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, 16S 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.