Role of the gut microbiome in nonalcoholic fatty liver disease progression

The gut microbiome (GM) is a multifaceted environment wherein nearly 10¹⁴ microorganisms play various roles in host immune regulation, intestinal cell proliferation, bone mineralization, xenobiotics metabolism, and protection against pathogens. GM is also strongly coupled with the development and progression of nutrition-related diseases such as nonalcoholic fatty liver disease (NAFLD), wherein the gut-liver axis plays a major role as the gut and liver are functionally and anatomically associated through the portal vein. Dysbiosis causes leaky gut, resulting in the activation of inflammatory processes in the liver. Disruption of the gut barrier enhances microbial infiltration into the sub-mucosae, which through the bloodstream causes harmful microbial metabolites, such as butyrate, long-chain fatty acids, endotoxins, and indole-3-acetic acid, to seep into the liver. In NAFLD patients, these metabolites can lead to the development of nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). In this review, we will discuss the important molecular pathways through which various metabolites and other signaling substances released by the GM regulate liver biology, under both physiological and pathological conditions. Finally, we highlight numerous therapeutic attempts, such as probiotics, prebiotics, and fecal microbial transplantation (FMT), to reprogram the gut-liver axis for decreasing liver diseases.