Role of Lactobacillus. Comfortis

(L reuteri)

in

Colic & Easy digestion -

Comfortable and Healthy Baby

Dr Kuntal Biswas

MBBS, DPH, DNB(P), FCCP, FCAM, FMCESA

Medical Registrar

Medical College & Hospitals, Kolkata.

What is Crying?

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• Crying is a normal reflex every newborn has , and

one of the neonatal reflex babies are born with. It

is a brilliant way of getting attention and it is a

powerful connection between the baby and the

mother.

• It is estimated to be 80 - 100 db sound of

prolonged period (most adult can’t do)

• 50% of infant age 6 week cry almost 2h/day and

at 12 weeks this cry decrease to 1h/day

• Crying of early infancy is an excellent signal of

need. But poor signal of what is needed.

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Functional gastrointestinal disorders

• More than half of all infants experience mild functional

gastrointestinal symptoms.

Functional gastrointestinal disorders, i.e. those not caused by organic

illness, are very common in infants during the first months of life.

This stems from the fact that the gastrointestinal tract must first “get

used” to its new functions after birth.

• The clinical symptoms of functional gastrointestinal

disorders include colic, spitting up, flatulence, constipation

and mild diarrhoea.

• Some probiotics bacteria have the potentiality to provide

“gut comfort”, but not all probiotics bacteria are equal.

• L. reuteri DSM 17938 - a strain that provide “gut comfort”

Symptoms + signs that suggest a

diagnosis other than colic

•Failure to thrive

•Irritability that is almost continuous, rather than episodic

•Irritability that lasts beyond 3 or 4 months

•Vomiting, Diarrhea, constipation

•Heme positive stool

•Rash

•Respiratory symptom

•Point tenderness in an extremity

•Anal fissures

•Subtle dysmorphic facial features

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Definition of Colic

• Paroxysm of irritability, fussing

or crying lasting more than 3

hours/day

• For more than 3 days/week

after other causes for crying .

• resolve by 3 month of age.

• Colic starts at two weeks of age

and last till 3 month

• In premature babies it starts

two weeks after the due date.

• Incidence: 2 % to 12 %

5

Causes of Colic

•There is an association between low birth

weight and increased incidence of colic.

• It is equally likely to occur in both breastfed

and formula-fed infants due to aerophagia.

• Increased levels of certain biochemical markers,

such as motilin, alpha lactalbumin, and

urinary 5-hydroxy-3-indole acetic acid (5-OH HIAA).

• Psychosocial stress during and after pregnancy is

associated with colicky babies.

• Colic affects 10-30% of infants worldwide.

• Some evidence that there is an increased allergic disorders

and certain psychological disorders.

Classic Treatment

1.Recommend that the smell of the mother is familiar to the baby.

2.Dicyclomine hydrochloride is an anticholinergic drug that is

effective in the treatment of colic.

Because of serious, although rare, adverse effects (e.g., apnea, breathing

difficulty, seizures, syncope), its use cannot be recommended.

3.Train parents about the importance of sign of hunger of the baby, changing

wet diapers, and comforting a baby who is cold and crying as a result of

kinking of respiratory tube.

Soothing music accompanied with parental attention (including eye contact,

talking, touching, walking, and playing) may be effective in some infants.

4.Encourage parents to discuss their feelings and concerns with each other to

obtain support.

Emphasize the responsibility of the whole family in the care of a colicky baby.

Causes of Infantile Colic Past investigations included:

• Inadequate or inappropriate

mother-infant interaction

• Mother’s anxiety

• Abnormal Gastrointestinal

Function

• Transient Relative Lactase

Deficiency

• Exposure to Cow’s Milk

Proteins

8

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What are probiotics?

• The WHO definition of Probiotics bacteria “life micro

organisms, which when consumed in adequate

amounts, confer a health effect on the host“

(WHO/FAO).

• Probiotics includes a whole range of completely

different micro organisms endowed with different

properties and effects.

• Some of the mechanisms behind the beneficial effects

are valid for all of the genera and strain lactobacilli and

bifidobacteria.

• Many properties and effects are strain-specific.

