Gut microbiota shaping fatty liver disease progression

The gut-liver axis is an important regulator of homeostasis, and its dysregulation has been implicated in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). In this review, we summarize current knowledge on both compositional alterations of the gut microbiome in MASLD and the functional consequences of these changes. We first discuss changes across major microbial domains, including bacteria, archaea, eukaryota, and bacteriophages, and then focus on microbiota-derived metabolites, such as short-chain fatty acids, trimethylamine and its derivative trimethylamine N-oxide, tryptophan-derived indoles, secondary bile acids, and other bioactive compounds. Their complex impacts on intestinal barrier integrity, inflammation, lipid and glucose metabolism, and immune and hormonal signaling in the liver are highlighted. We further examine mechanisms involving the translocation of microbial products and the modulation of nuclear and membrane receptors. Finally, we outline current challenges and knowledge gaps that need to be addressed to better understand the role of the gut microbiota in MASLD.