Hypsizygus marmoreus and β-Muricholic Acid Attenuate High-Fat-Diet-Associated Hepatic Steatosis: Integrated Mycobiome, Metabolomic, and Transcriptomic Analyses

ABSTRACT:

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly important health concern in children and adolescents. Gut microbial dysbiosis and microbe-derived metabolites may contribute to hepatic metabolic dysfunction, but the potential roles of the edible mushroom Hypsizygus marmoreus and its metabolites remain incompletely understood. Objective: To characterize gut fungal differences associated with MAFLD, evaluate the effects of H. marmoreus in a high-fat-diet mouse model, and investigate beta-muricholic acid (beta-MCA) as a candidate metabolite associated with these effects. Methods: Fecal samples from 31 participants with MAFLD and 16 healthy controls were analyzed using fungal internal transcribed spacer sequencing. Fungal diversity and differential taxa were evaluated using community diversity analyses and LEfSe. The effects of H. marmoreus intervention were assessed in high-fat-diet-fed mice by liver histology, organ and adipose tissue weights, serum aminotransferases, and lipid profiles. Untargeted metabolomic analyses of mouse feces and liver, together with clinical plasma metabolomics, were used to prioritize candidate metabolites. beta-MCA was subsequently evaluated in a mouse intervention, and liver transcriptomic data were analyzed to identify differentially expressed genes and enriched pathways. Results: Fungal community structure differed between participants with MAFLD and healthy controls (Bray-Curtis-based PERMANOVA, P = 0.016). LEfSe analysis suggested enrichment of Hypsizygus-related taxa and the family Lyophyllaceae in healthy controls. In high-fat-diet-fed mice, H. marmoreus intervention was associated with reduced hepatic steatosis, lower liver and epididymal fat weights, decreased serum AST and ALT levels, and an improved lipid profile. beta-MCA intervention showed a similar pattern of phenotypic improvement. Liver transcriptomic analysis identified 295 upregulated and 439 downregulated genes using the reported thresholds of |log2 fold change| >= 1 and nominal P < 0.05. Pathway enrichment highlighted PI3K-AKT signaling and the biosynthesis of unsaturated fatty acids. These findings suggest that beta-MCA-associated changes in lipid metabolism and signaling may contribute to the observed phenotype; however, the proposed involvement of PI3K/AKT/mTOR signaling and autophagy requires direct experimental validation. Conclusions: The findings support further investigation of H. marmoreus and beta-MCA as potential modulators of diet-associated hepatic steatosis. The human fungal findings are associative, and additional targeted metabolomic, molecular, and functional experiments are needed to establish the causal relationship between beta-MCA, signaling pathways, autophagy, and hepatic protection.

INSTRUMENT(S): Liquid Chromatography MS - alternating - hilic

PROVIDER: MTBLS16135 | MetaboLights | 2026-10-23

REPOSITORIES: MetaboLights