Update on the Role of Gut Microbiota Modulation for the … · 2020-03-31 · brain-gut connection...

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Update on the Role of Gut Microbiota Modulation for the Treatment & Prevention of Mood & Anxiety

David J. Scheiderer, MD, MBA, DFAPADirector of Education, Integrative Psychiatry, Inc., Sarasota, Florida

President, Tiberius Enterprises, Inc., Roanoke, Virginia

Roger S. McIntyre, MD, FRCPCProfessor of Psychiatry and Pharmacology, University of Toronto

Head of the Mood Disorders Psychopharmacology Unit, University Health Network, and

Executive Director, Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada

March 2018 MRC2.CORP.D.00337


Today’s Speakers

2

David J. Scheiderer MD, MBA, DFAPAIntegrative Psychiatry, Inc. and Tiberius Enterprises, Inc.Dr. Scheiderer is a Medical Director and the Director of Education at Integrative Psychiatry, Inc. in Sarasota, Florida and is also the President of Tiberius Enterprises, Inc. in Roanoke, Virginia. He received his medical degree from The Ohio State University, completed his Behavioral Medicine and Psychiatry residency at the University of Virginia, and received his MBA from Averett College in Virginia. Dr. Scheiderer is certified by The American Board of Psychiatry and Neurology.

Roger S. McIntyre, MD, FRCPCUniversity of Toronto, University Health Network, and Brain and Cognition Discovery FoundationDr. McIntyre is a Professor of Psychiatry and Pharmacology at the University of Toronto, Head of the Mood Disorders Psychopharmacology Unit at the University Health Network, and the Executive Director of the Brain and Cognition Discovery Foundation in Toronto, Ontario, Canada. He received his medical degree at Dalhousie University, and his Psychiatry residency training at the University of Toronto in Canada.

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Speakers are paid consultants for Otsuka Pharmaceutical Development & Commercialization, Inc.



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• Provide an overview of the origins and importance of the brain-gut connection

• Examine the relationship between the brain-gut-microbiome axis and chronic inflammation

• Consider current evidence of the brain-gut connection’s impact on mental health

• Discuss the impact of modern life on the microbiome • Consider potential implications of the gut-brain

connection for the treatment of mental illness

Objectives

5


The Brain-Gut Connection: Origins and Importance


1. Wang HX, Wang YP. Chin Med J (Engl). 2016;129(19):2373-80. 2. Evrensel A, Ceylan ME. Clin Psychopharmacol Neurosci. 2015;13(3):239-44.

7

The Gut-Brain Connection: A Topic of Much Interest

In 2014 and 2015, NIMH offered a fund of $1 million to study the gut microbiota-brain axis1

In 2015, the US Navy Institute announced a fund of $14.5 million over the next 6–7 years to research the role of the gut in cognitive and stress disorders1

The European Union launched a 5-year “MyNewGut” project ($10.1 million US dollars) for research on brain development and related disorders1

In 2014, >$1 million was transferred to the Human Microbiome Project, supported by the NIH, which aims to understand microbiome diversity and determine roles of microorganisms in health and disease2


1. Chen X, D'Souza R, Hong ST. Protein Cell. 2013;4(6):403-14.2. Verdino J. Health Psychol Open. 2017;4(2):2055102917724335.3. Evrensel A, Ceylan ME. Clin Psychopharmacol Neurosci. 2015;13(3):239-44.

4. Petra AI, et al. Clin Ther. 2015;37(5):984-95.5. Dinan TG, et al. Journal of Psychiatric Resarch. 2015;63:1-9.

• The gut and brain originate from the same tissue during embryogenesis, the neural crest, and influence each other during development1

• Bacteria, mostly residing in the gut, outnumber the body’s cells 10:1 and are referred to as a microbiome1–3

– A microbiome comprises the entirety of microscopic organisms and their genetic material that inhabit a particular environment

8

Origins and Colonization of the Gut Microbiota

Gut microbiotaHuman brain

~1 kg5

• Gut microbiota begin to colonize the GI tract at birth with a complex microbiome forming after the first year of age4

• Gut bacteria have been estimated to consist of >1000 species and >7,000 subspecies3

• The bacteria in our microbiome have co-evolved with us and interact with our body in a bidirectional manner2


Routes for, and Blockages of, Microbial Colonization of Westernized Humans

Toh MC & Allen-Vercoe E. Microb Ecol Health Dis. 2015;26:26309.

