GUT Microbiota in health and disease

Moderator – Dr Sunil K MathaiPanelists –

Dr Benoy Sebastian, Dr Geetha M, Dr Antony Chettupuzha, Dr Joseph John

GUT : How sterile is it? – AC

Sterile at birth…

Gut MicrobiotaNumber of intestinal microbial cells is 10 times greater than the number of human body cells

Approximately 150 times larger than the human gene complement, with an estimated set of 3.3 million microbial gene

FirmicutesBacteroides

Proteobacteria

Cyanobacteria

FusobacteriaVerrucomicrobia

Actinobacteria

Infant feeding: Role in development of GUT microbiota - GM

Infant feeding – Role in devpt of microbiota

• Best microbiota in babies born by vaginal delivery , roomed-in with mother & breast-fed

• Worst in ceasarian delivery, admitted in ICU, formula-fed and administered IV antibiotics

GUT Microbiota a Vital organ – BS

Microbial ecosystem

• Upto 100 trillion bacteria - 500 different species• Outnumber human somatic and germ cells by 10

fold• Marked microbial diversity among different

individuals• Each person has his own distinctive pattern of

microbial composition • Determined by genetic and environmental factors

Hidden Metabolic Organ

Protective Function

• Pathogen Displacement• Antimicrobial factors• Immune system development• Promotes anti inflammatory cytokines and

down regulates pro inflammatory cytokines• Induces regulatory T cells

Structural Functions

• Barrier Fortification• Induction of IgA• Apical tightening of tight junction• Enhanced mucin prodution

Metabolic Functions

• Short chain fatty acids • Metabolizes dietary carcinogens • Synthesis of vitamins• Ion absorption

GUT Microbiota in Growth and Development – GM

GUT microbiota in growth and development

• Gut and microbiotia – symbiotic relationship• Modulates gut immune system via “ cross-

talk”

• In the newborn period commensal bacteria provide the immune system with stimuli which causes maturation

• If you get the right bacteria – prevents a number of AI conditions, atopy, allergy etc

GUT dysbiosys – Good, Bad and Ugly – JJ

Good

• Dysbiosis is a state in which the microbiota becomes altered due to an alteration in the composition of the microbiota, a change in bacterial metabolic activity and/or a shift in local distribution of communities.

• Role in several diseases.• Factors altering the gastrointestinal ecosystem include• antibiotics, • psychological and physical stresses, • radiation,• altered peristalsis and • dietary changes

Bad

Ugly

Probiotic, Prebiotic and Synbiotic – The concept – AC

Probiotic means for life…

WHO definition(2001): “Live micro-organisms which, when administered in adequate amounts, confer a health benefit on the host”

Ilya Ilyich Mechnikov

Sour milk with lactobacilli prolongs life 1907

Lilly, D. M. and R. H. Stillwell. 1965. Probiotics: growth promoting factors produced by microorganisms. Science 147:747-748

Parker, R. B. 1974. Probiotics, the other half of the antibiotic story. Anim. Nutr. Health. 29:4-8

Fuller, R. 1989. Probiotics in man and animals. J. Appl. Bacteriol. 66:365-378

PrebioticDefinition: “A dietary prebiotic is a selectively fermented ingredient that results in specific changes, in the composition and/or activity of the gastrointestinal microbiota, thus conferring benefit(s) upon host health.”

Term coined by Glen Gibson 1995

They are dietary fibers with a well-established positive impact on the intestinal

microflora

Non-digestible Oligosaccharides Inulin

Oligofructose(trans)galactooligosaccharides

Synbiotics

Selection of a Probiotic candidate – Which organism and why – BS

• A probiotic strain is identified by the genus, species, and an alphanumeric designation

An ideal probiotic

• Able to survive the passage through the digestive system

• Able to attach to the intestinal epithelia and colonise.• Able to maintain good viability • Able to utilise the nutrients and substrates in a normal

diet• Non pathogenic and non toxic• Capable of exerting a benificial effect on the host• Stability of desired characteristics during processing,

storage and transportation

Clinically Useful strains• Lactobacillus sp.

– reuteri– casei– ramnosus– Acidophilus

• Streptococcus sp.• Bifidobacterium sp.

– Infantis (breastmilk)– lactis– longum– breve– bifidum

• Sacharomyces boulardii • Enterococcus sp• Mixtures

Before marketing

• Purified strain of microbe• In vivo safety and efficacy studies in animals• In vivo safety,efficacy and effectiveness studies

in human beings

Labeling Requirements

• Genus,species and strains • Minimum valuable number of each probiotic

strain at which efficacy is claimed • Shelf life • Evidence based health claims • Serving size• Storage conditions

Mechanism of action of Probiotics JJ

• Antimicrobial actions:• Inhibit growth of pathogenic enteric bacteria by:• Decreasing luminal pH• Secreting bactericidal proteins• Resisting colonisation• Competing for nutrients with pathogens• Modifying pathogen-derived toxins• Stimulating defensin production• Blocking epithelial binding• Stimulating mucus production

