that can be

caused by stress are often underestimated It primarily affects the nervous system but

prolonged exposure leads to cardiovascular musculoskeletal diseases and even affects the

reproductive system Claude Bernard (1865-1961) observed that the maintenance of life is

essentially dependent on keeping our internal milieu constant in the face of a changing

environment Thus sustaining a state of homeostasis is vital for a healthy life Workplace

stress and depression is on the rise it is the health epidemic of 21 st century a frequently

reported problem According to WHO depression is among the leading causes of disability

globally There is a compelling need to confront the ameliorating and deleterious effects of

stress inflicted on an individual These health risks can be prevented or managed A multi

targeted approach is required to tackle a problem as severe as stress It can be controlled in

the healthy way by nourishing and stimulating the gut microbes in our body to act on the

brain which increases the release of neurotransmitters to help relieve the effects of stress

Nutrient supplements referred to as nutraceuticals has been introduced to influence the brain

activity and protect it from the negative impact of stress hormones These nutraceuticals help

to enhance the quality of life by modulating the gut health They prevent the alteration of

microbiome during stress Extensive research has been conducted in the field of gut microbes

and nutraceuticals and their efficacy towards alleviating stress has been proved We are

moving towards the direction of exploring psych biotics as a mode of treatment for anxiety

15

depression and various psychiatric issues However it is a recently introduced term and

research and is still on-going whether it has proven benefits or not Dietary interventions with

food supplements designed to modulate responses to stress that can be administered

effectively Managing stress in the natural way is proven to be the most favorable method

Acknowledgements

The authors are thankful to Chettinad Academy of Research and Education (CARE) for the

support

Conflicts of interest

We declare no conflict of interest All co-authors have agreed to transfer the copyright to the

publisher if it is accepted for publication This study was partially financially supported by

Chettinad Hospital amp Research Institute (CHRI) Chettinad Academy of Research and

Education (CARE) Kelambakkam Chennai-603103 India

16

References

Anderson JW Baird P Davis RH Ferreri S Knutdson M Koraym A Waters V

Williams CL (2009) Health benefits of dietary fibre Nutrition Reviews 67188-205

Andres RH Ducray AD Schlattner U Wallimann T Widmer HR (2008) Functions

and effects of creatine in the central nervous system Brain Research Bulletin 76(4)329-43

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged blueberry-fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2)111-20

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged-blueberry fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2) 111-20

Barrett E Ross RP OToole PW Fitzgerald GF Stanton C (2012) gamma-

Aminobutyric acid production by culturable bacteria from the human intestine Journal of

applied microbiology 113411ndash417

Bazan NG (2005) Lipid signaling in neural plasticity brain repair and neuroprotection

Molecular Neurobiology 32(1)89-103

Bercik P Denou E Collins J Jackson W Lu J Jury J Deng Y Blennerhassett P

Macri J McCoy KD Verdu EF Collins SM (2011) The intestinal microbiota affect

central levels of brain-derived neurotropic factor and behavior in mice Gastroenterology

141599-609

Borre YE OKeeffe GW Clarke G Stanton C Dinan TG Cryan JF (2014)

Microbiota and neurodevelopmental windows implications for brain disorders Trends in

Molecular Medicine 20509-518

Bravo JA Forsythe P Chew MV (2011) Ingestion of Lactobacillus strain regulates

emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

17

communication cognitive skills calcium buffering ability improve movement control and

prevent memory loss Supplements derived from berry fruits like blueberry cranberry

strawberry have been reported to be effective in reversing motor and behavioral deficits and

control sensory inputs These tiny fruits laden with healing properties are referred to as brain

protective fruits berries are rich in bioflavonoids such as anthocyanins and proanthocyanins

both of which are scavengers of free radicals Active phytochemicals present in the blueberry

confer the benefit of being able to cross the blood-brain-barrier Anthocyanins have been

shown to penetrate the brain and their concentrations correspond to appropriate cognitive

performances (Lacueva et al 2005) They upregulate TNF α IL-1β NF-κB and

consequently suppress ageing and improve blood flow to the brain Blueberries are

responsible for reducing expression of stress signals and results in increasing protective

signals and impact cell signalling molecule expression (Shukitt-Hale et al 2008) The

anthocyanins elevate the level of BDNF (Brain derived neurotropic factor) which is crucial to

boost neuronal communication influencing cognitive function Heat shock proteins are

known to fight free radicals and inflammation inducing agents to support healthy brain

tissues The ability to generate heat shock proteins declines with age dramatically However

researchers have found that consumption of blueberries could restore heat shock protein

response and help protect against neurodegeneration processes associated with ageing

Blueberries play an essential role in reducing the toxicity of kainic acid on hippocampal cells

Kainic acid is an amino acid which is naturally abundant in seaweeds and can be neurotoxic

because of its potent ability to stimulate neurons by activating receptors for glutamate This

aminoacid can be induced in laboratory animal models to study various neurodegenerative

disorders

12

PUFAs

Polyunsaturated fatty acids (PUFAs) are critical components of neuronal cell membranes and

are involved in neurotransmitter communication within the neural networks They are

responsible for maintaining membrane fluidity essential synaptic vesicle fusion and serve as

precursors for lipid messengers which participate in signalling processes to promote neuronal

protection (Bazan et al 2005) Flaxseeds fish soybeans walnuts are rich in PUFA

specifically omega- 6 fatty acid linoleic acid omega-3 α linolenic acid

Intake of PUFA supplements for improve cognitive function

In most neurological conditions inflammation manifests in the nervous tissue and this

inflammation is a therapeutic target by the pharmaceutical industries During high levels of

stress the body cannot regulate an inflammatory response which leads to a greater risk of

development of other diseases Anti-inflammatory agents containing nutraceuticals is the

focus of development Oxymatrine derived from the root of a Chinese herb Sophora

flavescens has been reported to have anti-inflammatory actions and decreases damage

observed after hypoxic- ischaemic brain injury in neonatal rat models (Zhao et al 2015)

Apocynin obtained from the root of Picrorhiza kurroa is also believed to have anti-

inflammatory properties and attenuate the cholesterol oxidation product induced apoptosis in

neuronal cells by preventing production of reactive oxygen species (Simonyi et al 2012)

Quercetin known to be found in vegetables fruits have antioxidant effects regulate proteins

transcription factors and kinase dependent signalling pathways Nutraceutical additive actions

of quercetin expedite optimal delivery and improve brain activity Naturally occurring 7 8-

dihydroxyflavone rescues cognition deficits and serve as a novel treatment for autism and

schizophrenia Trans-resveratrol and pterostilbene are plant derived synergistic phytonutrients

improving brain health and having diverse actions against oxidative stress (Poulose et al

2015) Creatine is a natural substance when taken as supplements in recommended dose is

13

beneficial to enhance brain function and improve cognitive function (Wallimann 2008) (Table

1)

Management of stress

Nutrient supplements have the potential to overcome the debilitating effects of stress They

act as prophylactic and therapeutic agents and are more efficient and safe in comparison to

pharmaceutical drugs (Pandey et al 2010) Botanically derived ingredients are used to treat

mild depression anxiety improve sleep patterns and maintain good health Since a persistent

level of cortisol in circulation is the chief cause of depression and stress naturally derived

products target this hormone to annihilate the stress factors and boost mental health and

cognition Researchers have studied the effects of probiotics against stress in a zebrafish

model by introducing the bacterial strain Lactobacillus plantarum into the tank (Davis et al

2016) The objective is to bring the body back to homeostasis maintaining a balanced level

of cortisol The actions of gut microbes and nutraceuticals work interdependently to help

reduce the dangerous outcomes of stress upon the body Experiments with germ free mice

have been used to probe the role of microbiota in adult hippocampal neurogenesis Also

disruptions of gut microbiome induced mice behaviour resulted in anxiety depression and

even autism Gut microbes are the key modulators of brain plasticity cognitive functions and

help to optimize the bodyrsquos response to stress by regulating their synthesis of

neurotransmitters like serotonin to lower the cortisol level Studies have shown that during

stress there is an increased population of certain bacterial strains in the gut such as