Routes for microbial colonization

• Vaginal delivery

• Breastfeeding

• Environmental interaction

Impediments to microbial colonization

• C-section delivery

• Mother treated with antibiotics

• Feeding by formula only

• Indoor living

• Excessive sanitation

• Food preservatives

Early life stagesGestation

Newborn

Infant


Communication Along the Microbiota-Gut-Brain Axis1-3

1. Mayer EA et al., J Neurosci. 2014;34(46):15490-96.2. Kelly JR et al., Frontiers in Cellular Neuroscience. 2015;9:3923. Cryan JF & Dinan TG. Nature Reviews Neuroscience. 2012;13:701-12..

CORTISOLOH

H

O

O

OH

H

NH

NH2

HO

SEROTONIN

Neural CommunicationVagus nerve

Sympathetic Nervous System

Systemic Communication: EndocrineHPA axis

NeurotransmittersBacterial metabolites

Systemic Communication: ImmuneCytokines

Bacterial metabolites



Diseases Associated with Dysbiosis of Gut Microbiota

Psychiatric and mood disorders• Anxiety5,6

• Depression5,6

• Autism spectrum disorder5,6

• Bipolar Disorder6

• Schizophrenia6

Neurodegenerative disorders• Multiple sclerosis1

• Parkinson’s disease2

Cardiovascular disease• Coronary artery disease3

• Hypertension4

Metabolic disorders• Metabolic syndrome5

• Obesity5,7

• Types 1 and 2 diabetes5,7Intestinal disorders• Inflammatory Bowel Disease5

• Crohn’s disease• Ulcerative colitis

• Irritable Bowel Syndrome5,6

• Celiac disease5

Pregnancy-related conditions• Gestational hypertension8

• Gestational diabetes8

1. Cekanaviciute E, et al. Proc Natl Acad Sci U S A. 2017;114(40):10713-10718.2. Sampson TR, et al Cell. 2016;167(6):1469-1480.e12.3. Senthong V, et al. J Am Heart Assoc. 2016 Jun 10;5(6).4. Li J, et al. Microbiome. 2017;5(1):14.

5. Carding S, et al. Microb Ecol Health Dis. 2015; 26:26191.6. Fond G, et al. Pathol Biol (Paris). 2015;63(1):35-42.7. Tai N, et al. Rev Endocr Metab Disord. 2015;16(1):55-65.8. Dunlop AL, et al. Adv Neonatal Care. 2015;15(6):377-85.


1. Prinsloo S and Lyle RR. NeuroRegulation. 2015;2(4):158-161.2. Petra AI, et al. Clin Ther. 2015;37(5):984-95.3. Verdino J. Health Psychol Open. 2017;4(2):2055102917724335.

• An individual’s gut microbiome composition is impacted by:1,2

• When an unhealthy imbalance of bacteria (dysbiosis) occurs, health problems may arise3

• Research suggests that chronic states of bacterial imbalance in the gut may play a role in psychiatric and behavioral problems3

– Evidence supports a link between the microbial state of the gut and overall health, emotional functioning, immune response, and mental health1,3

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Impact of Imbalance of Gut Microbiota on Mental Health

Vaginal birth Genetics Age Diet Physical activity

Environment Stress Infections Other diseases Antibiotic use


Th, T-helper; HPA, hypothalamo-pituitary-adrenal; Treg, regulatory T-cells.1. Sudo N et al. J Physiol. 2004 Jul 1;558(Pt 1):263-75. 2. Gur TL, Worly BL, Bailey MT. Front Psychiatry. 2015;6:5.

• Negative in-utero and early life experiences alter initial gut colonization, which predisposes an individual to stress-induced inflammation later in life by:1,2

• Establishing a hyperactive HPA axis1

• Altering immune system activity2

• Increasing intestinal permeability2

• Influencing epigenetic regulation2

• In essence, early life experiences, through modification of the gut ecology, magnify stressors, amplify the stress response, and inhibit corrective homeostatic mechanisms resulting in chronic sustained inflammation

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Early Life Adversity and the Microbiome


Discussion


The Brain-Gut Connection and Inflammation

15


A Healthy Microbiome1,2

1. Kelly JR et al., Frontiers in Cellular Neuroscience. 2015;9:3922. Cryan JF & Dinan TG. Nature Reviews Neuroscience. 2012;13:701-12.

