Gut microbiota, fatty liver disease, and hepatocellular carcinoma

Abstract

Intestinal bacteria contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Recently developed microbial profiling techniques are beginning to shed light on the nature of the changes in the gut microbiota that accompany NAFLD and non-alcoholic steatohepatitis (NASH). In this review, we summarize the role of gut microbiota in the development of NAFLD, NASH, and hepatocellular carcinoma (HCC). We highlight the mechanisms by which gut microbiota contribute to NAFLD/NASH, including through alterations in gut epithelial permeability, choline metabolism, endogenous alcohol production, release of inflammatory cytokines, regulation of hepatic Toll-like receptor (TLR), and bile acid metabolism. In addition, we analyze possible mechanisms for enhanced hepatic carcinogenesis, including alterations in bile acid metabolism, release of inflammatory cytokines, and expression of TLR-4. Finally, we describe therapeutic approaches for NAFLD/NASH and preventive strategies for HCC involving modulation of the intestinal microbiota or affected host pathways. Although recent studies have provided useful information, large-scale prospective studies are required to better characterize the intestinal microbiota and metabolome, in order to demonstrate a causative role for changes in the gut microbiota in the etiology of NAFLD/NASH, to identify new therapeutic strategies for NAFLD/NASH, and to develop more effective methods of preventing HCC.

Keywords: Fatty liver disease; Gut microbiota; Hepatocellular carcinoma (HCC); Intestinal microbiome; Metabolome; Metagenome; Non-alcoholic fatty liver disease (NAFLD); Non-alcoholic steatohepatitis (NASH).

Conflict of interest statement

Conflict of interest The authors declare that they have no conflict of interest.

Figures

Fig. 1. Effects of the intestinal microbiota on NAFLD/NASH

HFD feeding results in dysbiosis and intestinal bacterial overgrowth. Dysbiosis leads to greater production of ethanol (EtOH) and SCFA, which are metabolized in the liver. Dietary choline is metabolized by the intestinal microbiota to form TMA, resulting in choline deficiency and hepatic steatosis. The intestinal microbiota suppresses expression of the Fiaf gene by intestinal epithelial cells, resulting in enhanced activity of LPL and greater liberation of free fatty acids (FFA). Greater intestinal permeability leads to translocation of microbial products to the liver and causes inflammation through activation of TLRs and production of inflammatory cytokines, which can drive NAFLD/NASH progression. Dysbiosis also affects bile acid metabolism, which influences the progression of NAFLD through modulation of FXR and TGR5. Abbreviations: HFD, high fat diet; SCFA, short-chain fatty acid; TMA, trimethylamine; Fiaf, fasting-induced adipocyte factor; LPL, lipoprotein lipase; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; FXR, farnesoid X nuclear receptor; TGR5, G-protein-coupled receptor.

Fig. 2. Effects of the intestinal microbiota on HCC tumorigenesis

Long term ingestion of a HFD results in dysbiosis and intestinal bacterial overgrowth. Greater intestinal permeability leads to translocation of microbial products to the liver and causes inflammation and TLR activation, which can stimulate HSCs to produce pro-fibrotic factors, In addition, changes in the gut microbiota can result in higher levels of DCA, which provoke a senescence-associated secretory phenotype (SASP) in HSCs. All of these factors promote the development of HCCs. Abbreviations: HCC, hepatocellular carcinoma; HFD, high fat diet; TLR, Toll-like recepter; HSCs, hepatic stellate cells; DCA, deoxycholic acid; SCFA, short-chain fatty acid.