Yanxiao Di'naer decoction attenuates metabolic dysfunction-associated steatohepatitis through the regulation of gut microbiota and the metabolism of bile acid.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: Metabolic dysfunction-associated steatohepatitis (MASH), a chronic liver disease characterised by ballooning degeneration of hepatocytes, inflammation and fibrosis, has become a global health concern. Yanxiao Di'naer decoction (YD) is a Uyghur medical compound used for the treatment of hepatitis. Nevertheless, the mechanism underlying the effects of YD on MASH remains to be clarified. AIM OF THE STUDY: This study was designed to evaluate the therapeutic efficacy of YD in high-fat high-cholesterol diet (HFHCD)-induced MASH, and to explore its mechanism of action through the utilisation of metabolomics and 16S RNA sequencing techniques. MATERIALS AND METHODS: Mice with MASH were treated with YD (250 or 500 mg/kg). The efficacy of YD in MASH mice was evaluated using histological staining and biochemical assays. Mice serum were analysed by metabolomics and targeted metabolomics analysis of mouse faecal bile acids was performed. The protective effect of YD on the intestinal barrier was evaluated using RT-qPCR and Western blotting. Additionally, mouse intestinal microbiota was analysed by 16S RNA sequencing. The effect of gut microbes on YD treatment of MASH was validated using pseudo-germ-freemice. RESULTS: The experimental results indicated that YD significantly improved hepatic steatosis and fibrosis, alleviated abnormal lipid metabolism and liver damage. Metabolomic analysis revealed that 94 metabolites were significantly altered by YD, primarily enriched in pathways related to bile acid metabolism. Fecal bile acid metabolomics demonstrated that the YD significantly altered 23 bile acids. Histological examination of colonic tissue revealed that YD exerted a protective effect against damage to the intestinal barrier. 16S RNA sequencing revealed that YD increased the diversity of the intestinal microbiota and modulated the relative abundance of specific bacterial taxa. Spearman's correlation analysis revealed a significant correlation between YD-mediated improvement of MASH and alterations in the gut microbiota, which was further validated through pharmacodynamic studies in pseudo-germ-free mice. CONCLUSIONS: These findings demonstrate that YD improves hepatic lipid metabolism abnormalities, inflammation, and fibrosis in MASH mice by regulating bile acid metabolism, and that its therapeutic effects are associated with modulation of the gut microbiota.