The Gut–Liver Axis in Metabolic Dysfunction-Associated Steatotic Liver Disease

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) or non-alcoholic fatty liver disease (NAFLD) is now regarded as a leading global cause of chronic liver disease associated with metabolic syndrome. The key element here is the gut-liver axis, which, through dysbiosis, leads to the appearance and development of NAFLD. Metabolic damage reduces the number of intestinal bacteria that affect liver function, tight junction protein expression, and intestinal permeability; this results in lipopolysaccharides and other bacterial metabolites entering the liver through the portal vein. At the same time, short-chain fatty acids are suppressed, as well as the FXR nuclear receptor, which regulates the synthesis of bile acids in the liver. This spiral leads to increased levels of triglycerides in hepatocytes and their accumulation in the liver (over 5% of liver volume). Translocation of endotoxins activates Toll-like receptors (TLR4) and NF-κB transcription factor in Kupffer cells and hepatocytes; this triggers the secretion of pro-inflammatory cytokines (TNFα, IL-6). Inflammatory factors activate hepatic stellate cells, which leads to fibrosis and extracellular matrix deposition. Thus, MASLD progresses to fibrosis and cirrhosis of the liver. The term MASLD is used to describe patients with a wide range of phenotypes, from healthy people with fatty infiltration to severe liver failure with complications such as ascites, jaundice, and hepatic encephalopathy. Measures to regulate the gut-liver axis, such as prebiotics, probiotics, synbiotics, and postbiotics, have shown good results in reducing intestinal permeability and inflammation in patients with NAFLD. However, the results of histological changes were not consistent enough to recommend these drugs for therapeutic use. Therefore, it is necessary to consolidate the data obtained using multi-omics technologies and to conduct clinical trials in order to develop methods for personalized medicine that would be applicable in the clinic.