Shenling Baizhu San Ameliorates MASH and Associated Depression-like Behavior in Mice by Impacting Gut Microbiota and Carbohydrate Enzymes.

Abstract

Introduction: A major clinical concern of Metabolic Dysfunction-Associated Steatohepatitis (MASH) is its potential to progress to cirrhosis and hepatocellular carcinoma. Although Shenling BaiZhu San (SLBZS) has shown potential in managing MASH, its underlying therapeutic mechanisms remain unclear. This study sought to explore how SLBZS ameliorate MASH, particularly its regulatory effects on gut microbiota and carbohydrate enzymes (CAZymes).

Methods: 15 male C57BL/6 mice were assigned to three groups: control (normal diet, ND), MASH (Western diet combined with CCl₁, WDC), and treatment (WDC plus daily SLBZS, WDC-SLBZS). After 12 weeks, the physiological, biochemical, pathological and behavioral indicators of the mice were assessed, and 16S rRNA gene sequencing was conducted, along with characterization of CAZymes in fecal samples from all experimental groups.

Result: The treated mice showed reduced hepatic steatosis and fibrosis, with significantly lower liver lipids (TC and TG), serum enzymes (AST and ALT), and pro-inflammatory cytokines (IL6, IL-1β, and MCP-1), accompanied by alleviation of depression-like behavior. 16S rRNA gene analysis revealed that beneficial bacteria (Muribaculum, Rikenellaceae, and Prevotellaceae) were significantly decreased in the MASH mice, whereas potentially harmful taxa (Klebsiella, Corynebacterium, and Faecalibaculum) were increased; these trends were reversed in the treatment group, especially for Rikenellaceae (P < 0.05). CAZymes, markedly diminished in MASH (P < 0.05), were partially restored after treatment. Correlation analysis showed that declines in Rikenellaceae and increases in Corynebacterium both positively correlated with depression-like behavior (r ≥ 0.7, P < 0.05).

Discussion: The benefits of SLBZS against MASH and associated depression are not simply in rebuilding the gut microbiota, but in reshaping carbohydrate metabolism through regulated CAZymes, which restores the intestinal barrier and energy balance, thereby attenuating liver lipid accretion and the inflammatory cascade. Although efficacy has been validated, the "microbiotaCAZyme-host metabolism" causal chain at finer taxonomic and functional levels needs further analysis.

Conclusion: SLBZS may relieve liver lipid accumulation, inflammatory damage, and associated depression-like behavior in MASH by partially restoring beneficial bacteria (e.g., Rikenellaceae) and related CAZymes.