Enterobacteriaceae Proteobacteria Actinobacteria and this can be controlled by increasing

the administration of probiotics containing Lactobacillus and Bifidobacterium species

Experiments have been conducted with Bifidobacterium longum and results showed that this

strain was able to reverse hippocampal and BDNF abnormalities

14

CONCLUSION

In today lsquos ambitious world so much importance is being given to performance perfection

competition that it leads to an insidious increase in stress depression anxiety Stress is a

psychological issue which predisposes a person to various other ailments It is inevitable in

the life of any individual but the duration and intensity differs According to Hans Selye who

coined the term stress in 1936 it is the non- specific response of the body to any demand for

change Stress levels are rising worldwide it is a top health concern The damages that can be

caused by stress are often underestimated It primarily affects the nervous system but

prolonged exposure leads to cardiovascular musculoskeletal diseases and even affects the

reproductive system Claude Bernard (1865-1961) observed that the maintenance of life is

essentially dependent on keeping our internal milieu constant in the face of a changing

environment Thus sustaining a state of homeostasis is vital for a healthy life Workplace

stress and depression is on the rise it is the health epidemic of 21 st century a frequently

reported problem According to WHO depression is among the leading causes of disability

globally There is a compelling need to confront the ameliorating and deleterious effects of

stress inflicted on an individual These health risks can be prevented or managed A multi

targeted approach is required to tackle a problem as severe as stress It can be controlled in

the healthy way by nourishing and stimulating the gut microbes in our body to act on the

brain which increases the release of neurotransmitters to help relieve the effects of stress

Nutrient supplements referred to as nutraceuticals has been introduced to influence the brain

activity and protect it from the negative impact of stress hormones These nutraceuticals help

to enhance the quality of life by modulating the gut health They prevent the alteration of

microbiome during stress Extensive research has been conducted in the field of gut microbes

and nutraceuticals and their efficacy towards alleviating stress has been proved We are

moving towards the direction of exploring psych biotics as a mode of treatment for anxiety

15

depression and various psychiatric issues However it is a recently introduced term and

research and is still on-going whether it has proven benefits or not Dietary interventions with

food supplements designed to modulate responses to stress that can be administered

effectively Managing stress in the natural way is proven to be the most favorable method

Acknowledgements

The authors are thankful to Chettinad Academy of Research and Education (CARE) for the

support

Conflicts of interest

We declare no conflict of interest All co-authors have agreed to transfer the copyright to the

publisher if it is accepted for publication This study was partially financially supported by

Chettinad Hospital amp Research Institute (CHRI) Chettinad Academy of Research and

Education (CARE) Kelambakkam Chennai-603103 India

16

References

Anderson JW Baird P Davis RH Ferreri S Knutdson M Koraym A Waters V

Williams CL (2009) Health benefits of dietary fibre Nutrition Reviews 67188-205

Andres RH Ducray AD Schlattner U Wallimann T Widmer HR (2008) Functions

and effects of creatine in the central nervous system Brain Research Bulletin 76(4)329-43

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged blueberry-fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2)111-20

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged-blueberry fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2) 111-20

Barrett E Ross RP OToole PW Fitzgerald GF Stanton C (2012) gamma-

Aminobutyric acid production by culturable bacteria from the human intestine Journal of

applied microbiology 113411ndash417

Bazan NG (2005) Lipid signaling in neural plasticity brain repair and neuroprotection

Molecular Neurobiology 32(1)89-103

Bercik P Denou E Collins J Jackson W Lu J Jury J Deng Y Blennerhassett P

Macri J McCoy KD Verdu EF Collins SM (2011) The intestinal microbiota affect

central levels of brain-derived neurotropic factor and behavior in mice Gastroenterology

141599-609

Borre YE OKeeffe GW Clarke G Stanton C Dinan TG Cryan JF (2014)

Microbiota and neurodevelopmental windows implications for brain disorders Trends in

Molecular Medicine 20509-518

Bravo JA Forsythe P Chew MV (2011) Ingestion of Lactobacillus strain regulates

emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

17

PUFAs

Polyunsaturated fatty acids (PUFAs) are critical components of neuronal cell membranes and

are involved in neurotransmitter communication within the neural networks They are

responsible for maintaining membrane fluidity essential synaptic vesicle fusion and serve as

precursors for lipid messengers which participate in signalling processes to promote neuronal

protection (Bazan et al 2005) Flaxseeds fish soybeans walnuts are rich in PUFA

specifically omega- 6 fatty acid linoleic acid omega-3 α linolenic acid

Intake of PUFA supplements for improve cognitive function

In most neurological conditions inflammation manifests in the nervous tissue and this

inflammation is a therapeutic target by the pharmaceutical industries During high levels of

stress the body cannot regulate an inflammatory response which leads to a greater risk of

development of other diseases Anti-inflammatory agents containing nutraceuticals is the

focus of development Oxymatrine derived from the root of a Chinese herb Sophora

flavescens has been reported to have anti-inflammatory actions and decreases damage

observed after hypoxic- ischaemic brain injury in neonatal rat models (Zhao et al 2015)

Apocynin obtained from the root of Picrorhiza kurroa is also believed to have anti-

inflammatory properties and attenuate the cholesterol oxidation product induced apoptosis in

neuronal cells by preventing production of reactive oxygen species (Simonyi et al 2012)

Quercetin known to be found in vegetables fruits have antioxidant effects regulate proteins

transcription factors and kinase dependent signalling pathways Nutraceutical additive actions

of quercetin expedite optimal delivery and improve brain activity Naturally occurring 7 8-

dihydroxyflavone rescues cognition deficits and serve as a novel treatment for autism and

schizophrenia Trans-resveratrol and pterostilbene are plant derived synergistic phytonutrients

improving brain health and having diverse actions against oxidative stress (Poulose et al

2015) Creatine is a natural substance when taken as supplements in recommended dose is

13

beneficial to enhance brain function and improve cognitive function (Wallimann 2008) (Table

1)

Management of stress

Nutrient supplements have the potential to overcome the debilitating effects of stress They

act as prophylactic and therapeutic agents and are more efficient and safe in comparison to

pharmaceutical drugs (Pandey et al 2010) Botanically derived ingredients are used to treat

mild depression anxiety improve sleep patterns and maintain good health Since a persistent

level of cortisol in circulation is the chief cause of depression and stress naturally derived

products target this hormone to annihilate the stress factors and boost mental health and

cognition Researchers have studied the effects of probiotics against stress in a zebrafish

model by introducing the bacterial strain Lactobacillus plantarum into the tank (Davis et al

2016) The objective is to bring the body back to homeostasis maintaining a balanced level

of cortisol The actions of gut microbes and nutraceuticals work interdependently to help

reduce the dangerous outcomes of stress upon the body Experiments with germ free mice

have been used to probe the role of microbiota in adult hippocampal neurogenesis Also

disruptions of gut microbiome induced mice behaviour resulted in anxiety depression and

even autism Gut microbes are the key modulators of brain plasticity cognitive functions and

help to optimize the bodyrsquos response to stress by regulating their synthesis of

neurotransmitters like serotonin to lower the cortisol level Studies have shown that during

stress there is an increased population of certain bacterial strains in the gut such as

Enterobacteriaceae Proteobacteria Actinobacteria and this can be controlled by increasing

the administration of probiotics containing Lactobacillus and Bifidobacterium species

