Transcript PPT - Cochin GUT Club

GUT Microbiota in health and
disease
Moderator – Dr Sunil K Mathai
Panelists –
Dr Benoy Sebastian, Dr Geetha M,
Dr Antony Chettupuzha, Dr Joseph John
GUT : How sterile is it? – AC
Sterile at birth…
Gut Microbiota
Number 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
Bacteroides
Firmicutes
Fusobacteria
Verrucomicrobia
Proteobacteria
Cyanobacteria
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 “ crosstalk”
• 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”
Sour milk
with
lactobacilli
prolongs
life 1907
Ilya Ilyich Mechnikov
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
Prebiotic
Definition: “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.”
They are dietary fibers with a wellestablished positive impact on the intestinal
microflora
Term coined by
Glen Gibson 1995
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 Platter
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
Diarrhoea
Clinical condition
Effectiveness
Organisms
Infectious Diarrhoea A
S.boulardii,LGG
Prevention of
Antibiotic
associated
diarrhoea
Prevention of PMC
A
S.boulardii,LGG,L.ca
sei,S.thermophilus
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 2004
Mimura 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
NASH
Role in MHE.Lactulose – a
prebiotic
No proven in overt HE
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 colonyforming 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 viable
bac, twice daily
Treatment of mildly active
ulcerative colitis or pouchitis
VSL# 3 mixture of eight strains (one S. 2 × 9 × 1011
thermophilus, four Lactobacillus,
cfu, twice daily
three Bifidobacterium)
Prevention and maintenance
of remission in pouchitis
VSL# 3 mixture of eight strains (one S. 2 × 4.5 ×1011
thermophilus, four Lactobacillus,
cfu, twice daily
three Bifidobacterium)
Alleviates some symptoms of
irritable bowel syndrome
Bifidobacterium
infantis 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
Enterococcus faecium LAB SF68
108 cfu, three
times daily
Saccharomyces. boulardii, strain of S.
cerevisiae
109 cfu per capsule
of 250mg, 2–6
capsules per day
Treatment of acute diarrhea
in adults
Disorder, action
Probiotic strain / prebiotic
Recommended dose
Prevention of antibiotic
associated diarrhea in adults
E. faecium LAB SF68
108 cfu, twice daily
S. boulardii, strain
of S. cerevisiae
1 g or 4 × 109 cfu per
day
L. rhamnosus GG
1010-1011 cfu, twice
daily
S. boulardii, strain
of S. cerevisiae
2–3 × 109 cfu for
28 days, followed for
another 4 weeks
L. rhamnosus
HN001 + L. acidophilus
NCFM
109 cfu each, once
daily
L. acidophilus + B. bifidum
(Cultech strains)
2 × 1010 cfu each strain,
once daily
Prevention of C. difficile diarrhea
in adults
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 trial
Lumia, 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