Microbial changes resulting from VSG attenuate MASLD by modulating bile acid metabolism and the intestinal FXR-FGF19 axis.

Vertical sleeve gastrectomy (VSG) is a highly effective intervention for metabolic dysfunction-associated steatotic liver disease (MASLD) and is associated with significant alterations in the gut microbiota. However, the precise mechanisms underlying its metabolic benefits remain poorly understood. In this study, we revealed that VSG mitigates MASLD by reshaping gut microbiota-mediated bile acid metabolism. Through integrated 16S rRNA sequencing, targeted metabolomics, and functional validation experiments, we demonstrated that VSG markedly enhances bile salt hydrolase (BSH) activity within the gut microbiota, resulting in elevated levels of unconjugated bile acids. These unconjugated bile acids serve as potent agonists for the intestinal farnesoid X receptor (FXR), thereby activating the intestinal FXR-fibroblast growth factor 19 signaling pathway. This activation leads to significant improvements in metabolic health, including enhanced glucose regulation and attenuated hepatic lipid accumulation. Fecal microbiota transplantation (FMT) from VSG-treated rats replicated these metabolic improvements, whereas antibiotic treatment abolished these beneficial effects, highlighting the indispensable role of the gut microbiota in mediating the anti-MASLD effects of VSG. Importantly, inhibition of intestinal FXR signaling negated the metabolic benefits of FMT, further emphasizing the critical role of the gut microbiota-BSH-FXR axis. Our findings reveal a novel mechanism by which VSG alleviates MASLD through gut microbiota-dependent activation of intestinal FXR, offering new perspectives for microbiome-targeted therapeutic strategies in MASLD. IMPORTANCE: Fecal transplantation from bariatric surgery patients and mice to germ-free mice has shown that the gut microbiota may contribute to metabolic benefits after bariatric surgery. However, the mechanisms by which the gut microbiota contributes to metabolic benefits after bariatric surgery require further investigation. To address this gap, we investigated the effects of the vertical sleeve gastrectomy (VSG) gut microbiota on metabolic dysfunction-associated steatotic liver disease (MASLD)