Experiments have been conducted with Bifidobacterium longum and results showed that this

strain was able to reverse hippocampal and BDNF abnormalities

14

CONCLUSION

In today lsquos ambitious world so much importance is being given to performance perfection

competition that it leads to an insidious increase in stress depression anxiety Stress is a

psychological issue which predisposes a person to various other ailments It is inevitable in

the life of any individual but the duration and intensity differs According to Hans Selye who

coined the term stress in 1936 it is the non- specific response of the body to any demand for

change Stress levels are rising worldwide it is a top health concern The damages that can be

caused by stress are often underestimated It primarily affects the nervous system but

prolonged exposure leads to cardiovascular musculoskeletal diseases and even affects the

reproductive system Claude Bernard (1865-1961) observed that the maintenance of life is

essentially dependent on keeping our internal milieu constant in the face of a changing

environment Thus sustaining a state of homeostasis is vital for a healthy life Workplace

stress and depression is on the rise it is the health epidemic of 21 st century a frequently

reported problem According to WHO depression is among the leading causes of disability

globally There is a compelling need to confront the ameliorating and deleterious effects of

stress inflicted on an individual These health risks can be prevented or managed A multi

targeted approach is required to tackle a problem as severe as stress It can be controlled in

the healthy way by nourishing and stimulating the gut microbes in our body to act on the

brain which increases the release of neurotransmitters to help relieve the effects of stress

Nutrient supplements referred to as nutraceuticals has been introduced to influence the brain

activity and protect it from the negative impact of stress hormones These nutraceuticals help

to enhance the quality of life by modulating the gut health They prevent the alteration of

microbiome during stress Extensive research has been conducted in the field of gut microbes

and nutraceuticals and their efficacy towards alleviating stress has been proved We are

moving towards the direction of exploring psych biotics as a mode of treatment for anxiety

15

depression and various psychiatric issues However it is a recently introduced term and

research and is still on-going whether it has proven benefits or not Dietary interventions with

food supplements designed to modulate responses to stress that can be administered

effectively Managing stress in the natural way is proven to be the most favorable method

Acknowledgements

The authors are thankful to Chettinad Academy of Research and Education (CARE) for the

support

Conflicts of interest

We declare no conflict of interest All co-authors have agreed to transfer the copyright to the

publisher if it is accepted for publication This study was partially financially supported by

Chettinad Hospital amp Research Institute (CHRI) Chettinad Academy of Research and

Education (CARE) Kelambakkam Chennai-603103 India

16

References

Anderson JW Baird P Davis RH Ferreri S Knutdson M Koraym A Waters V

Williams CL (2009) Health benefits of dietary fibre Nutrition Reviews 67188-205

Andres RH Ducray AD Schlattner U Wallimann T Widmer HR (2008) Functions

and effects of creatine in the central nervous system Brain Research Bulletin 76(4)329-43

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged blueberry-fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2)111-20

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged-blueberry fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2) 111-20

Barrett E Ross RP OToole PW Fitzgerald GF Stanton C (2012) gamma-

Aminobutyric acid production by culturable bacteria from the human intestine Journal of

applied microbiology 113411ndash417

Bazan NG (2005) Lipid signaling in neural plasticity brain repair and neuroprotection

Molecular Neurobiology 32(1)89-103

Bercik P Denou E Collins J Jackson W Lu J Jury J Deng Y Blennerhassett P

Macri J McCoy KD Verdu EF Collins SM (2011) The intestinal microbiota affect

central levels of brain-derived neurotropic factor and behavior in mice Gastroenterology

141599-609

Borre YE OKeeffe GW Clarke G Stanton C Dinan TG Cryan JF (2014)

Microbiota and neurodevelopmental windows implications for brain disorders Trends in

Molecular Medicine 20509-518

Bravo JA Forsythe P Chew MV (2011) Ingestion of Lactobacillus strain regulates

emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

17

beneficial to enhance brain function and improve cognitive function (Wallimann 2008) (Table

1)

Management of stress

Nutrient supplements have the potential to overcome the debilitating effects of stress They

act as prophylactic and therapeutic agents and are more efficient and safe in comparison to

pharmaceutical drugs (Pandey et al 2010) Botanically derived ingredients are used to treat

mild depression anxiety improve sleep patterns and maintain good health Since a persistent

level of cortisol in circulation is the chief cause of depression and stress naturally derived

products target this hormone to annihilate the stress factors and boost mental health and

cognition Researchers have studied the effects of probiotics against stress in a zebrafish

model by introducing the bacterial strain Lactobacillus plantarum into the tank (Davis et al

2016) The objective is to bring the body back to homeostasis maintaining a balanced level

of cortisol The actions of gut microbes and nutraceuticals work interdependently to help

reduce the dangerous outcomes of stress upon the body Experiments with germ free mice

have been used to probe the role of microbiota in adult hippocampal neurogenesis Also

disruptions of gut microbiome induced mice behaviour resulted in anxiety depression and

even autism Gut microbes are the key modulators of brain plasticity cognitive functions and

help to optimize the bodyrsquos response to stress by regulating their synthesis of

neurotransmitters like serotonin to lower the cortisol level Studies have shown that during

stress there is an increased population of certain bacterial strains in the gut such as

Enterobacteriaceae Proteobacteria Actinobacteria and this can be controlled by increasing

the administration of probiotics containing Lactobacillus and Bifidobacterium species

Experiments have been conducted with Bifidobacterium longum and results showed that this

strain was able to reverse hippocampal and BDNF abnormalities

14

CONCLUSION

In today lsquos ambitious world so much importance is being given to performance perfection

competition that it leads to an insidious increase in stress depression anxiety Stress is a

psychological issue which predisposes a person to various other ailments It is inevitable in

the life of any individual but the duration and intensity differs According to Hans Selye who

coined the term stress in 1936 it is the non- specific response of the body to any demand for

change Stress levels are rising worldwide it is a top health concern The damages that can be

caused by stress are often underestimated It primarily affects the nervous system but

prolonged exposure leads to cardiovascular musculoskeletal diseases and even affects the

reproductive system Claude Bernard (1865-1961) observed that the maintenance of life is

essentially dependent on keeping our internal milieu constant in the face of a changing

environment Thus sustaining a state of homeostasis is vital for a healthy life Workplace

stress and depression is on the rise it is the health epidemic of 21 st century a frequently

reported problem According to WHO depression is among the leading causes of disability

globally There is a compelling need to confront the ameliorating and deleterious effects of

stress inflicted on an individual These health risks can be prevented or managed A multi

targeted approach is required to tackle a problem as severe as stress It can be controlled in

the healthy way by nourishing and stimulating the gut microbes in our body to act on the

brain which increases the release of neurotransmitters to help relieve the effects of stress

Nutrient supplements referred to as nutraceuticals has been introduced to influence the brain

activity and protect it from the negative impact of stress hormones These nutraceuticals help

to enhance the quality of life by modulating the gut health They prevent the alteration of

microbiome during stress Extensive research has been conducted in the field of gut microbes

and nutraceuticals and their efficacy towards alleviating stress has been proved We are

moving towards the direction of exploring psych biotics as a mode of treatment for anxiety

15

depression and various psychiatric issues However it is a recently introduced term and

research and is still on-going whether it has proven benefits or not Dietary interventions with

food supplements designed to modulate responses to stress that can be administered

effectively Managing stress in the natural way is proven to be the most favorable method

Acknowledgements

The authors are thankful to Chettinad Academy of Research and Education (CARE) for the

support

Conflicts of interest

We declare no conflict of interest All co-authors have agreed to transfer the copyright to the

publisher if it is accepted for publication This study was partially financially supported by

Chettinad Hospital amp Research Institute (CHRI) Chettinad Academy of Research and

Education (CARE) Kelambakkam Chennai-603103 India

16

References

Anderson JW Baird P Davis RH Ferreri S Knutdson M Koraym A Waters V

Williams CL (2009) Health benefits of dietary fibre Nutrition Reviews 67188-205

Andres RH Ducray AD Schlattner U Wallimann T Widmer HR (2008) Functions

and effects of creatine in the central nervous system Brain Research Bulletin 76(4)329-43

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged blueberry-fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2)111-20

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged-blueberry fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2) 111-20

Barrett E Ross RP OToole PW Fitzgerald GF Stanton C (2012) gamma-

Aminobutyric acid production by culturable bacteria from the human intestine Journal of

applied microbiology 113411ndash417

Bazan NG (2005) Lipid signaling in neural plasticity brain repair and neuroprotection

