Functional Role of Gut Microbiota in Chronic Liver Disease

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1 PennCHOP MICROBIOME PROGRAM Functional Role of Gut Microbiota in Chronic Liver Disease Gary D. Wu, M.D. Ferdinand G. Weisbrod Professor of Medicine Division of Gastroenterology Perelman School of Medicine University of Pennsylvania

2 Agenda The Intestinal Microbiome The Microbiome and Cholestatic Liver Disease: Plausible Interactions Effect of Microbiome on Bile Acids and Potential Therapeutic Interventions

3 The Human Microbiome Comprised of bacteria, viruses, and other micro-organisms 1 Distinctive microbiomes at each body site (eg, gut, lung, skin, mucosa) 2 The gut microbiota Human gut is home to ~100 trillion bacterial cells 3 Density of to per gram in the colon 4 Large numbers of species present, many uncultured 1.Tabibian JH, et al. Liver Int. 2016;36: Spor A, et al. Nat Rev Microbiol. 2011;9: Llorente C, et al. Cell Mol Gastroenterol Hepatol. 2015;1: Goel A, et al. J Gastroenterol Hepatol. 2014;29: Graphic with permission from Spor A, et al. Nat Rev Microbiol. 2011;9:

4 Host-Microbial Mutualism in the Gut Host benefits to bacteria 1 Provides unique niche Intestinal mucus provides source of nutrition Bacteria benefits to host 1 Fermentation of indigestible carbohydrates and production of SCFAs Biotransformation of conjugated bile acids Urease activity participates in nitrogen balance Synthesis of certain vitamins Metabolize drugs Education of the mucosal immune system Abbreviations: AMP, antimicrobial peptides; Ig, immunoglobulin; PSA, polysaccharide A; SCFA, short-chain fatty acids; SFB, segmented filamentous bacteria; Treg, regulatory T-cells. 1. Wu GD. Nestle Nutr Inst Workshop Ser. 2014;79: Graphic courtesy of American Gastroenterological Association. Gastroenterology, May 2014, cover.

5 Agenda The Intestinal Microbiome The Microbiome and NAFLD/NASH: Plausible Interactions Effect of Microbiome on Bile Acids and Potential Therapeutic Interventions

6 The Gut Microbiome and Liver Disease Liver is first portal that emerges from intestinal mucosal surface Receives approximately 75% of blood supply from splanchnic circulation 1 Potential liver diseases affected by gut microbiome NASH and NAFLD Cholestatic liver disease (PBC and PSC) Cirrhosis Hyperammonemia and hepatic encephalopathy Hepatic drug metabolism Abbreviations: NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis. 1. Tabibian JH, et al. Liver Int. 2016;36:

7

8 HIV and Liver Disease Joshi et al. Lancet 2011;377:1198

9 The Gut Lumen Contents and it Role in Energy Balance and Metabolic Function

10 Immune Function Diet Murine Models Demonstrating Cause-and-Effect Relationships Between the Gut Microbiome and the Development of Obesity SCFAs Anatomic Cox et al. Cell Metabolism, Volume 17, Issue 6, 2013,

11 Dietary Fiber, the Production of Short Chain Fatty Acids, and Their Effects on the Host Tremaroli et al. Nature 2012;489:242

12 Mechanisms by Which Gut Microbes May Influence the Development of Metabolic Syndrome Effect of Microbial Metabolites (i.e. SCFAs) Direct Effect of Microbes on Immune Activation Cox et al. Cell Metabolism, Volume 17, Issue 6, 2013,

13 Bacteroides Prevotella Dietary Effects on Human Gut Microbiome and its Association with Disease Wu et al. Science 2011;334:105-8 Decrease gut microbiome richness (decreased number of various bacteria and their genes) is associated with both disease states and the consumption of a Westernized diet Individuals with marked obesity, insulin resistance, dyslipidemia, and inflammatory phenotype have low bacterial richness Increased consumption of an agrarian diet, rich in fruits and vegetables with higher fiber, is associated with increased bacterial gene richness Energy-restricted diets increase bacterial gene richness

14 Bacteroides Prevotella Bacteroides Prevotella European African PNAS 2010;107:

15 Success rate of around 90% when fecal microbiota transplantation (FMT) is used to treat CDI Prescreening of donors to prevent transmission of currently known pathogens Homogenization, filtration, and administration usually through a colonoscope. FMT and the Treatment of Type 2 Diabetes

16 FMT: Clinical trials C difficile infection (38) Crohn s (5) Ulcerative Colitis (15) Pouchitis (3) IBD (9) IBS (6) Constipation (4) NAFLD/NASH (3) PSC Intestinal pseudoobstruction Autologous FMT (preventative) Obesity/metabolic syndrome (5) HIV DM-II (2) Pancreatitis (2) Hepatitis B MRSA enterocolitis Drug-resistant organisms (4) Hepatic encephalopathy (2) Post-stem cell transplant (2) Clinicaltrials. gov 06/02/2016

17 Gut Microbiome in NAFLD/NASH Schnabl and Brenner. Gastro 2014

18 Alterations or Dysbiosis of the Gut Microbiota in NAFLD and NASH in Humans Schnabl and Brenner. Gastro 2014 The Gut Microbiome as a Biomarker of Cirrhosis

19 Agenda The Intestinal Microbiome The Microbiome and NAFLD/NASH: Plausible Interactions Effect of Microbiome on Bile Acids and Potential Therapeutic Interventions

20 Role of Bile Acids and Microbiota Effect Produced from cholesterol as conjugated bile acids in liver to be secreted into small intestine 1 Absorbed in terminal ileum and returned to liver Important for 1 Absorption of dietary fat and vitamins Direct bacteriostatic effect Ligands for FXR and TGR5 Intestinal microbiota may affect liver by modifying intestinal bile acids and altering FXR signaling 1 The gut microbiota converts primary into secondary bile acids 1 Bile acid production in germ-free vs conventionally housed mice is altered by differential bile acid activation of FXR 2 Activation of FXR enhances small intestinal barrier function 3 Abbreviation: FXR, farnesoid X receptor. 1. Schnabl B, Brenner DA. Gastroenterology. 2014;146: Sayin SI,et al. Cell Metab. 2013;17: Stojancevic M, et al. Can J Gastroenterol. 2012;26:

21 Bile Salt Transformations by the Gut Microbiome and FXR Obetacholic Acid (OCA) Ridlon et al. J. Lipid Res. 2006

22 Activation of FXR is beneficial in the treatment of liver disease in both rodents and humans OCA produced marked reduction in high rate of gut bacterial translocation in Cirrhotic rats via: Reduction of fecal bacterial load Partial recovery of intestinal dysbiosis Improvements in intestinal barrier function and gut inflammation Reduced liver fibrogenesis

23 The Gut Lumen Contents and it Role in Energy Balance and Metabolic Function: Potential Therapeutic Targets Weight Control Diet and Weight Control Reverse Dysbiosis Enhance Barrier Function FXR

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