Perché viene la NASH (2): microbiota e permeabilità intestinale G. Svegliati-Baroni

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1 Perché viene la NASH (2): microbiota e permeabilità intestinale G. Svegliati-Baroni Clinica di Gastroenterologia SOS Epatopatie Croniche e Trapianto di Fegato Università Politecnica delle Marche Ancona

2 Gianluca Svegliati Baroni Clinica di Gastroenterologia Università Politecnica delle Marche Il sottoscritto dichiara di non aver avuto negli ultimi 12 mesi conflitto d interesse in relazione a questa presentazione e che la presentazione contiene discussione di farmaci in studio o ad uso off-label Acido Obeticolico. Agonisti Recettore GLP1, Acidi Grassi ω-3

3 Microbiota and microbiome Aron-Wisnewsky, Nat Rev Gastr Hepatol 2012

4 COMPOSITION OF THE COLONIC MICROBIOTA: MOLECULAR APPROACH Eckburg et al, Science 2005 Arumugam et al., Nature 2011

5 PROTECTIVE FACTORS ADVERSE FACTORS Quali-quantitative alterations of gastric, digiuno-ileal and colonic flora DYSBIOSIS (bacterial overgrowth/reduction) GUT microbiota-related diseases

6 Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa De Filippo et al., PNAS 2010

7 Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa De Filippo et al., PNAS 2010

8 Diet rapidly and reproducibly alters the human gut microbiome David et al., Nature 2014

9 Richness of human gut microbiome correlates with metabolic markers Le Chatelier et al., Nature 2013

10 Richness of human gut microbiome correlates with metabolic markers Le Chatelier et al., Nature 2013

11 Intestinal microbiota determines development of nonalcoholic fatty liver disease in mice LeRoy et al, GUT 2012; Serino et al., GUT 2012

12 THE OBESE MICROBIOTA INHERITED? Kalliomaki et al., Am J Clin Nutr 2008 Collado et al., Am J Clin Nutr 2010 Turnbaugh et al, Nature 2009 Hildebrandt et al, Gatroenterology 2009 DIET-INDUCED? De Filippo et al., PNAS 2010 Wu et al., Science 2011 Muegge et al., Science 2011 Ley et al., Nature 2006 Western lifestyle vs Mediterranean diet Saturated fat Carnithine and choline Industrial fructose AGING? Claesson et al., Nature 2012

13 Human gut microbes associated with obesity Ley et al., Nature 2006; Zhang et al., PNAS 2009; Turnbaugh et al., Nature 2009; Nadal et al., Int J Obes 2008; Ridaura et al., Science 2013

14 Richness of human gut microbiome correlates with metabolic markers Le Chatelier et al., Nature 2013

15 GUT HEALTH Depends on ethnic, genetic, geographic and dietary factors; Depends on a delicate balance between food, the microbiota, and immunity. Disruption of this homeostasis balance can initiate metabolic and/or inflammatory diseases (IBD, rheumatoid arthritis, metabolic syndrome, atherosclerosis, psoriasis, etc ) Sartor RB, Gastroenterology 2008

16 Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosi (Koeth et al., Nat Med 2013) Wang et al., Nature 2011; Howitt & Garrett Nat Med 2012; Tremaroli & Backhed Nature 2012; Tang et al., NEJM 2013.

17 INFLAMMATORY MECHANISMS OF FOOD COMPONENTS Tilg & Moschen, Gastroenterology 2015

18 ANTI-INFLAMMATORY MECHANISMS OF FOOD COMPONENTS Bacteroides tetaiotamicron Fecalibacterium prausnitzii Tilg & Moschen, Gastroenterology 2015

19 Gut-adipose tissue axis in hepatic fat accumulation in humans Munukka et al., J Hepatol 2014

20 Gut-adipose tissue axis in hepatic fat accumulation in humans Munukka et al., J Hepatol 2014

21 EFFECT OF A WESTERN LIFESTYLE DIET ON GUT MICROBIOTA COMPOSITION 10 9,5 9 8,5 8 7,5 7 6,5 6 5,5 5 A. Alpha-diversity B. * ** *** WT chow WT HFHC NLRP3 chow NLRP3 HFHC Beta-diversity C. WT mice D. Nlrp3 -/- mice Chow HFHC Chow HFHC Firmicutes Bacteroidetes Proteobacteria Verrucomicrobia Agostinelli L et al., submitted

22 Dysbiosis contributes to fibrogenesis in the course of chronic liver injury. De Minicis et al., Hepatology 2013

23 Characterization of the gut microbiome in non-alcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH Zhu et al., Hepatology 2013

24 Intestinal Microbiota in Patients With Nonalcoholic Fatty Liver Disease There is an inverse and diet-/bmi-independent association between the presence of NASH and percentage Bacteroidetes in the stool Mouzaki M. et al, Hepatology 2013