Molecular Neurobiology 32(1)89-103

Bercik P Denou E Collins J Jackson W Lu J Jury J Deng Y Blennerhassett P

Macri J McCoy KD Verdu EF Collins SM (2011) The intestinal microbiota affect

central levels of brain-derived neurotropic factor and behavior in mice Gastroenterology

141599-609

Borre YE OKeeffe GW Clarke G Stanton C Dinan TG Cryan JF (2014)

Microbiota and neurodevelopmental windows implications for brain disorders Trends in

Molecular Medicine 20509-518

Bravo JA Forsythe P Chew MV (2011) Ingestion of Lactobacillus strain regulates

emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

17

CONCLUSION

In today lsquos ambitious world so much importance is being given to performance perfection

competition that it leads to an insidious increase in stress depression anxiety Stress is a

psychological issue which predisposes a person to various other ailments It is inevitable in

the life of any individual but the duration and intensity differs According to Hans Selye who

coined the term stress in 1936 it is the non- specific response of the body to any demand for

change Stress levels are rising worldwide it is a top health concern The damages that can be

caused by stress are often underestimated It primarily affects the nervous system but

prolonged exposure leads to cardiovascular musculoskeletal diseases and even affects the

reproductive system Claude Bernard (1865-1961) observed that the maintenance of life is

essentially dependent on keeping our internal milieu constant in the face of a changing

environment Thus sustaining a state of homeostasis is vital for a healthy life Workplace

stress and depression is on the rise it is the health epidemic of 21 st century a frequently

reported problem According to WHO depression is among the leading causes of disability

globally There is a compelling need to confront the ameliorating and deleterious effects of

stress inflicted on an individual These health risks can be prevented or managed A multi

targeted approach is required to tackle a problem as severe as stress It can be controlled in

the healthy way by nourishing and stimulating the gut microbes in our body to act on the

brain which increases the release of neurotransmitters to help relieve the effects of stress

Nutrient supplements referred to as nutraceuticals has been introduced to influence the brain

activity and protect it from the negative impact of stress hormones These nutraceuticals help

to enhance the quality of life by modulating the gut health They prevent the alteration of

microbiome during stress Extensive research has been conducted in the field of gut microbes

and nutraceuticals and their efficacy towards alleviating stress has been proved We are

moving towards the direction of exploring psych biotics as a mode of treatment for anxiety

15

depression and various psychiatric issues However it is a recently introduced term and

research and is still on-going whether it has proven benefits or not Dietary interventions with

food supplements designed to modulate responses to stress that can be administered

effectively Managing stress in the natural way is proven to be the most favorable method

Acknowledgements

The authors are thankful to Chettinad Academy of Research and Education (CARE) for the

support

Conflicts of interest

We declare no conflict of interest All co-authors have agreed to transfer the copyright to the

publisher if it is accepted for publication This study was partially financially supported by

Chettinad Hospital amp Research Institute (CHRI) Chettinad Academy of Research and

Education (CARE) Kelambakkam Chennai-603103 India

16

References

Anderson JW Baird P Davis RH Ferreri S Knutdson M Koraym A Waters V

Williams CL (2009) Health benefits of dietary fibre Nutrition Reviews 67188-205

Andres RH Ducray AD Schlattner U Wallimann T Widmer HR (2008) Functions

and effects of creatine in the central nervous system Brain Research Bulletin 76(4)329-43

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged blueberry-fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2)111-20

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged-blueberry fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2) 111-20

Barrett E Ross RP OToole PW Fitzgerald GF Stanton C (2012) gamma-

Aminobutyric acid production by culturable bacteria from the human intestine Journal of

applied microbiology 113411ndash417

Bazan NG (2005) Lipid signaling in neural plasticity brain repair and neuroprotection

Molecular Neurobiology 32(1)89-103

Bercik P Denou E Collins J Jackson W Lu J Jury J Deng Y Blennerhassett P

Macri J McCoy KD Verdu EF Collins SM (2011) The intestinal microbiota affect

central levels of brain-derived neurotropic factor and behavior in mice Gastroenterology

141599-609

Borre YE OKeeffe GW Clarke G Stanton C Dinan TG Cryan JF (2014)

Microbiota and neurodevelopmental windows implications for brain disorders Trends in

Molecular Medicine 20509-518

Bravo JA Forsythe P Chew MV (2011) Ingestion of Lactobacillus strain regulates

emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

17

depression and various psychiatric issues However it is a recently introduced term and

research and is still on-going whether it has proven benefits or not Dietary interventions with

food supplements designed to modulate responses to stress that can be administered

effectively Managing stress in the natural way is proven to be the most favorable method

Acknowledgements

The authors are thankful to Chettinad Academy of Research and Education (CARE) for the

support

Conflicts of interest

We declare no conflict of interest All co-authors have agreed to transfer the copyright to the

publisher if it is accepted for publication This study was partially financially supported by

Chettinad Hospital amp Research Institute (CHRI) Chettinad Academy of Research and

Education (CARE) Kelambakkam Chennai-603103 India

16

References

Anderson JW Baird P Davis RH Ferreri S Knutdson M Koraym A Waters V

Williams CL (2009) Health benefits of dietary fibre Nutrition Reviews 67188-205

Andres RH Ducray AD Schlattner U Wallimann T Widmer HR (2008) Functions

and effects of creatine in the central nervous system Brain Research Bulletin 76(4)329-43

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged blueberry-fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2)111-20

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged-blueberry fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2) 111-20

Barrett E Ross RP OToole PW Fitzgerald GF Stanton C (2012) gamma-

Aminobutyric acid production by culturable bacteria from the human intestine Journal of

applied microbiology 113411ndash417

Bazan NG (2005) Lipid signaling in neural plasticity brain repair and neuroprotection

Molecular Neurobiology 32(1)89-103

Bercik P Denou E Collins J Jackson W Lu J Jury J Deng Y Blennerhassett P

Macri J McCoy KD Verdu EF Collins SM (2011) The intestinal microbiota affect

central levels of brain-derived neurotropic factor and behavior in mice Gastroenterology

141599-609

Borre YE OKeeffe GW Clarke G Stanton C Dinan TG Cryan JF (2014)

Microbiota and neurodevelopmental windows implications for brain disorders Trends in

Molecular Medicine 20509-518

Bravo JA Forsythe P Chew MV (2011) Ingestion of Lactobacillus strain regulates

emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

17

References

Anderson JW Baird P Davis RH Ferreri S Knutdson M Koraym A Waters V

Williams CL (2009) Health benefits of dietary fibre Nutrition Reviews 67188-205

Andres RH Ducray AD Schlattner U Wallimann T Widmer HR (2008) Functions

and effects of creatine in the central nervous system Brain Research Bulletin 76(4)329-43

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged blueberry-fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2)111-20

Andres-Lacueva C Shukitt-Hale B Galli RL Jauregui O Lamuela-Raventos

RM Joseph JA (2005) Anthocyanins in aged-blueberry fed rats are found centrally and

may enhance memory Nutritional Neuroscience 8(2) 111-20

Barrett E Ross RP OToole PW Fitzgerald GF Stanton C (2012) gamma-

Aminobutyric acid production by culturable bacteria from the human intestine Journal of

applied microbiology 113411ndash417

Bazan NG (2005) Lipid signaling in neural plasticity brain repair and neuroprotection

Molecular Neurobiology 32(1)89-103

Bercik P Denou E Collins J Jackson W Lu J Jury J Deng Y Blennerhassett P

Macri J McCoy KD Verdu EF Collins SM (2011) The intestinal microbiota affect

central levels of brain-derived neurotropic factor and behavior in mice Gastroenterology

141599-609

Borre YE OKeeffe GW Clarke G Stanton C Dinan TG Cryan JF (2014)

Microbiota and neurodevelopmental windows implications for brain disorders Trends in

Molecular Medicine 20509-518

Bravo JA Forsythe P Chew MV (2011) Ingestion of Lactobacillus strain regulates

emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

17

Proceedings of the National Academy of Sciences of the United States of America 10816050-

