The Role of Gut-Liver Axis in Gut Microbiome Dysbiosis Associated NAFLD and NAFLD-HCC

Abstract

Nonalcoholic fatty liver disease (NAFLD) is considered as one of the most prevalent chronic liver diseases worldwide due to the rapidly rising prevalence of obesity and metabolic syndrome. As a hepatic manifestation of metabolic disease, NAFLD begins with hepatic fat accumulation and progresses to hepatic inflammation, termed as non-alcoholic steatohepatitis (NASH), hepatic fibrosis/cirrhosis, and finally leading to NAFLD-related hepatocellular carcinoma (NAFLD-HCC). Accumulating evidence showed that the gut microbiome plays a vital role in the initiation and progression of NAFLD through the gut-liver axis. The gut-liver axis is the mutual communication between gut and liver comprising the portal circulation, bile duct, and systematic circulation. The gut microbiome dysbiosis contributes to NAFLD development by dysregulating the gut-liver axis, leading to increased intestinal permeability and unrestrained transfer of microbial metabolites into the liver. In this review, we systematically summarized the up-to-date information of gut microbiome dysbiosis and metabolomic changes along the stages of steatosis, NASH, fibrosis, and NAFLD-HCC. The components and functions of the gut-liver axis and its association with NAFLD were then discussed. In addition, we highlighted current knowledge of gut microbiome-based treatment strategies targeting the gut-liver axis for preventing NAFLD and its associated HCC.

Keywords: gut microbiome; gut–liver axis; intestinal barrier; metabolites; non-alcoholic fatty liver disease.

Figure 1

The diagrammatic representation of gut–liver axis. The communication between gut and liver in NAFLD is the intestinal barrier, which is composed of mucus layer, intestinal epithelium, mucosal immune system, and gut vascular barrier (GVB). The gut microbiota and their metabolites as well as some proinflammatory products can pass through the intestinal barrier and enter the liver through the portal system. In the liver, they can promote or inhibit the progression of NAFLD through different mechanisms. Meanwhile, liver can also regulate intestinal function and gut microbiota balance through the bile acid circulation, which is an important enterohepatic circulation in regulating NAFLD (Created with BioRender.com).

Figure 2

The role of gut–liver axis in the gut microbiota dysbiosis and microbiome-based NAFLD treatment. When the gut microbiota is in homeostasis, it is difficult for the pathogenic bacteria and metabolites to go through the intestinal barrier and reach the liver. When the gut microbiota is dysbiosis, the intestinal barrier is damaged (decreased mucus layer, increased epithelium, and endothelium layer permeability); thus, the pathogenic bacteria and metabolites can easily go through the intestinal barrier, come to the portal system, and finally reach the liver, where they can promote NAFLD progression. Microbiome-based treatment (probiotics and beneficial metabolites) can repair the intestinal barrier and the beneficial metabolites can reach the liver through the portal vein to prevent NAFLD progression (Created with BioRender.com, https://biorender.com/, accessed on 4 February 2022).