Polyporus umbellatus β-glucan ameliorates metabolic dysfunction-associated steatohepatitis by remodeling the gut microbiota-bile acid-FXR signaling axis.

ETHNOPHARMACOLOGICAL RELEVANCE: Polyporus umbellatus (Pers.) Fries has been used in traditional Chinese medicine for millennia to "promote water metabolism and eliminate dampness", a pathogenic concept central to metabolic dysfunction-associated steatohepatitis (MASH). Its polysaccharide extract is clinically applied in China for dampness-heat related liver disorders, but its specific bioactive components and mechanisms against MASH remain unknown. AIM OF THE STUDY: To evaluate the anti-MASH efficacy of the (1,3),(1,6)-β-D-glucan from P. umbellatus (PUP) and determine its mechanisms, focusing on the gut microbiota-bile salt hydrolase (BSH)-bile acid (BA)-farnesoid X receptor (FXR) signaling axis. MATERIALS AND METHODS: MASH was induced in mice using a methionine-choline-deficient (MCD) diet. Biochemical, histological, 16 S rRNA sequencing, targeted BA metabolomics, and molecular assays assessed hepatic injury, steatosis, inflammation, fibrosis, gut microbiota, BA profiles, and FXR signaling. Antibiotic intervention and co-housing verified the causal role of gut microbiota. RESULTS: PUP reduced serum transaminases, total BAs, and bilirubin, and alleviated hepatic steatosis, inflammation, ballooning, and fibrosis. PUP normalized the Firmicutes/Bacteroidota ratio and enriched BSH-producing genera, notably Alistipes and Lactobacillus, thereby restoring fecal BSH activity. BA profiling showed increased fecal excretion of FXR agonists (DCA, LCA) and reduced hepatic hydrophobic free BAs (Fre-BAs). PUP restored intestinal FXR-FGF15 and hepatic FXR-SHP signaling, suppressed CYP7A1, and re-established BA negative feedback. Antibiotic depletion abolished PUP's effects, while co-housing partially recapitulated its hepatoprotective action. CONCLUSIONS: PUP alleviates MASH via a gut microbiota-BSH-BA-FXR axis by remodeling the gut microbiota, enhancing BSH-dependent BA metabolism, and restoring physiological FXR feedback signaling. This indirect, safe, and multi-targeted mechanism supports PUP as a promising microbiota-dependent FXR modulator for MASH treatment.