• Barrier function:• Improve epithelial and mucosal barrier function by:• Producing SCFAs• Increase barrier integrity• Enhance mucus production• Immune function:• Alter host immune response by:• Modulating cytokine profiles - induce IL-10 and TGF-

secretion and decrease TNF and IFN- expression• Activating local macrophages and increase secretory IgA

production both locally and systemically• Activating Treg cells• Inducing hyporesponsiveness to food antigens• Dampening inflammatory responses

Daily Kerala diet; Is it probiotic rich? GM

Daily Kerala Diet – is it probiotic rich?• Traditional fare – – Fermented rice– Healthy and “prebiotic rich”

• Newer diets– Neither healthy nor probiotic rich– Added probiotics may benefit

Available probiotic preparations; are all the same? AC

Probiotic PlatterVSL#3

Streptococcus thermophilus ,

bifidobacterium breve ,

bifidobacterium longum ,

bifidobacterium infantis ,

lactobacillus acidophilus ,

lactobacillus plantarum ,

lactobacillus paracasei ,

lactobacillus delbrueckii spp

bulgaricus.

DAROLAC

lactobacillus acidophilus

lactobacillus rhamnosus

bifidobacterium longum

Saccharomyces boulardii.

ENTEROGERMINA

bacillus clausii

BIFILAC

Streptococcus

lactobacillus

clostridium butyricum

bacillus mesentericus

ECONORM

Saccharomyces

boulardii

VELGUT lactobacillus acidophilus ,

lactobacillus plantarum , lactobacillus

casei , lactobacillus rhamnosus ,

bifidobacterium breve ,

bifidobacterium longum ,

bifidobacterium infantis ,

Streptococcus thermophilus ,

Saccharomyces boulardii

fructooligosaccharides

YOGUT oligofructose ,

lactobacillus acidophilus ,

lactobacillus rhamnosus ,

bifidobacterium bifidum ,

bifidobacterium infantis ,

bifidobacterium longum.

BECELAC-PB

Streptococcus faecalis

clostridium butyricum

bacillus mesentericus

lactobacillus sporogenes

PREPRO

Streptococcus faecalis

clostridium butyricum

bacillus mesentericus

lactobacillus

acidophilus

PRO-GURT

: , fructo oligosaccharide 100 mg, lactobacillus

acidophilus 700 million cells, lactobacillus

rhamnosus 400 million cells, lactobacillus paracasei

300 million cells, lactobacillus plantarum 300 million

cells, lactobacillus bulgaricus 300 million cells,

bifidobacterium longum 300 million cells,

bifidobacterium infantis 300 million cells,

bifidobacterium breve 300 million cells,

Streptococcus thermophilus 400 million cells,

Saccharomyces boulardi

Are all the same?

Indications of Probiotics in Adults BS

Irritable Bowel syndrome

• Metaanalysis - Moyyedi et al Gut 2010• 19 RCTs – 1650 patients • Significant reduction in symptoms with an

NNT of 4• Trend towards improving pain and bloating • No effect on constipation • Bifidobacterium infantis 35624 – superior

DiarrhoeaClinical condition Effectiveness Organisms

Infectious Diarrhoea A S.boulardii,LGG

Prevention of Antibiotic associated diarrhoea

A S.boulardii,LGG,L.casei,S.thermophilus

Prevention of PMC B LGG,S.boulardii

Treatment of PMC B LGG,S.boulardii

Prophylaxis of Travellers Dirrhoea

B LGG,S.boulardii

Inflammatory Bowel Disease

• Yet to meet the high expectations predicted by the theoretical data

• No significant or consistent benefit in Crohn’s disease

• In UC a modest effect in inducing and maintaining remession in mild to moderate UC

• Escherichia coli Nissle and VSL # 3

Pouchitis

• Significant reduction first episode of pouchitis • Maintenance of remission of recurrent or

refractory pouchitis • Used VSL # 3

Gosselink etal Dis Colon Rectum 2004Mimura et al Gut 2004

Other GI Diseases

Disease Comments

H.Pylori Significant reduction in AAD.No difference in eradication rates

Lactose Intolerance Significant benefit

Hepatic Encephalopathy Role in MHE.Lactulose – a prebioticNo proven in overt HE

NASH Emerging data

Radiation Enteritis Effect is only minimal

Indications of Probiotics in infants and Children GM

Indications of probiotics in Infants an children

• Definite indications– Antibiotic induced diarrhoea(Probiotics for the Prevention and Treatment of Antibiotic-Associated Diarrhea - A

Systematic Review and Meta-analysis. JAMA. 2012)

– Traveller’s diarrhoea– Rotaviral Diarrhoea– Necrotizing Enterocolitis(Probiotics Reduce All-Cause Mortality and Necrotizing Enterocolitis. Pediatrics 2010)

• Other indications ( Value not proven)– IBD– IBS– H Pylori

Dosage and Administration of Probiotics; Issues to consider JJ

• Pay close attention to the strain (not just the genus and species).