Every strain and every combination of different strains must

be tested separately in clinical studies for its beneficial

effects on the host.

Probiotics

• Induction of dendritic cell (DC) maturation.

• Enhancement of serum antibody response to orally and

systemically administered antigens.

• Enhanced immuno -reactivity of spleenic cells and

phagocytes.

• Activation of the gene for human beta defence in

intestinal mucosa Induction of oral tolerance to

beta lactoglobulin.

• Production of beta- galactosidase - improvement of

lactose intolerance

• Induction to reduce local inflammation in GIT 10

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How can the same probiotic strain help with so

many different

functional gastrointestinal disorders?

It also houses the body’s largest immune system, gut-associated lymphoid tissue (GALT),

and the enteric nervous system (ENS).

The gastrointestinal tract is

not just a digestive system;

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Cont….

There is a 4th organ in the gut: the gut micro flora .

It influences the maturation and regulation of the functions

of all 3 organ systems through direct effects as the gut flora

is still subject to important changes at that age .

Lactobacillus reuteri

• It is an obligatory heterofermentative

resident in the gastrointestinal tracts of

humans.

• It produces compounds that exhibit

antagonistic activity, i.e. reuterin and

reutericyclin, which are water-soluble,

broad-spectrum antimicrobials,

effective over a wide pH range,

and resistant to

proteolytic and lipolytic enzymes.

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What do we know about the effect

mechanisms of L. reuteri?

- Modulates gut flora

- Modulates the immune responses und inflammatory

responses in the gut mucosa

- Promotes postnatal intestinal neuronal development,

thereby furthering gut motility

- Inhibits visceral pain coming from the gastrointestinal

tract and decrease tonic contractions of the muscles of

the colon caused by pressure

- Normalizes disturbed sleep patterns

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How does L.reuteri modulate

gut microbiota? • It temporarily colonize the gut and

increases their number after ingestion.

• It ferment easily fermentable sugars to

produce energy.

• During this process they produce lactic

acid, which reduces the intra-luminal

pH value.

• The acid milieu inhibits the growth of

potentially pathogenic bacteria in the

gut while promoting the growth of

lactobacilli and bifidobacteria.

Changes in the number of

E. coli & lactobacilli

It compete with potential pathogens for nutrients and

the attachment sites for docking onto the gut mucosa

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Cont…….

• It produces reuterin

(3-hydroxyproprionaldehyde),

an anti-microbial compound

• Reuterin is active against a wide

spectrum of gram-positive and

gram-negative bacteria (e.g.

E. coli), yeasts, fungi and viruses.

• It kills the pathogenic bacteria,

whereas it does not touch the

good bacteria.

• The direct contact of L. reuteri with

other bacteria, such as E. coli,

stimulate reuterin production or

secretion.

• Reuterin inhibits bacterial growth

by inducing oxidative stress in the

bacterial cell.

• L. reuteri itself is highly resistant to

the effects of reuterin

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L. reuteri compared to other Probiotics:

effects on pathogens

Histamine Derived from Probiotic L. reuteri

suppresses TNF

• Histamine is produced from L-histidine via histidine

decarboxylase by some fermentative bacteria including

lactobacilli.

• Targeted mutagenesis of each gene present in the

histidine decarboxylase gene cluster in L. reuteri 6475

demonstrated the involvement of histidine decarboxylase

pyruvoyl type A (hdcA), histidine/histamine antiporter

(hdcP), and hdcB in production of the TNF-inhibitory factor.

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For which clinical effects is the modulation of

the gut microflora through L.reuteri

especially important?

Clinical

effects

Findings and/or rationale Potential effect mechanisms

L. Reuteri

reduces

crying

time

in

colicky

infants

Colicky infants have a

lower prevalence of

lactobacilli and higher

counts of fecal E. coli

than healthy infants

Fecal gas-forming E. coli were

significantly reduced during L. reuteri,

but not during placebo

supplementation.

