Abstract
BackgroundNon-alcoholic liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, and it can progress to non-alcoholic steatohepatitis (NASH). Alterations in the gut microbiome have been implicated in the development of NAFLD/NASH, although the underlying mechanisms remain unclear.ResultsWe found that the consumption of the prebiotic inulin markedly ameliorated the phenotype of NAFLD/NASH, including hepatic steatosis and fibrosis, in mice. Inulin consumption resulted in global changes in the gut microbiome, including concomitant enrichment of the genera Bacteroides and Blautia, and increased concentrations of short-chain fatty acids, particularly acetate, in the gut lumen and portal blood. The consumption of acetate-releasing resistant starch protected against NAFLD development. Colonisation by Bacteroides acidifaciens and Blautia producta in germ-free mice resulted in synergetic effects on acetate production from inulin. Furthermore, the absence of free fatty acid receptor 2 (FFAR2), an acetate receptor, abolished the protective effect of inulin, as indicated by the more severe liver hypertrophy, hypercholesterolaemia and inflammation. These effects can be attributed to an exacerbation of insulin resistance in the liver, but not in muscle or adipose tissue.ConclusionThese findings demonstrated that the commensal microbiome–acetate–FFAR2 molecular circuit improves insulin sensitivity in the liver and prevents the development of NAFLD/NASH.1auxpva_RZCTQ5SP89UX9TVideo abstract
Highlights
Non-alcoholic liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, and it can progress to non-alcoholic steatohepatitis (NASH)
Prebiotic consumption prevents diet-induced Non-alcoholic fatty liver disease (NAFLD)/ NASH development To determine the influence of the intestinal environment on the development of NAFLD/NASH, we fed mice either a low-fat/fructose/cholesterol (LFC), high-fat/fructose/cholesterol (HFC) or 10% (w/w) inulinsupplemented HFC diet (HFC+IN; Supplementary Table 1)
Inulin consumption significantly reduced the number of liver-infiltrating CD8+ T cells with the effector/memory phenotype, which plays a role in the development of NASH [18] (Fig. 1g)
Summary
Non-alcoholic liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, and it can progress to non-alcoholic steatohepatitis (NASH). NAFLD is strongly associated with metabolic syndrome, obesity, diabetes and insulin resistance. NAFLD is characterised by greater lipid (triglyceride and cholesterol) deposition in the liver, In recent years, several lines of evidence have suggested that the gut microbiome represents a significant environmental factor contributing to NAFLD development and its progression to NASH. Gut microbe-derived imidazole propionate impairs glucose tolerance and insulin resistance in hepatocytes [11]. These observations raise the possibility that the microbial alterations in the intestine may significantly contribute to the pathogenesis of NASH, and manipulation of the gut microbiome represents an emerging strategy for the prevention of NAFLD/NASH
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