The gut microbiota-bile acid-FXR axis in NAFLD: from progression to therapeutic applications

Non-alcoholic fatty liver disease (NAFLD), now recognized as metabolic dysfunction-associated steatotic liver disease (MASLD), has emerged as the predominant chronic liver condition globally. Although pharmacological options have recently emerged for selected patients with MASH and moderate-to-advanced fibrosis, pharmacological treatment remains limited. Recent studies have provided compelling evidence demonstrating that both the gut microbiota and bile acids (BAs) undergo remarkable alterations in NAFLD and contribute substantially to disease progression. The farnesoid X receptor (FXR), a crucial nuclear receptor, plays a central role in the synthesis and metabolism of BAs and also regulates glucose and lipid metabolism while attenuating inflammatory responses. Because of these diverse functions, FXR has become a key focus as a potential therapeutic target for NAFLD. This review provides a comprehensive summary of the interactions between the gut microbiota and BAs, detailing their specific metabolic alterations in NAFLD. It also explains the molecular mechanisms through which FXR regulates glucose and lipid metabolism and offers an up-to-date overview of emerging therapeutic strategies that target the gut microbiota-BA-FXR axis for NAFLD. This review integrates current evidence to clarify how the gut microbiota-BA-FXR axis contributes to NAFLD/MASLD pathogenesis and therapeutic development, which are expected to offer new insights for filling the current unmet clinical need in NAFLD treatment.