25 METABOLIC INFECTION (Amir EMBO Mol Med 2011)

26 Increased Intestinal Permeability and Tight Junction Alterations in Nonalcoholic Fatty Liver Disease Miele et al., Hepatology 2009

27 Intestinal permeability is increased in children with non-alcoholic fatty liver disease, and correlates with liver disease severity 0% NAFLD 67% NASH Giorgio et al., Dig Liv Dis 2014

28 Obesity and intestinal inflammation Pendyala et al., Am J Clin Nutr 2011; Ding et al., PLoS One 2010

29 Mediators of the interactions between the host and the microbiome Ethanol Choline Microbial products

30 Innate immunity Antigen-presenting cells express receptors that can sense microbial products (PAMPs), and activation of these receptors initiates an inflammatory response; Antigen-presenting cells sense endogenous signals released by damaged cells(damps) to trigger an immune response under sterile conditions i.e in the absence of microbial pathogens. Matzinger P. Ann Rev Immunol 1994; Shi Y JCI 2010

31 Inflammasome involved in liver disease Szabo & Petrasek, Nat Rev Gastro 2015

32 HCC Development Is Associated to Peripheral Insulin Resistance in a Mouse Model of NASH De Minicis et al., PloS One 2014

33 Fatty Acid and Endotoxin Activate Inflammasomes in Mouse Hepatocytes that Release Danger Signals to Stimulate Immune Cells Csak et al., Hepatology 2011

34 Inflammasomes as systems integrators in low-signal liver diseases Szabo & Petrasek, Nat Rev Gastro 2015

35 Henao-Mejia et al, Nature 2012; Mehal WZ, Nat Rev Gastroenterol Hepatol 2013

36 Dysbiosis contributes to fibrogenesis in the course of chronic liver injury. De Minicis et al., Hepatology 2013

37 EFFECT OF A WESTERN LIFESTYLE DIET ON GUT MICROBIOTA COMPOSITION Chow diet HFHC HFHC + Atbx Agostinelli L et al., submitted

38 Lade et al., Curr Opin Oncol 2014

39 The gut microbiota manages host metabolism Cani PD, Nat Rev Endocrinol 2014

40 Insight into the prebiotic concept: lessons from an exploratory, double blind intervention study with inulin-type fructans in obese women Increase in Bifidobacterium and Faecalibacterium Prausnitzii; Significant corelation between LPS levels and microbiota modification; No signifcant effects on metabolic and anthropometric parameters DeWulf et al., GUT 2012

41 Transfer of Intestinal Microbiota from Lean Donors Increases Insulin Sensitivity in Subjects with Metabolic Syndrome Vrieze at al., Gastroenterology 2012, brief report

42 Dietary intervention impact on gut microbial gene richness HGC Hip circumference Total fat mass LGC Circulating cholesterol C-reactive protein Cotillard et al., Nature 2013

43 Quantifying Diet-Induced Metabolic Changes of the Human Gut Microbiome (Shoale et al.,cell Metabolism 2015)

44 Quantifying Diet-Induced Metabolic Changes of the Human Gut Microbiome (Shoale et al.,cell Metabolism 2015)

45 GUT MICROBIOTA, BILE ACIDS AND METABOLISM

46 FLINT Primary Endpoint -Improvement in NAS score 2 pts -No worsening of fibrosis p = % Neuschwander-Tetri et al., Lancet 2014

47 The beneficial effects of VSL#3 in obese children with nonalcoholic steatohepatitis n = 44, BMI > 85 th percentile and steatosis Alisi A et al. Aliment Pharmacol Ther 2014

48 The beneficial effects of VSL#3 in obese children with nonalcoholic steatohepatitis n = 44, BMI > 85 th percentile and steatosis Alisi A et al. Aliment Pharmacol Ther 2014

49 MECHANISMS OF GLP-1 EFFECTS ON HEPATIC STEATOSIS AND INFLAMMATION Svegliati-Baroni G et al., Liv Intern 2011; Gastaldelli A & Svegliati-Baroni G, Hepatology, in revision.

50 LIRAGLUTIDE IS EFFECTIVE IN THE HISTOLOGICAL CLEARANCE OF NASH IN A MULTICENTER, DOUBLE-BLINDED, RANDOMIZED, PLACEBO-CONTROLLED PHASE II TRIAL. NASH resolution % p = Armstrong et al., EASL 2015 #G01

51 Food, immunity and the microbiome.as we associate changes in the microbiome with features of diseases, it is not clear which causes the other. In studies of obesity or malnutrition, it is not clear whether associated changes in the microbiota occurred before, during, or as a result of these disorders..a key question is whether a disease-promoting microbiota can be modified either by a dietary approach or by the use of pre- or pro-biotics in humans with NASH. Tilg & Moschen, Gastroenterology 2015

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