The abundance of gas-

forming E. coli may lead

to excessive intestinal

air load and consequent

abdominal pain

Higher counts of E. coli in colicky

infants, suggests that reduction of

faecal gas-forming E. coli by

L. reuteri can help to reduce

crying time in colicky infants

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Cont…. Clinical

effects

Findings

and/or rationale

Potential effect mechanisms

L. reuteri improves functional constipation

There are

indications that

the intestinal

flora is

disturbed in

children with

chronic

constipation

L. Reuteri & lactobacilli,

produce lactic acid and other

acids.

This reduces the pH value in

colon.

A lower pH enhances

peristalsis of the colon and

subsequently decreases

colonic transit time, which in

turn helps against constipation

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Modulation of the immune responses und

inflammatory responses of the gut mucosa

• The gut-associated lymphoid tissue (GALT) is largest immune organ.

It includes more than 2/3 of the total lymphoid tissue of the human

organism and around 80% of all IgA producing plasma cells.

• Gut bacteria are the “coaches” of the gut immune system.

• One advantage of “good” probiotic vs. “bad”, i.e. potentially pathogenic

bacteria is that they “train”.

As a result, the immune system maturates without risk of disease.

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What do we know about the beneficial

immunomodulatory effects of L. reuteri?

The role of T helper cells

The major players in the specific, “acquired” or adaptive immune system are

T cells and B-cells.

T-helper (Th) cells are a subset of T-cells. Th cells are also called CD4 positive

(CD4+) T cells, as they have the surface protein CD4. Th cells play a central role

in immune protection, i.e. to secrete antibodies..

They send an order to the B-cells which produce specific “weapons-chemical

messengers” cytokines (immunoregulatory proteins)” against foreign

substances.

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A clinical study shows:

The ingestion of L. reuteri induces colonization of the ileum & is associated with a significantly higher amount of T-helper cells in the ileal mucosa

T-helper cells in ileal mucosa

A) before (“dispersed cells or aggregations of cells”);

B) after L. reuteri administration for 28 days

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For which clinical effects immunomodulatory

effects of L. reuteri especially important?

Clinical effect Findings Potential effect mechanisms

L. Reuteri

reduces

crying

time

in infants

Calprotectin

(marker of Gut

inflammation)

levels are

significantly

higher (2-fold)

in infants with

colic compared

with control

infants

The increased

calprotectin -

levels in infants with

colic show that colic is

associated with a low-

grade gut

inflammation. The effect of L. reuteri of down-regulating pro-inflammatory cytokine IFN-γ in the intestine &

inhibiting gut inflammation

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Promotes postnatal intestinal neuronal development & development &

regulation of a normal motility of the gastrointestinal tract The digestive system has its own enteric nervous system (ENS).

The total number of enteral neurons in the human GI tract is about 100 million.

The principal components of the ENS are two networks or plexuses of neurons, both

of which are embedded in the wall of the digestive tract and extend from

oesophagus to anus:

1)The myenteric plexus, which exerts control primarily over digestive tract motility

2)The sub mucosal plexus of which the principal role is sensing the environment

within the lumen.

In the jejunum L. reuteri supplementation increased the contractile response to

acetylcholine whereas it had no effect in the colon .

The contractile response to EFS was significantly increased in both jejunum & colon

which suggests that L. reuteri promoted the development and function of the enteric

nervous system (ENS).

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Inhibitory effects on visceral pain

Specialized “pain receptors”, nociceptors, are

located in the walls of the G.I tube.

They are particularly sensitive to stretch

and over-distension of the walls of the

gastrointestinal tract tube.

Once a certain degree of distension is reached,

the nocireceptors “feel” the pressure &

“respond” by translating the mechanic stimulus

into electrical signals and conducting the

signals into the spinal cord through afferent*

spinal nerves.

Visceral pain is typically accompanied by a slowed heart rate

When strong mechanical stimuli such as extreme distension of the walls of

the gastrointestinal tract tube, the vagus nerve (vagal afferent) is also

stimulated. This can induce automatic responses to painful stimuli.

Typical automatic responses to painful stimuli include a slowed heart rate

and a reduction in blood pressure.

From the spinal cord, the nerve fibers transmit the electrical signals on to

the brain. When they reach the brain, we become aware of the pain.