16055

Brianna B Andrew WH Benschoten V Cimermancic P Donia MS Zimmermann

M Taketani M Ishihara A Kashyap PC Fraser JS Fischbach MA (2014)

Discovery and characterization of gut microbiota decarboxylases that can produce the

neurotransmitter tryptamine Cell Host Microbe 16(4)495ndash503

Catanzaro R Anzalone M G Calabrese F Milazzo M Capuana M L Italia A

Occhipinti S Marotta FThe gut microbiota and its correlations with the central nervous

system disordersPanminerva Medica 2015 57(3)127-43

Collinder E Lindholm A Midtvedt T Norin E (1998) The usefulness of microbial-

associated characteristics (MACs) for studies of microbial intestinal functions in different

species Microbial Ecology in Health and Disease 10203ndash4

Cryan JF Dinan TG (2012) Mind-altering microorganisms the impact of the gut

microbiota on brain and behaviour Nature Reviews Neuroscience 13701ndash712

Davis DJ Doerr HM Grzelak AK Busi SB Jasarevic E Ericsson AC Bryda

EC (2016) Lactobacillus plantarum attenuates anxiety-related behavior and protects

against stress-induced dysbiosis in adult zebrafish Scientific Reports 633726

Devkota S Wang Y Musch MW Leone V Fehlner-Peach H Nadimpalli

A Antonopoulos DA Jabri B Chang EB (2012) Dietary-fat-induced taurocholic acid

promotes pathobiont expansion and colitis in Il10-- mice Nature 487(7405)104-8

Duthie GG Gardner PT Kyle JAM (2003) Plant polyphenols are they the new magic

bullet Proceedings of the Nutrition Society 62599-603

Eckburg PB Bik EM Bernstein CN Purdom E Dethlefsen L Sargent M Gill

SR Nelson KE Relman DA (2005) Diversity of the human intestinal microbial flora

Science 3081635-1638

18

Forsythe P Bienenstock J Kunze WA (2014) Vagal pathways for microbiome-brain-gut

axis communication Advances in experimental medicine and biology 817115-133

Foster JA Neufeld KA (2013) Gut-brain axis how the microbiome influences anxiety

and depression Trends in neurosciences 36305-312

Gibson GR Roberfroid MB (1995) Dietary modulation of the human colonic microbiota

introducing the concept of prebiotics Journal of Nutrition 1251401-1412

Gould E McEwen BS Tanapat P Galea LA Fuchs E (1997) Neurogenesis in the

dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor

activation Journal of Neurosciences 172492-2498

Gould E Tanapat P (1999) Stress and hippocampal neurogenesis Biological Psychiatry

461472ndash1479

Homayouni RadA Mehrban Roudbaneh M Ghasemnezhad TabrizianV JavadiM

HaratiN Homayouni RadH and KasaieZ Chocolate as a Probiotic carrier food ndash A

ReviewInternational Journal of Probiotics and Prebiotics 37-42 2016

Heijtz DR Wang S Anuar F Qian Y Bjoumlrkholm B Samuelsson A Hibberd ML

Forssberg H Pettersson S (2011) Normal gut microbiota modulates brain development

and behavior Proceedings of the National Academy of Sciences of the United States of

America 1083047-3052

Kimura M SirilunS ChaiyasutSIsolation of an efficient Lactobacillus pentosus strain

capable of stimulating lymphoid cells to produce IL-10International Journal of Probiotics

and Prebiotics 1277-82 2017

Lagace DC Donovan MH DeCarolis NA Farnbauch LA Malhotra S Berton

O Nestler EJ Krishnan V Eisch AJ (2010) Adult hippocampal neurogenesis is

functionally important for stress-induced social avoidance Proceedings of the National

Academy of Sciences of the United States of America 107(9)4436-41

19

Li TSC (2008) Vegetables and Fruits Nutritional and Therapeutic Values (Taylor and

Francis Group Boca Raton Fla USA) Vol 169 195 198

Lyte M (2013) Microbial endocrinology in the microbiome-gut-brain axis how bacterial

production and utilization of neurochemicals influence behaviour PLoS pathogens 9

e1003726

Maddi VS Aragade PD Digge VG Nitaliker MN (2007) Importance of

nutraceuticals in health management Pharmacognosy Reviews 1377-379

Malik A (2008) The potentials of Nutraceuticals Pharmainfonet 6

Pandey M Verma RK Saraf SA (2010) Nutraceuticals new era of medicine and health

Asian Journal of Pharmaceutical and Clinical Research 311-15

Pepping J (1999) Omega-3 essential fatty acids American Journal of Health-System

Pharmacy 56719-724

Poulose SM Thangthaeng N Miller MG Shukitt-Hale B (2015) Effects of

pterostilbene and resveratrol on brain and behavior Neurochemistry International 89227-

233

Ravinder Nagpal Hariom Yadav Francesco MarottaGut Microbiota The Next-Gen Frontier

in Preventive and Therapeutic Medicine Front Med (Lausanne) 2014 1 15

Rishi RK (2006) Nutraceuticals borderline between food and drug Pharmacological

Reviews pp 51-53

Shukitt-Hale B Lau FC Carey AN Galli RL Spangler EL Ingram DK Joseph

JA (2008) Blueberry polyphenols attenuate kainic acid-induced decrements in cognition

and alter inflammatory gene expression in rat hippocampus Nutritional Neuroscience

11(4)172-82

Simonyi A Serfozo P Lehmidi TM Cui J Gu Z Lubahn DB Sun AY Sun GY

(2012) The neuroprotective effects of apocynin Frontiers in Bioscience 42183-2193

20

Wall R Cryan JF Ross RP Fitzgerald GF Dinan TG Stanton C (2014) Bacterial

neuroactive compounds produced by psychobiotics Advances in Experimental Medicine and

Biology 817221-39

Takadanohara H Catanzaro R Chui de H He F Yadav H Ganguli A Sakata Y Solimene U

Minelli E Kobayashi R Nagamachi Y Marotta FBeneficial effect of a symbiotic preparation

with S boulardii lysate in mild stress-induced gut hyper-permeability Acta Biomed 2012 8

3(3)208-16

Zhao LR Navalitloha Y Singhal S Mehta J Piao CS Guo WP Kessler JA

Groothuis DR (2007) Hematopoietic growth factors pass through the blood-brain barrier in

intact rats Experimental neurology 204569ndash573

Zhao P Zhou R Zhu XY Hao YJ Li N Wang J Niu Y Sun T Li YX Yu

JQ (2015) Matrine attenuates focal cerebral ischemic injury by improving antioxidant

activity and inhibiting apoptosis in mice International Journal of Molecular Medicine

36(3)633-44

Zucchi R Chiellini G Scanlan TS Grandy DK (2006) Trace amine associated

receptors and their ligands British Journal of Pharmacology 149967ndash978

Figure legends

Figure 1 Schematic representation of various factors that affect the intestinal gut microbes