Healthy Microbiome

• Normal gut microbiota• Normal behavior and cognition• Healthy levels of inflammatory

cells/mediators• Normal intestinal permeability


Causes and Consequences of Dysbiosis1,2

*Examples of potential causes of dysbiosis. Not an exhaustive list.1. Kelly JR et al., Frontiers in Cellular Neuroscience. 2015;9:392.2. Cryan JF & Dinan TG. Nature Reviews Neuroscience. 2012;13:701-12.

Dysbiosis

• Increased inflammation• Altered behavior and cognition• Increased gut permeability


We’ve Gone Wrong Somewhere in the Modern World

DM1, type 1 diabetes; MS, multiple sclerosis. Bach JF. N Engl J Med. 2002;247(12):911-920



“Classic” vs Chronic Inflammation

Egger G. Prev Chronic Dis. 2012;9:E95.

Cla

ssic

al In

flam

mat

ion • Described ~2000 years ago

• Pain (dolor)• Redness (rubor)• Heat (calor)• Swelling (tumor)

• Short-term response to infection and injury

• Aims to remove infective stimulus and allow repair of damaged tissue

Chr

onic

infla

mm

atio

n (“

Met

afla

mm

atio

n”)

• Described in 1993• Low-grade, causing only a small

rise in immune system markers• Persistent, resulting in chronic,

rather than acute, allostasis• Has systemic, rather than local

effects• Has antigens that are less apparent

as foreign (“inducers”)• Appears to perpetuate, rather than

resolve disease• Is associated with reduced, rather

than increased metabolism


Rook GA, et al. Clin Exp Immunol. 2014;177(1):1-12.

Hypothesis: The immune system evolved to require input from organisms collectively termed the “old friends”:

i. Commensal microbiota ii. Commonly encountered organisms from the natural environmentiii. Relatively harmless, subclinical ‘old’ infections that could persist in small isolated hunter-

gatherer groups Loss of contact with “old friends” leads to immune dysregulation, which, in turn, contributes to the development of immunoregulatory disorders (e.g. allergic and autoimmune conditions)

Supporting Evidence• Some “old friends” are known to specifically expand regulatory T cell populations• Chronic inflammatory disorders tend to increase when populations immigrate from low-income to

developed high-income countries• Within any given country, chronic inflammatory disorders are more common in urban than in rural

communities• This is equally true for psychiatric disorders, including autism, schizophrenia, and depression

• Contact with animals (e.g., farm animals, dogs) has a protective effect from allergic disorders and correlates with a better ability to control background inflammation in humans

• Cesarean birth has been linked with an increased risk of type I diabetes, asthma and celiac disease

20

The “Old Friends” Hypothesis


Kelly JR et al., Frontiers in Cellular Neuroscience. 2015;9:392.

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Leaky Gut, Inflammation and the Brain

PrebioticsProbioticsGood Diet

Neuroinflammation

HPA activation

Immune activation

Disrupted intestinal barrier

“Leaky Gut”

Stress

Bacteria translocation

Cognitive DysfunctionDepression

AnxietyDecreased Social Function

Intact intestinal barrier

InfectionAntibioticsPoor Diet

Proinflammatory cytokines


Pro-inflammatory Anti-inflammatory or neutral

Inactivity Fast food/Western-style diet

Exercise Capsaicin

Obesity High omega 6:omega 3 ratio

Weight loss Cocoa/chocolate

Excessive energy intake Low fiber intake Restricted energy intake High fiber intake

Smoking Fructose/glucose Smoking cessation Garlic

Sleep deprivation High glycemic load Fish/fish oils Grapes/raisins

Stress/anxiety/depression Air pollution Fruits/vegetables Mediterranean diet

High fat diet/Saturated and trans fats

Inequality/economic insecurity

Nuts Moderate alcohol

Secondhand smoke Domesticated meat Monounsaturated fats Tea/green tea

Excessive exercise Excessive alcohol Lean game meat Eggs

Egger G. Prev Chronic Dis. 2012;9:E95.

