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Gary D. Wu, M.D Ferdinand G. Weisbrod Professor of Medicine Division of Gastroenterology Perelman School of Medicine University of Pennsylvania The Microbiome:

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Presentation on theme: "Gary D. Wu, M.D Ferdinand G. Weisbrod Professor of Medicine Division of Gastroenterology Perelman School of Medicine University of Pennsylvania The Microbiome:"— Presentation transcript:

1 Gary D. Wu, M.D Ferdinand G. Weisbrod Professor of Medicine Division of Gastroenterology Perelman School of Medicine University of Pennsylvania The Microbiome: What’s the immune system got to do with it?

2 Comprised of Bacteria, Viruses, others (Archaea, Eukaryotes) Distinctive microbiomes at each body site (gut, lung, skin, mucosa etc.) The Gut Microbiota Human gut is home to ~ 100 trillion bacterial cells Density of 10 11 to 10 12 per gram in the colon Genome size of microbiota at least 100- fold greater than human Large numbers species present, most uncultured Nat. Rev. Micro. 2011;9:279-290 The Human Microbiome

3 Association of the Gut Microbiota with Disease Pathogenesis involves both genetic and environmental factors All associated with inflammation Many show rapidly increasing incidence over the past few decades Many associated geographically with more industrialized nations Diabetes : Type 1 DM (MyD88-dependent in NOD Mice); Type 2 DM (TLR4 and TLR5 KOs) Colon Cancer: Enterotoxigenic Bacteroides fragilis and Fusobacterium Atherosclerosis: Oral, gut and plaque microbiota; Microbial metabolism of choline to TMA Inflammatory Bowel Disease: Dysbiosis Asthma : Sanitized environment Many associated with diet

4 Host Gene-Microbial Interactions in the Pathogenesis of Immune- Mediated Diseases in “Modern Society” Parental genotype Infant Adapted from Virgin et al. Cell 2011;147:44 Establish normal microbiome Normal immune system Immune tolerance Regulated inflammation Infections Autoantigens Health “Sanitized” Environment Antibiotics Diet Failure to establish normal microbiome Inflammation & autoimmunity- prone immune system Environmental cofactors Microbial products Autoantigens Crohn’s Disease Asthma Type 1 Diabetes Other Bacteria Viruses Diet Other Perinatal

5 Germ-free Colonic and Lung iNKT Cells Oxazolone Colitis and Asthma ++++ Conventionally Housed + + Olszak et al. Science 2012;336:489 Adult Microbial Colonization ++++ Perinatal Microbial Colonization + + Perinatal Effects of the Gut Microbiota on Host Immunity PNAS 2011;108:4578

6 Medzhitov. Nat. Rev. Immunol. 2001;1:135 Kanneganti et al. Immunity 2007;27:549 Innate Immune Receptors Recognize Bacterial Products Known as “Pathogen Associate Molecular Patterns” (PAMPS)

7 Maloy KJ and Powie F. Nature 2011;747:298 Differential Effects of Bacteria and Their Products on Epithelial vs. Innate Immune Cells

8 Kostic A D et al. Cancer Immunol Res 2013;1:150-157 The Gut Microbiota, Inflammation and Colon Cancer Sears, CL Cell Host & Microbe 2014

9 Jin et al. Cell Met. 2013;17:873 Vjay-Kumar Cell Met. 2012;15:419 Nature 2012;482:179 The Gut Microbiota, Inflammation and Metabolic Disease

10 Normon et al. Gastro 2014, in press Bacteria Viruses FungiArchaea Competition Syntrophy Enhanced Pathogenicity Predator-Prey Relationship

11 The Intestinal Mycobiome Proportion of total reads 18S and ITS amplicons for eukaryote detection Hoffmann et al. PLoS One 2013;e66019 Dollive et al. Genome Biol. 2012;13:R60

12 The Mycobiome in IBD ASCA and Crohn’s Disease

13 Khor et al. Nature 2011;474:307 Genetic Polymorphisms Associated with IBD Occur in Distinct Pathways

14 Anti-Inflammatory Treg Pro-Inflammatory Th17 B Cell Plasma Cell Gut Lumen Epithelium Lamina Propria The Gut Microbiota, Maturation of the Mucosal Immune System, and IBD Genetics X X X X = Genetic Polymorphisms Associated with IBD XXXXX X IgA SFB B. Fragilis (PSA) Clostridium sp. SCFAs

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