Figure 2 Description of the bidirectional gut-brain communication

Figure 3 Schematic diagram displays the effect of chronic stress on the brain characteristic

of increased cortisol levels

Figure 4 Foods rich in antioxidants

21

Table 1 Herbal supplements and their applications

Herbal supplements Applications

Ginseng sp Popular herbal medicine induce calmness lower inflammation

levels

Valeriana officinalis Anti-anxiety

Hypericum perforatum Anti-depression effect

Rhodiola rosea Reduces moderate depression

Melissa officinalis Anti-anxiety

22

• Coping with Stress related effects on the Brain ndash Role of Neuro-nutraceuticals and Gut microbes
• Pathak S1 Suhanya P1 Sushmitha S1 Murugesan R1 Fang He2 Marotta F3 Banerjee A1
• Authorsrsquo Affiliations
• 1 Department of Allied Health Sciences Chettinad Hospital amp Research Institute (CHRI) Chettinad Academy of Research and Education (CARE) Kelambakkam Chennai-603103 India
• 2 Department of Nutrition and Food Hygiene West China School of Public Health Sichuan University China
• 3 ReGenera RampD International for Aging Intervention Milano Italy and San Babila Clinic Healthy Aging Unit by Genomics and Biotechnology Milano Italy
• Corresponding Author Antara Banerjee Chettinad Hospital amp Research Institute (CHRI) Chettinad Academy of Research and Education (CARE) Kelambakkam Chennai-603103 India E-mail antarabanerjee27gmailcom Contact +91 9566072596
• Francesco Marotta ReGenera RampD International for Aging Intervention Milano Italy and San Babila Clinic Healthy Aging Unit by Genomics and Biotechnology Milano Italy
• Email fmarchimedeliberoit
• Number of pages in manuscript 20
• Number of figures (Black and white) 4
• Number of tables 1
• Keywords Brain development depression gut microbes hippocampus nutraceuticals stress
• Running title Role of nutraceuticals in brain
• Abstract
• Human brain is the control system of body which helps in coordinating the function of every organ and maintaining homeostasis A functioning brain receives information from the body and interprets information guiding the bodyrsquos response to it There is found to be an interaction between the brain and the intestinal flora of the body Apart from known benefits of microbes such as digestion and host defense the gut microbiome also impacts mental health Stress is being the major cause of occurrence of various mental health problems Neuroinflammation and neurodegeneration are the pathophysiological implications of stress as it disturbs the generation of neurons Gut microbes have been found to help ease the effects of stress such as anxiety depression but there is a negative consequence of their composition being altered in case of chronic stress or emotional trauma Specific food supplements maintain the gut population as well as protects the brain from stress induced debilitating effects Nutraceuticals synthesized to nutrify the microbiome and influence cognitive functions and development of brain can be referred as neuro-nutraceuticals This review aims to highlight the multi-targeted action of nutraceuticals and gut-microbiota upon brain during stress and their specific effects on normal brain functioning and development
• INTRODUCTION
• Gut Microbiome
• Every individual being is host to a diverse population of microbial organisms with varying complexity About a 100 trillion (1014) microbes is present which is equivalent to 1011-1012 cellsg colonic content with a biomass of gt1 kg This includes close to over 500 different species (Eckburg et al 2005) These microbes are in a symbiotic relationship of mutualism with the host and maintain a state of homeostasis with the hostrsquos immune system The gut microbe is distinct for each individual depending on age geographic location diet medication host related factors They are also found to differ within the same individual according to the body niche Predominantly anaerobes make up the population of microbes in the host The oral cavity contains a complex population of anaerobes such as Bifidobacteria Bacteroides Leptotrichia Propionibacteria Fusobacteria Veillonella and Peptostreptococci Anaerobes like Propionibacteria along with aerobes such as Staphylococci and Coryne bacteria reside on the skin The stomach region has gram positive aerobes like Lactobacillus Helicobacter pylori and Streptococci Likewise the composition varies for the intestinal regions and vagina The microflora acquire nutrients like dietary fibres starch oligosaccharides sugars lipids proteins from the host intestinal tract and endogenous mucins sloughed epithelial enterocyte tissues bile acids and cholesterol Experimental studies using germ-free mice have demonstrated the relevance of commensal microbial organisms in normal physiological and metabolic activities Deregulation in the gut microbial communities has resulted in various health implications Human gut microbiome is the focal point of research impacting the functional aspects of the human body and can be exploited for their potential therapeutic effects (Ravinder Nagpal et al2014)Change in the diet can bring about a major transformation in the gut microbiota The various other disruptive factors which impact the hostrsquos normal flora include use of antibiotics immune suppression stress pathological condition and surgery (Figure 1)
• Microbiome characteristics
• The functions performed by the microbiota are referred to as microflora associated characteristics (MAC) by various researchers (Collinder et al 1998) Among several functions the important ones include digestion of metabolite substrates vitamin K and B production drug metabolism mucosal cell development stimulation of immune system protection against pathogenic organisms where it has been found to induce antimicrobial proteins such as cathelicidins C-type lectins and (pro) defensins The microbial gene products impact the metabolism and health status of the host Recent research findings on the interaction of gut microbiome and the brain have paved the way for more in-depth studies on understanding the impact of these simple microbes on the complex distant organ the brain thereby transforming neurosciences opening frontiers for therapeutic strategies for neurodevelopment disorders
• Gut-brain signalling
• There is increasing evidence of the critical role played by gut microflora in neuro and immune modulatory functions during development and adulthood The normal microbiota is responsible for synaptogenesis to occur and its absence denotes behavioral and histopathological abnormalities (Cryan et al 2012) A homeostatic communication is maintained between the brain and the gut intraluminal milieu through various signals including neural hormonal and immunological A more recent observation has been the pathogenesis of several Central nervous system disorders correlated with a perturbed gut-microbiota population (Catanzaro R et al2015)During infancy there are innumerable synaptic connections which provide the essential substrate for functional brain activities such as cognition perception and action A study shows that the commensal microbiota is necessary for the development of brain (Heijtz et al 2011) The authors hypothesized that gut microbiota modulates synaptogenesis Intestinal microorganisms are also critical for activation of systemic immunity They regulate the function of macrophages that reside in the lamina propria of the intestine The pathways that link the intestinal flora to the brain are (1) Via the activation of the vagus nerve from mature enteric nervous system (ENS) to central nervous system (CNS) (Forsythe et al 2014) (2) Through circulatory system various metabolites pass through intestine barriers and then across the blood brain barrier to regulate neurological function (3) Via immune cells- Microbe associated molecular pattern (MAMPPAMPs) such as bacterial lipoprotein lipopolysaccharide and polysaccharide A Signals are sent to brain through cytokines like dendritic cells macrophages T cells and B cells
• Microbiota mediated alterations in behaviour and mood
• The intestinal microbes send signals affecting the hypothalamic-pituitary-adrenal axis (HPA) which reveals a bidirectional communication system between the host gut and brain (Figure 2) There are a high proportion of neurotransmitters in the gut which have the potential to modulate activity of vagus nerve which is the primary nerve connecting enteric nervous system to CNS and subsequently influence brain function (Bravo et al 2011) During fetal development the microbiota plays a crucial role in programming the phenotype they influence the levels of serotonin (5-HT 5 hydroxy tryptamine) BDNF (Brain derived neurotropic factor) in regions of Amygdala and Hippocampus These factors play a regulatory role in neurogenesis and synaptic plasticity
• BDNF is a protein encoded by BDNF gene important for long term memory helps support survival of existing neurons and encourage growth and differentiation of new neurons generation of synapses The symbiotic organisms residing in the GI tract largely affect the production and regulation of its function Reduced levels of BDNF are seen in neurological conditions like schizophrenia depression Alzheimerrsquos mood disorders like anxiety and epilepsy (Foster et al 2013)
• Serotonin is a monoamine neurotransmitter acquired from the amino acid tryptophan It is responsible for the well-being regulation of mood sleep and cognitive functions Deficit of serotonin causes depression 5-HT synthesis requires tryptophan and this is generated by the intestinal microbiota which can cross the blood brain barrier for the synthesis Neurophysiology can be changed by actions of the microbiome such as by altering the permeability of blood brain barrier allowing flux of metabolites into and out of the brain (Bercik et al 2014) In absence of microbes there is a decreased level of neurotransmitters such as dopamine and GABA Specific intestinal bacteria produce small molecules such as serotonin dopamine epinephrine and norepinephrine (Wall et al 2014 Lyte et al 2013)
• Mechanism of action