Selected Pro- and Anti-inflammatory “Inducers” of Metaflammation

Strength of Evidence:Strong Moderate Limited


Discussion


The Role of the Brain-Gut Connection in Mental Health


1. Prinsloo S and Lyle RR. NeuroRegulation. 2015;2(4):158-161.2. Schnorr SL, Bachner HA. Yale J Biol Med. 2016;89(3):397-422.3. The Cleveland Clinic. The Gut-Brain Connection. November 27, 2017. Available at: https://my.clevelandclinic.org/health/treatments/16358-gut-brain-connection. Accessed February

27, 2018.

• Common co-occurrence of GI-related comorbidities with a variety of psychiatric conditions (anxiety, depression, schizophrenia)1,2

• GI problems can create stress and anxiety; conversely, stress and anxiety can make GI problems worse3

• Experiencing emotion, such as excitement or nervousness, may impact the digestive system, causing the “butterflies in the stomach” feeling3

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Clinical Observations Suggestive of Brain-Gut Connection


CRP, C-reactive protein; FMT, fecal matter transplant.Kelly JR, et al. J Psychiatr Res. 2016;82:109-118.

• Kelly et al., demonstrated a connection between depressive behavior and the microbiome:

The Microbiota in Major Depression

Depressed patients• ↓ microbiota richness and diversity• ↑ inflammatory markers• ↑ cortisol levels

Healthy controls

Microbiota-depleted rats FMTFMT

Compared to healthy controls:↑ Anhedonia like behavior ↑ Anxiety like behaviors ↑ Intestinal transit timeTrend toward increased levels of plasma CRP


1. Verdino J. Health Psychol Open. 2017;4(2):2055102917724335.2. Evrensel A, Ceylan ME. Clin Psychopharmacol Neurosci. 2015;13(3):239-44.

Preclinical• Most research in this area is based on preclinical studies. Connections between

microbiome and anxiety-related behaviors in animals have been shown in many studies1,2

1. Stress in rats has been reported to lead to a reduction in diversity of the GI microbiome1

2. The naturally exaggerated physiological response to stress in germ-free mice was reversed when they were colonized with a particular strain of bacteria1

3. Rats given a strain of bacteria for 28 days showed a decline in both anxiety and depression scores2

Clinical (limited)• A double-blind, placebo-controlled trial of 66 subjects who ingested a fruit bar

containing a probiotic formula for 30 days reported significantly lower levels of anxiety, anger, depression, and somatization as well as lower cortisol levels in the probiotic group1

• A placebo-controlled study assessing the effect of a fermented milk product containing probiotics on the brain activity of healthy women reported significant impact on the regions controlling emotional and sensory processing1

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Evidence of the Brain–Gut Connection


Effect of Gut Microbiota on Mood-Related Behavior

GF, germ free; MDD, major depressive disorder; SPF, specific pathogen free.Zheng et al. Mol Psychiatry. 2016;21:786-796.


Huang R et al., Nutrients. 2016;8:483.

• In a systematic review and meta-analysis of 5 randomized controlled trials of the anti-depressant effects of probiotics:

– One study examined anti-depressant effects in depressed patients, and reported that probiotics significantly improved depression scores in subjects vs placebo

– The remaining four studies examined the effect of probiotics in non-depressed individuals and the analysis suggested a role for probiotics in reducing the risk of depression

Probiotics for Depression


Discussion


1. Verdino J. Health Psychol Open. 2017;4(2):2055102917724335.2. Schnorr SL, Bachner HA. Yale J Biol Med. 2016;89(3):397-422.

• Mental health disorders are unlikely to be treated with probiotics and prebiotics alone1

• While mental health requires specialized care provided by mental health professionals, complimentary therapeutic strategies should also be utilized2

– Sufficient rest, digestion, exercise, mindful relaxation, and eating a nutritionally rich and varied diet may be considered2

• Additional studies are required to identify strains of bacteria which may confer mental health benefits, as well as those associated with specific symptoms1

– It is the hope that additional research can lead to nutritionally based and psychobiotictreatments that can be combined with traditional psychological and psychotropic approaches

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Future Considerations for the Brain-Gut Connection in the Treatment of Mental Illness

Psychotropic intervention:

Focus on biology and

neurochemistry

Nutritional therapy:Focus on the impact of the microbial environment of the gut on mental health

Therapy:Focus on

behavioral and psychological

variables

Areas of Focus in Treatment of Psychiatric Illness1


Discussion


QUESTIONS


CLOSING

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