The Gut-Liver Axis in Metabolic Dysfunction-Associated Steatotic Liver Disease and Associated Hepatocellular Carcinoma: Pathogenesis and Therapeutic Interventions.

Metabolic dysfunction-associated steatotic liver disease (MASLD) comprises a spectrum of liver diseases from simple steatosis to metabolic dysfunction-associated steatohepatitis and its associated fibrosis, cirrhosis, and MASLD-associated hepatocellular carcinoma (MASLD-HCC). MASLD affects over one-third of the global adult population and is closely associated with insulin resistance, obesity, genetic factors, and increasingly recognized, gut microbiome dysbiosis. The gut-liver axis, referring to the communication network between the intestinal microbiota and liver, is critical to the progression of MASLD. The gut microbiota composition and/or functions are disrupted, leading to intestinal barrier destruction, systemic inflammation and modulation of hepatic metabolism and immune responses. The review aims to summarize the effects of gut microbiota on MASLD and its malignant transition to associated HCC based on their roles of microbial metabolites, immune regulation and their associated genetic factors, and to discuss the potential application of microbiome-targeted therapeutic strategies, including probiotics and prebiotics, synbiotics and postbiotics, fecal microbiota transplantation, engineered bacteria and bacteriophage therapy, small molecule inhibitors, microbiota-derived metabolites, with the aim of providing a new vision in the treatment of MASLD and MASLD-HCC. Finally, we discuss current challenges in basic and clinical research of the role of microbiome in MASLD and propose future directions to drive progress in this field.