• The microbes send signals to enterochromaffin cells which produce neurotransmitters and enteric neurons glia The decarboxylation of the amino acid tryptophan by neurotransmitter tryptamine is initiated by specific microbes residing in the namely Clostridium sporogenes and Ruminococccus gnavus (Williams et al 2014) In the brain tryptamine a monoamine alkaloid is a non-selective serotonin receptor agonist which plays an inhibitory role in the response to serotonin and modulate mood and appetite (Zucchi et al 2006) while in the gut tryptamine can also induce enterochromaffin cells to release 5-HT The gut microbiota is also responsible for release of another neuromodulator tyramine which has higher affinity for TAAR1 receptor found in the brain Lactic acid bacteria such as Lbrevis and enterococcus species act locally via vagus nerve via the periphery (Barett et al 2012)
• Studies have shown that microbiota derived signals can induce non-inflammatory cytokine pathways For instance the plasma G-CSF can cross the blood brain barrier and acts to stimulate neurogenesis in the brain (Zhao et al 2007) Through G-CSF production the microbiota influences the rate of neurogenesis
• With the knowledge of the important role played by microbes in neurological activities research studies and findings progress towards maintaining this rich microbiota and stimulating them to contribute to the host a positive effect Dietary macronutrients have a great effect on the gut microbiome Bacteroidetes Firmicutes Actinobacteria are 3 major phyla that inhabit the large intestine The diet can significantly change the composition of the microbiota From birth the diet is involved in the development of microbial communities in GI tract
• Stress and its effects on brain
• Human beings are susceptible to stress factors at some point of time irrespective of age gender economic status As a matter of fact all organisms have some form of exposure to stress It weakens the physiological functioning of the entire body and fails to maintain homeostasis Stress has been known to cause many unfavorable effects in the body the first among them equals derangement of gut mucosa permeability and compromised intestinal morphology which indirectly impacts the brain leading to increased inflammation in conditions like depression A symbiotic composition of Saccharomyces boulardii lysate has been investigated to impede the stress induced gut hyper-permeability and other related parameters were monitored (Takadanohara H et al 2012) It also triggers a chemical change in the brain that modifies the synapses thereby disturbing the neuronal connectivity During the period of exposure to stress there is elevated levels of cortisol commonly referred to as ldquostress hormonerdquo is the bodyrsquos natural response to stress Response to stress is an essential part of survival However while enabling the body to manage the effects of stress this hormone has devastating effects on the brain The high levels of glucocorticoid activity are associated with reduced neurogenic activity (Gould et al 1997a 1999b Lagace DC et al 2010) The hypothalamic-pituitary-adrenal axis (HPA) is considered as the central response system in the body it reticulates the central nervous system and endocrine system and coordinates a defective response to stress factors HPA axis is responsible for the prominent increase in behaviour altering chemicals including glucocorticoids catecholamines and mineralocorticoids Its activity is regulated by afferent nerve fibres of the parasympathetic system such as vagus nerves oculomotor nerves limbic system which includes hippocampus amygdala basal ganglia and sympathetic systems
• The hippocampus is a horse shaped region near to the amygdala in the midbrain Our experiences emotions memory retention rely entirely on the hippocampus to function correctly Neuroscientists have confirmed that chronic stress can damage the brain severely and have a long-term effect involving changes in brain structure such as shrinking the hippocampus volume loss of memory retention neuroinflammation suppressing the neural activity and increasing the size of amygdala which heightens flightfight response The maintenance of stability in the brain is disturbed due to continual exposure of stress Raised levels of cortisol is involved in the synthesis of neurotransmitter glutamate which is a chemical used to transmit signals to other nerve cells This excitatory neurotransmitter when released in high amounts has neurotoxic effects by generating free radicals Cortisol also damages the receptors of the neurotransmitters serotonin and dopamine which are regulators of mood pleasure happiness and motivation Prolonged stress is known to alter the blood brain barrier permitting the entry of pathogens heavy metal toxins which damage the brain cells (Figure 3) There is an immense loss of neurons and brain cells due to inhibitory action of cortisol on the brain derived neurotropic factor (BDNF) which is a protein used to maintain healthy brain cells and for synthesis of new cells in the brain
• Role of nutraceuticals
• The term ldquonutraceuticalrdquo was coined by Stephen L Defelice in 1979 According to Defelice it is defined as food or parts of food that dispense medicalhealth benefits including prevention and treatment It is a composite of nutrition and pharmaceutical which helps to maintain the physiological functions of the body These nutrient factors provide sufficient nutrients to meet the fundamental nutritional requirements for quality living balance and growth (Maddi et al 2007) They are also referred to as medical foods and designer foods These products are derived from food sources with additional health benefits besides providing the basic nutritional value in foods (Rishi et al 2006) Nutraceutical compounds specifically targeting the neurodevelopment processes are referred to ldquoneuro-nutraceuticalsrdquo a term that has been recently introduced These supplements are chemically identified molecules that beneficially affect the brain at molecular level Their actions are directed to aid in improvement of cognition improve memory positively impact the production of neurotransmitters reduce inflammations and ageing of brain management of neurodegenerative and neuropsychiatric disorders (Malik et al 2008) In line with the subject they also are known to enhance the gut microbes and influence their activities A healthy gut impacts the brain development and signalling mechanisms It helps to lower the stress levels and maintain a good mood Foods can infuse our brains with energy to make us think faster and better Nutraceuticals range from isolated nutrients such as vitamins minerals fatty acids probiotics prebiotics antioxidants polyaminoacids polysaccharides herbal products genetically engineered foods and phytochemicals which include (Carotenoids- fruits vegetables and egg yolk Flavonoid polyphenolics- berries fruits vegetables legumes are potent antioxidants Non-flavonoid polyphenolics- dark grapes raisins berries peanuts turmeric roots)
• Effects of nutrients on gut and brain
• The diverse composition of gut microbiota in humans depends on dietary habits The key mechanisms to maintain gut health are considered to increase the intake of high fibre diet polysaccharides polyunsaturated fatty acids antioxidants and phytochemicals High-fibre rich foods stimulate fermentation which proliferates the bacteria and increase biomass Fermentation causes carbohydrates to undergo chemical changes which result in organic acids that provide energy for the microbes Short chain fatty acids (SCFA) are the end products of carbohydrate fermentation which help to inhibit the growth of pathogenic microorganisms The intake of short-chain non-digestible carbohydrates which include inulin-type fructans fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS) are source of prebiotics that typically target growth of bacterial groups such as Bifidobacterium and Lactobacillus These prebiotic fibres help to ease anxiety depression restore healthy sleep patterns and protect beneficial gut bacteria Dietary saturated fats may increase the number of existing pro-inflammatory gut microbes by stimulating formation of taurine conjugated bile acids that promotes growth of these microbes (Devkota et al 2012) Polyphenol containing berries metabolized by resident microbiota results in bioactive products which impacts the health (Duthie et al 2003) Any gut malfunction has a negative impact on human health therefore it is highly essential to incorporate foods that enhance the microflora of the gut Artichokes have a strong probiotic potential the high content of inulin which is insoluble fibre ferments into healthy microflora (Gibson et al 1995) Adequate administration of probiotics is recognized to have balanced immunoregulatory activities Investigations on a particular probiotic strain Lactobacillus Pentosus has been shown to enhance the cytokine production especially IL-10 which is responsible for maintaining the host immunity by normalizing the T regulatory cells (M Kimura et al2017) Lately a fascinating finding has been that cocoa or chocolate the most craved food across the globe may modulate the gut commensal population They are found to contain flavonoids including procyanidins like catechin and epicatechin oligomers which enhance the action of the neurotransmitters in the brain A Homayouni Rad and his colleagues formulated chocolate as a potential carrier of probiotic culture strains including lactobacilluscasei and paracasei positively sustaining the intestinal microbiota population and also releasing stress busting endorphins Another notable strain is the lactic acid bacteria Streptococcus thermophilus widely used in the commercial production of fermented dairy products Because of its inability to survive in the healthy gastric pH of the stomach it has not been suggested as a ideal probiotic candidate Nonetheless Xiaohong Kangaan and colleagues conducted an intriguing study on the health promoting effects of milk fermented by Streptococcus thermophilus in mice the fermented milk was found to have an enhanced cell-mediated response and positive immunostimulatory effects (M Kimura et al2017) Bananas restore health of the bacterial community and reduce inflammation It is found to maintain harmony between the different phyla present in the gut Polenta is a corn-based complex carbohydrate which has fermentable components that fosters healthy microbiota because of its high fiber (Anderson et al 2009) Broccoli kale cauliflower cabbage consist of sulfur containing metabolites namely glucosinolates which are fragmented by the microbes to release substances that reduce inflammation (Li et al 2008)
