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The Microbiome: What’s the immune system got to do with it?

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

2 The Human Microbiome 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 1011 to 1012 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 ;9:

3 Association of the Gut Microbiota with Disease
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 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 Many associated with diet

4 Host Gene-Microbial Interactions in the Pathogenesis of Immune-Mediated Diseases in “Modern Society”
Parental genotype Establish normal microbiome Normal immune system Immune tolerance Regulated inflammation Infections Autoantigens Health Infant “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 Perinatal Adapted from Virgin et al. Cell 2011;147:44

5 Perinatal Effects of the Gut Microbiota on Host Immunity
PNAS 2011;108:4578 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 +

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

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

8 The Gut Microbiota, Inflammation and Colon Cancer
Microbial sensors and responders in colorectal cancer. Intestinal epithelial cells and myeloid cells sense microbe-associated molecular patterns (MAMP) through TLR and NLR PRRs. Interaction of MAMPs with cell surface-bound TLRs leads to activation of transcription factor NF-kB via the adaptor molecule MyD88. NF-kB signaling in epithelial cells alters the expression of antiapoptotic genes including Bcl2L1 and Bcl2, contributing to the transformation of epithelial cells. NF-κB activation in the myeloid cells upregulates levels of IL-6 and IL-23, which increase Th17 cells that play a critical role in colitis-associated colorectal cancer. IL-6 can directly contribute to the development of colon cancer through the activation of STAT3. PTGS2 (COX-2) is a key inflammatory mediator in colorectal cancer. Nlrp3 and Nlrp6, members of NLR family sense microbial and non-microbial patterns in the cytosolic compartment and are components of inflammasomes, which function in protection from colorectal cancer. Sears, CL Cell Host & Microbe 2014 Kostic A D et al. Cancer Immunol Res 2013;1:

9 The Gut Microbiota, Inflammation and Metabolic Disease
Vjay-Kumar Cell Met. 2012;15:419 Nature 2012;482:179 Obesity is associated with with chronic, low-grade inflammation termed metabolic inflammation. A variety of PAMPs and DAMPs derived from intestinal microbiota and dietary factors have been proposed to activate TLRs and NLRs during the development of metabolic diseases (Figure 1, green and blue arrows). First, excessive nutrients or their derivatives can be directly sensed by innate pathogen receptors. Mice deficient in TLR2, TLR5, NOD1/2, and NLRP3/NLRP6 inflammasomes have been shown to develop altered gut microbiota composition (Figure 1, red arrows) In general, innate immune receptor-mediated metabolic inflammation promotes peripheral insulin resistance in liver, muscle, and adipose tissue; disrupts central control of energy homeostasis in the hypothalamus; and impairs insulin secretion in pancreatic islets. In addition, innate immune receptors regulate the composition of the intestinal microbiota, which in turn affects various metabolic processes. The net effect of all these aspects contributes to the development of metabolic syndrome and T2DM (Figure 2). Jin et al. Cell Met. 2013;17:873

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

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

12 The Mycobiome in IBD ASCA and Crohn’s Disease

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

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


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