Results study of comparison of effectivity of

L.reuteri & Simethicone

• Primary Outcome

– Reduction of the daily average crying time,

from baseline to the end of the treatment

period, to <3 hours/day

• Secondary Outcome

– Number of responders vs. nonresponders in

each group at the end of treatment

• Responders = a decrease in the daily

average crying time of 50% during the

study. 27

Crying Time (min)

Day L. reuteri Simethicone Difference P-value

0 197 (180-276) 197 (180-278) 0 .987

1 192 (107-273) 192 (107-278) 0 .753

7 159 (54-211) 177 (38-241) -18 .005

14 95 (41-170) 153 (51-231) -58 <.001

21 74 (35-139) 154 (54-229) -80 <.001

28 51 (26-105) 145 (70-191) -94 <.001

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Comparison of effectivity of

L.reuteri & Simethicone

0

10

20

30

40

50

60

70

80

90

100

L. reuteri Simethicone

Responders

Nonresponders

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Normalization of disturbed sleep patterns

Sleep follows a regular cycle each night.

Sleep is divided into two main stages: rapid eye movement

(REM) and non-rapid REM (NREM) sleep.

REM sleep is characterized by muscle relaxation.

NREM sleep, time of quiet sleep, ranging from light to deep

phase.

In 8-hours of sleep, the human brain cycles through these

stages about 4-5 times.

An animal trial shows:

L. reuteri normalizes the 24-hour duration of wake & sleep

stages and sleep fragmentation

International Journal of

Food Microbiology 95 (2004) reports

• Lactobacillus reuteri in fermented bovine

milk decreases the oral carriage of mutants

streptococci.

• Bovine milk fermented by L. reuteri

decrease the risk of dental caries.

• This organism may be a useful probiotic

organism for dairy products.

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Confidential to Fonterra

Whey components linked to immune modulation

α -Lactalbumin

β –lactoglobulin

Blood Serum Albumin

Immunoglobulins

Proteose Peptones

Lactoferrin

Phosphatases

Amylases

Lipases

Catalases Peroxidase

αS1- Casein

αS2- Casein

β- Casein

γ- Casein

κ- Casein

CASEIN

WHEY

80%

20% Minor proteins

• Immunoglobulins

• Lactoferrin

• Alpha-lactalbumin

• Minor proteins

- Lactoperoxidase

- Lysozyme

- Proteose peptones

Confidential to Fonterra

Whey components linked to bone health

α -Lactalbumin

β –lactoglobulin

Blood Serum Albumin

Immunoglobulins

Proteose Peptones

Lactoferrin

Phosphatases

Amylases

Lipases

Catalases Peroxidase

αS1- Casein

αS2- Casein

β- Casein

γ- Casein

κ- Casein

CASEIN

WHEY

80%

20% Minor proteins

• Glycomacropeptide

• Lactoferrin

• Alpha-lactalbumin

• Minor proteins

• Fractions

Confidential to Fonterra

Primary components of whey protein and

their benefits Whey Component % of

Whey

Protein

Benefits

Beta-Lactoglobulin 50-55% Excellent source of essential amino acids especially

branched-chain amino acids

Alpha-Lactalbumin 20-25% Excellent source of essential amino acids; High in

Tryptophan which helps regulate sleep, mood & stress

Immunoglobulins 10-15% IgA, IgD, IgE, IgG, IgM – primarily IgG with immune

enhancing benefits

Lactoferrin 1-2% Antioxidant, anti-viral, anti-bacterial, anti-fungal; promotes

beneficial bacteria; regulates iron absorption

Lactoperoxidase 0.5% Inhibits bacterial growth

Bovine Serum

Albumin

5-10% Good profile of essential amino acids

Glycomacropeptide 10-15% Inhibits formation of dental plaque and cavities

Source: Alternative Medicine Review (2008), Vol 13 (4), pp 341-347

whole milk

1000 kg

(=1 tonne)

Cream

111 kg

Skim milk

889 kg

Casein

32 kg

Lactose

851 kg

Whey

6 kg

Casein whey

857 kg

Approximate yield from milk (assuming no losses)

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Summary

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Summary

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Thanking

You All