• Benefits of berry fruit polyphenols
• Oxidative stress is a serious threat triggering widespread increase in the occurrence of major diseases such as Alzheimerrsquos Parkinsonrsquos other neurodegenerative disorders and ageing Foods rich in antioxidant activity help to prevent age-related changes (Figure 4) Berry fruit polyphenols can neutralize the negative effects of free-radicals the harmful by-products of cellular metabolism which contribute to age related diseases They also possess a multiplicity of actions aside from antioxidant activity They stimulate brain activity neuronal communication cognitive skills calcium buffering ability improve movement control and prevent memory loss Supplements derived from berry fruits like blueberry cranberry strawberry have been reported to be effective in reversing motor and behavioral deficits and control sensory inputs These tiny fruits laden with healing properties are referred to as brain protective fruits berries are rich in bioflavonoids such as anthocyanins and proanthocyanins both of which are scavengers of free radicals Active phytochemicals present in the blueberry confer the benefit of being able to cross the blood-brain-barrier Anthocyanins have been shown to penetrate the brain and their concentrations correspond to appropriate cognitive performances (Lacueva et al 2005) They upregulate TNF α IL-1β NF-κB and consequently suppress ageing and improve blood flow to the brain Blueberries are responsible for reducing expression of stress signals and results in increasing protective signals and impact cell signalling molecule expression (Shukitt-Hale et al 2008) The anthocyanins elevate the level of BDNF (Brain derived neurotropic factor) which is crucial to boost neuronal communication influencing cognitive function Heat shock proteins are known to fight free radicals and inflammation inducing agents to support healthy brain tissues The ability to generate heat shock proteins declines with age dramatically However researchers have found that consumption of blueberries could restore heat shock protein response and help protect against neurodegeneration processes associated with ageing Blueberries play an essential role in reducing the toxicity of kainic acid on hippocampal cells Kainic acid is an amino acid which is naturally abundant in seaweeds and can be neurotoxic because of its potent ability to stimulate neurons by activating receptors for glutamate This aminoacid can be induced in laboratory animal models to study various neurodegenerative disorders
• PUFAs
• Polyunsaturated fatty acids (PUFAs) are critical components of neuronal cell membranes and are involved in neurotransmitter communication within the neural networks They are responsible for maintaining membrane fluidity essential synaptic vesicle fusion and serve as precursors for lipid messengers which participate in signalling processes to promote neuronal protection (Bazan et al 2005) Flaxseeds fish soybeans walnuts are rich in PUFA specifically omega- 6 fatty acid linoleic acid omega-3 α linolenic acid
• Intake of PUFA supplements for improve cognitive function
• In most neurological conditions inflammation manifests in the nervous tissue and this inflammation is a therapeutic target by the pharmaceutical industries During high levels of stress the body cannot regulate an inflammatory response which leads to a greater risk of development of other diseases Anti-inflammatory agents containing nutraceuticals is the focus of development Oxymatrine derived from the root of a Chinese herb Sophora flavescens has been reported to have anti-inflammatory actions and decreases damage observed after hypoxic- ischaemic brain injury in neonatal rat models (Zhao et al 2015) Apocynin obtained from the root of Picrorhiza kurroa is also believed to have anti-inflammatory properties and attenuate the cholesterol oxidation product induced apoptosis in neuronal cells by preventing production of reactive oxygen species (Simonyi et al 2012) Quercetin known to be found in vegetables fruits have antioxidant effects regulate proteins transcription factors and kinase dependent signalling pathways Nutraceutical additive actions of quercetin expedite optimal delivery and improve brain activity Naturally occurring 7 8-dihydroxyflavone rescues cognition deficits and serve as a novel treatment for autism and schizophrenia Trans-resveratrol and pterostilbene are plant derived synergistic phytonutrients improving brain health and having diverse actions against oxidative stress (Poulose et al 2015) Creatine is a natural substance when taken as supplements in recommended dose is beneficial to enhance brain function and improve cognitive function (Wallimann 2008) (Table 1)
• Management of stress
• Nutrient supplements have the potential to overcome the debilitating effects of stress They act as prophylactic and therapeutic agents and are more efficient and safe in comparison to pharmaceutical drugs (Pandey et al 2010) Botanically derived ingredients are used to treat mild depression anxiety improve sleep patterns and maintain good health Since a persistent level of cortisol in circulation is the chief cause of depression and stress naturally derived products target this hormone to annihilate the stress factors and boost mental health and cognition Researchers have studied the effects of probiotics against stress in a zebrafish model by introducing the bacterial strain Lactobacillus plantarum into the tank (Davis et al 2016) The objective is to bring the body back to homeostasis maintaining a balanced level of cortisol The actions of gut microbes and nutraceuticals work interdependently to help reduce the dangerous outcomes of stress upon the body Experiments with germ free mice have been used to probe the role of microbiota in adult hippocampal neurogenesis Also disruptions of gut microbiome induced mice behaviour resulted in anxiety depression and even autism Gut microbes are the key modulators of brain plasticity cognitive functions and help to optimize the bodyrsquos response to stress by regulating their synthesis of neurotransmitters like serotonin to lower the cortisol level Studies have shown that during stress there is an increased population of certain bacterial strains in the gut such as Enterobacteriaceae Proteobacteria Actinobacteria and this can be controlled by increasing the administration of probiotics containing Lactobacillus and Bifidobacterium species Experiments have been conducted with Bifidobacterium longum and results showed that this strain was able to reverse hippocampal and BDNF abnormalities
• CONCLUSION
• In today lsquos ambitious world so much importance is being given to performance perfection competition that it leads to an insidious increase in stress depression anxiety Stress is a psychological issue which predisposes a person to various other ailments It is inevitable in the life of any individual but the duration and intensity differs According to Hans Selye who coined the term stress in 1936 it is the non- specific response of the body to any demand for change Stress levels are rising worldwide it is a top health concern The damages that can be caused by stress are often underestimated It primarily affects the nervous system but prolonged exposure leads to cardiovascular musculoskeletal diseases and even affects the reproductive system Claude Bernard (1865-1961) observed that the maintenance of life is essentially dependent on keeping our internal milieu constant in the face of a changing environment Thus sustaining a state of homeostasis is vital for a healthy life Workplace stress and depression is on the rise it is the health epidemic of 21st century a frequently reported problem According to WHO depression is among the leading causes of disability globally There is a compelling need to confront the ameliorating and deleterious effects of stress inflicted on an individual These health risks can be prevented or managed A multi targeted approach is required to tackle a problem as severe as stress It can be controlled in the healthy way by nourishing and stimulating the gut microbes in our body to act on the brain which increases the release of neurotransmitters to help relieve the effects of stress Nutrient supplements referred to as nutraceuticals has been introduced to influence the brain activity and protect it from the negative impact of stress hormones These nutraceuticals help to enhance the quality of life by modulating the gut health They prevent the alteration of microbiome during stress Extensive research has been conducted in the field of gut microbes and nutraceuticals and their efficacy towards alleviating stress has been proved We are moving towards the direction of exploring psych biotics as a mode of treatment for anxiety depression and various psychiatric issues However it is a recently introduced term and research and is still on-going whether it has proven benefits or not Dietary interventions with food supplements designed to modulate responses to stress that can be administered effectively Managing stress in the natural way is proven to be the most favorable method
• Figure legends
• Figure 1 Schematic representation of various factors that affect the intestinal gut microbes
• Figure 2 Description of the bidirectional gut-brain communication
• Figure 3 Schematic diagram displays the effect of chronic stress on the brain characteristic of increased cortisol levels
• Figure 4 Foods rich in antioxidants
• Table 1 Herbal supplements and their applications
• Herbal supplements
• Applications
• Ginseng sp
• Popular herbal medicine induce calmness lower inflammation levels
• Valeriana officinalis
• Anti-anxiety
• Hypericum perforatum
• Anti-depression effect
• Rhodiola rosea
• Reduces moderate depression
• Melissa officinalis
• Anti-anxiety