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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
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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