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

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

Microbiota and microbiome

Aron-Wisnewsky, Nat Rev Gastr Hepatol 2012

COMPOSITION OF THE COLONIC MICROBIOTA: MOLECULAR APPROACH

Eckburg et al, Science 2005 Arumugam et al., Nature 2011

Quali-quantitative alterations of gastric, digiuno-ileal and colonic flora

GUT microbiota-related diseases

DYSBIOSIS (bacterial overgrowth/reduction)

PROTECTIVE FACTORS ADVERSE

FACTORS

De Filippo et al., PNAS 2010

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

Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa

Diet rapidly and reproducibly alters the human gut microbiome

David et al., Nature 2014

Richness of human gut microbiome correlates with metabolic markers

Le Chatelier et al., Nature 2013

Richness of human gut microbiome correlates with metabolic markers

Le Chatelier et al., Nature 2013

Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice

LeRoy et al, GUT 2012; Serino et al., GUT 2012

INHERITED?

THE “OBESE MICROBIOTA” Kalliomaki et al., Am J Clin Nutr 2008 Collado et al., Am J Clin Nutr 2010 Turnbaugh et al, Nature 2009

DIET-INDUCED? Hildebrandt et al, Gatroenterology 2009 De Filippo et al., PNAS 2010 Wu et al., Science 2011 Muegge et al., Science 2011 Ley et al., Nature 2006

AGING? Claesson et al., Nature 2012

Western lifestyle vs Mediterranean diet Saturated fat Carnithine and choline Industrial fructose

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

Richness of human gut microbiome correlates with metabolic markers

Le Chatelier et al., Nature 2013

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

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.

Tilg & Moschen, Gastroenterology 2015

INFLAMMATORY MECHANISMS OF FOOD COMPONENTS

Tilg & Moschen, Gastroenterology 2015

ANTI-INFLAMMATORY MECHANISMS OF FOOD COMPONENTS

Bacteroides tetaiotamicron Fecalibacterium prausnitzii

Gut-adipose tissue axis in hepatic fat accumulation in humans

Munukka et al., J Hepatol 2014

Gut-adipose tissue axis in hepatic fat accumulation in humans

Munukka et al., J Hepatol 2014

D. Nlrp3 -/- mice C. WT mice

Chow HFHC Chow HFHC

Alpha-diversity Beta-diversity

55,5

66,5

77,5

88,5

99,510

WT chow WT HFHC NLRP3 chow NLRP3 HFHC

** *** *

A. B.

Firmicutes Bacteroidetes Proteobacteria Verrucomicrobia

EFFECT OF A WESTERN LIFESTYLE DIET ON GUT MICROBIOTA COMPOSITION

Agostinelli L et al., submitted

Dysbiosis contributes to fibrogenesis in the course of chronic liver injury.

De Minicis et al., Hepatology 2013

Characterization of the gut microbiome in non-alcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH

Zhu et al., Hepatology 2013

Intestinal Microbiota in Patients With Nonalcoholic Fatty Liver Disease

Mouzaki M. et al, Hepatology 2013

There is an inverse and diet-/BMI-independent association between the presence of NASH and percentage Bacteroidetes in the stool

METABOLIC INFECTION (Amir EMBO Mol Med 2011)

Increased Intestinal Permeability and Tight Junction Alterations in Nonalcoholic Fatty Liver Disease

Miele et al., Hepatology 2009

0% NAFLD 67% NASH

Intestinal permeability is increased in children with non-alcoholic fatty liver disease, and correlates with liver disease severity

Giorgio et al., Dig Liv Dis 2014

Obesity and intestinal inflammation

Pendyala et al., Am J Clin Nutr 2011; Ding et al., PLoS One 2010

Mediators of the interactions between the host and the microbiome

• Ethanol

• Choline

• Microbial products

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

Inflammasome involved in liver disease

Szabo & Petrasek, Nat Rev Gastro 2015

HCC Development Is Associated to Peripheral Insulin Resistance in a Mouse Model of NASH

De Minicis et al., PloS One 2014

Csak et al., Hepatology 2011

Fatty Acid and Endotoxin Activate Inflammasomes in Mouse Hepatocytes that Release Danger Signals to Stimulate Immune Cells

Inflammasomes as systems integrators in low-signal liver diseases

Szabo & Petrasek, Nat Rev Gastro 2015

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

Dysbiosis contributes to fibrogenesis in the course of chronic liver injury.

De Minicis et al., Hepatology 2013

EFFECT OF A WESTERN LIFESTYLE DIET ON GUT MICROBIOTA COMPOSITION

Agostinelli L et al., submitted

Chow diet HFHC HFHC + Atbx

Lade et al., Curr Opin Oncol 2014

Cani PD, Nat Rev Endocrinol 2014

The gut microbiota manages host metabolism

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

Vrieze at al., Gastroenterology 2012, brief report

Transfer of Intestinal Microbiota from Lean Donors Increases Insulin Sensitivity in Subjects with Metabolic Syndrome

Dietary intervention impact on gut microbial gene richness

Cotillard et al., Nature 2013

↓ Hip circumference

↓ Total fat mass

↓ Circulating cholesterol

↓ C-reactive protein

LGC

HGC

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

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

GUT MICROBIOTA, BILE ACIDS AND METABOLISM

p = 0.0002

%

FLINT Primary Endpoint

-Improvement in NAS score ≥ 2 pts -No worsening of fibrosis

Neuschwander-Tetri et al., Lancet 2014

The beneficial effects of VSL#3 in obese children with non-alcoholic steatohepatitis

Alisi A et al. Aliment Pharmacol Ther 2014

n = 44, BMI > 85th percentile and steatosis

The beneficial effects of VSL#3 in obese children with non-alcoholic steatohepatitis

Alisi A et al. Aliment Pharmacol Ther 2014

n = 44, BMI > 85th percentile and steatosis

Svegliati-Baroni G et al., Liv Intern 2011; Gastaldelli A & Svegliati-Baroni G, Hepatology, in revision.

MECHANISMS OF GLP-1 EFFECTS ON HEPATIC STEATOSIS AND INFLAMMATION

LIRAGLUTIDE IS EFFECTIVE IN THE HISTOLOGICAL CLEARANCE OF NASH IN A MULTICENTER, DOUBLE-BLINDED, RANDOMIZED, PLACEBO-CONTROLLED

PHASE II TRIAL.

%

Armstrong et al., EASL 2015 #G01

NASH resolution

p = 0.019

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