Gut Microbiota and IBD Vahedi. H M.D Associate Professor of Medicine DDRI 1393.3.1
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GUT MICROBIOTA 100 Trillion Microbes - 10 times more than cells in our body Collective weight of about 1kg in human intestine 70% of Body s Immune System Balance of gut microbiota can have a very real impact on immune system Colonization begins immediately after birth Symbiotic bacteria provide benefits to the host: nutrient supply pathogen defense immune system development/ function O Hara and Shanahan, EMBO reports, 2006
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MICROBIOTA DISRUPTED BY Poor Digestive Function Medications: acid blockers, NSAIDs, antibiotics Food Additives antibiotics, preservatives Stress High protein, red meat, low fiber, high sugar Food Intolerances: gluten, dairy, soy, etc
KEEPING MICROBIOTA IN BALANCE Diet can change microbiota within 24 hours (J. Gordon, MD, Washington University St. Louis, 2009) Whole Food Diet, High Plant Fiber, Low Fat Avoid Processed Foods with Chemical Additives Prebiotic & Probiotic Supplements Fermented Foods!
TYPES OF FERMENTED FOODS Yogurt, Kefir, Cheeses Pickles, Sauerkraut, Vinegars Lactofermented Beverages Fruit and Vegetable Juices Kvass, Rejuvalac Breads, Seafood, Soy & many other Foods
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The greater than 90% of all phylotypes within the adult colonic microbiota belong to just two phyla: -Firmicutes (Gram-positive); mainly: -Clostridium coccoides -Clostridium leptum subgroups -Bacteroidetes (Gram-negative), with less abundant phyla including: -Proteobacteria -Actinobacteria -Verrucmicrobia Inflamm Bowel Dis Volume 18, Number 2, February 2012 15
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Role of intestinal microbial in IBD pathogenesis In healthy humans -the separation of bacteria from the mucosa is equal in the proximal and distal colon -and bacteria are never found in crypts -mucus layer is continuously renewed 17
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To protect the host: -effective barrier -natural (innate) immune system -acquired immune system The effective barrier depends upon: -an intact intestinal epithelium -normal peristalsis -secretion of numerous protective factors
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The conditions of disruption: -Disrupt mucus barrier -Loss of bacterial separation between mucosa and lumen -Bacterial adherence -Bacterial invasion -and bacterial translocation Development of Colitis by: -T cell spontaneous proliferation by microbiota and produce IL-6 -The production of (potentially toxic) metabolites may play a role in the onset or chronicity of IBD Gut Microbes 1:6, 388-391; November/December 2010 23
IBD IS DRIVEN BY T CELLS mucosal homeostasis cytokine production by T reg supresses pro-inflammatory responses T H 1, T H 2, T H 17 T Reg mucosal inflammation increased production of pro-inflammatory cytokines by T helper (T H ) cells TNF, IFNγ, IL-17 T Reg transfer can prevent the induction of experimental colitis adapted from Bouma and Strober, Nat rev Immunol., 2003 and Vignali et al., Nat rev Immunol., 2008
IBD GENETICS POINT TO AN INTERPLAY BETWEEN THE IMMUNE SYSTEM AND MICROBIOTA IN IBD CD susceptibility gene was NOD2, which: -stimulates an immune reaction NOD2 is expressed in Paneth cells, which: -are located predominantly in the terminal ileum at the base of intestinal crypts Defensins play a major role in defense against pathogen Reduction of ileal defensins may predispose to CD Mutations in NOD2 can have significant effects on the composition of the microbial milieu 25
Patients with IBD carrying NOD2 mutations have: -increased numbers of mucosa-adherent bacteria -decreased the anti-inflammatory cytokine IL10 Patients with IBD carrying NOD2 and ATG16L1, alterations in the structure of gut microbiota, including: -decreased levels of Faecalibacterium -increased levels of Escherichia Gastroenterology 2014;146:1489 1499 26
A second group of adherent and invasive bacteria is the Fusobacteria Fusobacterium species have been found to be at higher abundance in the colonic mucosa of patients with UC relative to control Fusobacterium isolates have been shown to directly promote tumorigenesis in a mouse model IBD is among the highest risk factors for the development of CRC Gastroenterology 2014;146:1489 1499 27
