The Multifaceted Roles of Gut Microbiota and Their Metabolites in Metabolic Dysfunction-associated Steatotic Liver...

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a major global health concern and encompasses a spectrum ranging from hepatic steatosis and metabolic dysfunction-associated steatohepatitis to liver fibrosis, cirrhosis, and ultimately hepatocellular carcinoma. Insulin resistance, the pathogenic cornerstone of MASLD, drives enhanced peripheral lipolysis and increased hepatic de novo lipogenesis, thereby overloading the liver with lipids and inducing steatosis. Subsequent lipotoxicity, inflammation, and gut microbiota dysbiosis further exacerbate disease progression. The gut microbiota and their metabolites communicate with the liver via the gut-liver axis, forming a complex signaling network that directly or indirectly modulates hepatic metabolism, systemic immune responses, oxidative stress, and intestinal barrier integrity. In this review, we synthesize evidence for the beneficial and detrimental effects of the major human gut microbial communities and their metabolites during the course of MASLD. We delineate how these gut-derived factors regulate hepatic function through an integrated tripartite "gut-liver axis-oxidative stress-metabolic reprogramming" mechanism. These insights may inform microbiome-based precision interventions and accelerate the development of therapeutic strategies targeting MASLD.