• Different probiotic strains exert their beneficial effects via different mechanisms and may be synergistic with other microbiota.

• Studies have used doses ranging from 2 × 107 colony-forming units (CFU) per day to 3.2 × 1012 CFU per day.

• No uniform dosing recommendations.• Frequency can range from twice daily to intermittent

weekly.

• Probiotic strains are generally safe.• Lactobacilli and bifidobacteria are normal

commensals of the GI tract.• Because probiotics are viable microorganisms, they

have the potential to cause invasive infections in hosts with compromised mucosal epithelia.

• Should be used with caution in children, elderly persons and individuals with major risk factors.

Disorder, action Probiotic strain / prebiotic Recommended dose

Maintenance of remission in ulcerative colitis

Escherichia coli Nissle 1917 5 × 1010 viablebac, twice daily

Treatment of mildly activeulcerative colitis or pouchitis

VSL# 3 mixture of eight strains (one S. thermophilus, four Lactobacillus,three Bifidobacterium)

2 × 9 × 1011

cfu, twice daily

Prevention and maintenance of remission in pouchitis

VSL# 3 mixture of eight strains (one S. thermophilus, four Lactobacillus,three Bifidobacterium)

2 × 4.5 ×1011

cfu, twice daily

Alleviates some symptoms of irritable bowel syndrome

Bifidobacteriuminfantis 35624

108 cfu, once daily

B. longum 101 (29%), L. acidophilus 102 (29%), Lactococcus lactis 103 (29%), and S. thermophilus 104(13%)

1010 cfu, once daily

Treatment of acute diarrhea in adults

Enterococcus faecium LAB SF68 108 cfu, threetimes daily

Saccharomyces. boulardii, strain of S. cerevisiae

109 cfu per capsule of 250mg, 2–6capsules per day

Disorder, action Probiotic strain / prebiotic Recommended dose

Prevention of antibiotic associated diarrhea in adults

E. faecium LAB SF68 108 cfu, twice daily

S. boulardii, strainof S. cerevisiae

1 g or 4 × 109 cfu per day

L. rhamnosus GG 1010-1011 cfu, twice daily

Prevention of C. difficile diarrheain adults

S. boulardii, strainof S. cerevisiae

2–3 × 109 cfu for28 days, followed foranother 4 weeks

L. rhamnosusHN001 + L. acidophilusNCFM

109 cfu each, once daily

L. acidophilus + B. bifidum (Cultech strains)

2 × 1010 cfu each strain, once daily

Safety of Probiotics. Are they safe in CLD, CKD, Immunosuppressed AC

Pre-, Pro-, and Synbiotics: Do They Have a Role in Reducing Uremic Toxins?

A Systematic Review and Meta-Analysis

Rossi, Int J Nephrol. 2012

•19 studies analysed•Supportive evidence for the effectiveness of pre- and probiotics on reducing toxins•No notable adverse effects

Probiotics prevent hepatic encephalopathy in patients with cirrhosis:

a randomized controlled trialLumia, Clin Gastroenterol Hepatol. 2014

•160 subjects•New Delhi•Found to be effective in preventing HE in patients with cirrhosis•No adverse effects noted

The efficacy and safety of probiotics in people with cancer: a systematic review

Redman, Ann Oncol 2014

• 17 studies analyzed• 1530 patients• 5 case reports showed probiotic-related

bacteraemia/fungaemia/positive blood cultures

Extra GI uses of probiotics BS

And many more…….

• Recurrent UTI• Vaginal infection• Atopic diseases• Food allergy• Recurrent URTI• Dental Caries• VAP

• Prevention of cancer• Immune Enhancement• Cardiovascular Risk

Reduction• Obesity• Type 2 Diabetes mellitus

Fecal Transplantation JJ

• Fecal microbiota transplantation (FMT) is the process of transplantation of fecal bacteria from a healthy individual into a recipient.

• Involves restoration of colonic flora by introducing healthy bacterial flora through infusion of stool from a healthy human donor.

• First description of FMT published in 1958 by Eiseman and colleagues, surgeons from Colorado, who treated four critically ill patients with fulminant pseudomembranous colitis.

• Hypothesis behind FMT rests on concept of bacterial interference.

• Production of antimicrobial agents (Bacteriocins) by the introduced colonic flora.

• Highly effective in treating recurrent C. difficile, and more effective than vancomycin alone.

• Also used to treat other conditions including ulcerative colitis, constipation, irritable bowel syndrome and neurological conditions like multiple sclerosis and Parkinson’s disease.

• Single to multiple infusions. • Donors tested for a wide array of bacterial and

parasitic infections.• Infusions administered via various routes depending

on suitability and ease - enema, colonoscope.• Modified form of fecal bacteriotherapy (Autologous

Restoration of Gastrointestinal Flora - ARGF) • Autologous fecal sample provided by the patient

before medical treatment is stored. Should the patient develop C. difficile, the sample is extracted with saline and filtered. The filtrate is freeze dried and enclosed in enteric coated capsules.

Concluding remarks

Thank you