PROTECTIVE EFFECTS OF MICROBES IN IBD Several evidence suggest that specific groups of gut bacteria may have protective effects against IBD One mechanism by which the commensal microbiota may protect the host, in which: -commensals occupy niches within the host -and prevent colonization by pathogens -and help outcompete pathogenic bacteria 28
Bifidobacterium, Lactobacillus, and Faecalibacterium genera, may protect the host from mucosal inflammation by several mechanisms, including: -down regulation of inflammatory cytokines -or stimulation of IL10, an antiinflammatory cytokine Low levels of mucosa-associated F prausnitzii are associated with a higher risk of recurrent CD after surgery Recovery of F prausnitzii after relapse is associated with maintenance of clinical remission of UC Gastroenterology 2014;146:1489 1499 29
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PROPOSED CAUSES OF DYSBIOSIS OF THE MICROBIOTA Increased incidence of immune-mediated disorders in developed countries could be due to alterations in the microbiota
DIET No specific diet has been shown to directly cause, prevent, or treat IBD Interactions between nutrients and microbiota; and the role of the microbiome in disease is important Gastroenterology 2014;146:1489 1499 34
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AGE There is an age related variation in the distribution of IBD phenotypes 3 distinct stages of onset: -A peak age of onset is typically 15 to 30 years of age -Late onset cases occurring closer to 60 years of age -Early onset occurring at younger than 10 years of age The latter group has had a significant increase in incidence over the past decade 36
In these stages the gut microbiota alters its: -diversity -stability Early life is marked by a microbiome of low complexity and low stability, and fluctuates with: -changes in diet (switch from breastfeeding to solid foods) -illness -and puberty In adulthood the microbial assemblage to reach maximal stability and complexity Decreased stability has been observed in elderly subjects (60 years of age or older) Gastroenterology 2014;146:1489 1499 37
Dysbiosis in ulcerative colitis UC is characterized by the presence of diffuse inflammation restricted to the mucosal layer of the colon that causes recurrent symptoms An infectious origin of UC was thoroughly investigated in the past, but never demonstrated UC has never been associated with infection by a single specific pathogen UC does not consistently improve with antibiotic treatment 38
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Dysbiosis in Crohn s disease CD is a heterogeneous disease that might affect any part of the GI tract, causing a wide variety of inflammatory lesions Despite intensive investigation, searches for organisms that cause CD have not led to the identification of a single specific pathogen In particular, Mycobacterium avium paratuberculosis was proposed as a causative agent of the disease following its isolation in 1984 from the diseased intestinal tissue of patients with CD 40
Microbial communities in individuals with CD differed from those: -in healthy individuals -in CD that predominantly involved the ileum -in CD that predominantly involved the colon A reduction of F. prausnitzii in ileal mucosal samples is associated with a higher risk of postoperative recurrence of ileal CD 41
Adherent-invasive E. coli (AIEC) and has been isolated from ileal mucosal of patients with CD AIEC can also be found in: -it is less prevalent in healthy people than in CD -does not adhere to ileal enterocytes in without CD These findings suggest that AIEC strains are associated specifically with the ileal phenotype of CD NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY VOLUME 9 OCTOBER 2012 42
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Interactions between the intestinal microbiota and the host have been suggested to play a role in the pathogenesis of IBD Distal ileum and the colon are the areas of the gut with the highest bacterial concentrations And are the more frequent sites of inflammation in IBD Decreasing bacterial numbers in the intestine, e.g. by using antibiotics, can lead to clinical improvement and decreased inflammation 45
NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY VOLUME 8 SEPTEMBER 2011 47
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