Human Gut Microbiome and Liver Diseases: From Correlation to Causation

Abstract

The important role of human gut microbiota in liver diseases has long been recognized as dysbiosis and the translocation of certain microbes from the gut to liver. With the development of high-throughput DNA sequencing, the complexity and integrity of the gut microbiome in the whole spectrum of liver diseases is emerging. Specific patterns of gut microbiota have been identified in liver diseases with different causes, including alcoholic, non-alcoholic, and virus induced liver diseases, or even at different stages, ranging from steatohepatitis, fibrosis, cirrhosis, to hepatocellular carcinoma. At the same time, the mechanism of how microbiota contributes to liver diseases goes beyond the traditional function of the gut–liver axis which could lead to liver injury and inflammation. With the application of proteomics, metabolomics, and modern molecular technologies, more microbial metabolites and the complicated interaction of microbiota with host immunity come into our understanding in the liver pathogenesis. Germ-free animal models serve as a workhorse to test the function of microbiota and their derivatives in liver disease models. Here, we review the current evidence on the relationship between gut microbiota and liver diseases, and the mechanisms underlying this phenotype. In addition to original liver diseases, gut microbiota might also affect liver injury in systemic disorders involving multiple organs, as in the case of COVID-19 at a severe state. A better understanding of the gut microbial contribution to liver diseases might help us better benefit from this guest–host relationship and pave the way for novel therapies.

Gut Microbiome and Alcohol-associated Liver Disease

“…Compositional and functional profiling revealed the association between human GM and multiple diseases affecting the liver. These diseases include hepatic steatosis, non-alcoholic fatty liver disease, alcohol-associated liver disease (ALD), alcohol-associated hepatitis (AH), chronic cholestatic conditions (e.g., primary biliary cholangitis and primary sclerosing cholangitis), autoimmune liver disease, complications of cirrhosis and portal hypertension such as hepatic encephalopathy (HE), infections such as spontaneous bacterial peritonitis, and hepatocellular carcinoma (2).…”

Role and Regulation of Hepatobiliary ATP-Binding Cassette Transporters during Chemical-Induced Liver Injury

“…By contrast, the presence of gut bacteria enhances ductular reactions, cell proliferation, deposition of collagen 1 and cell autophagy (Juanola et al, 2021). Despite the dramatic surge in microbiome research in the last decade, much more needs to be known about the relationship between the gut microbiome and health and disease, including how changes in its composition and function influences liver diseases, including DILI (Forootan et al, 2017;Chan and Benet, 2018;Li et al, 2021).…”

Gut Microbiota as the Link between Elevated BCAA Serum Levels and Insulin Resistance

“…For example, dietary fiber polysaccharides that cannot be cleaved by human glycosidases are fermented by gut microbiota to form short-chain fatty acids (SCFA) that exert pleiotropic effects on the host. They serve as the main energy source for colonocytes [3]; contribute to the maintenance of intestinal barrier [4]; stimulate the maturation of gut-associated immune cells with anti-inflammatory potential [5]; or regulate energy expenditure in the liver, adipose tissue, or skeletal muscle [6]. Among other wellstudied end-products are choline, an essential nutrient which is utilized by gut microbes and its deficiency leads to the NASH-like syndrome [7], or acetaldehyde derived from ethanol by intestinal microbiota, which has been shown to disrupt tight junctions between intestinal mucosal cells [8].…”