Objectives: Long-term Western diet-induced non-alcoholic steatohepatitis (NASH) can lead to liver cirrhosis and NASH-associated hepatocellular carcinoma, which are end-stage liver diseases. Meanwhile, NASH is associated with mental burden and worsens as the disease progresses. Atractylodes Macrocephala Koidz (AMK) is one of the main ingredients of Shenling Baizhu San, and the effect of Polysaccharide from AMK ameliorates (PAMK), as an important medicinal ingredient of AMK, on NASH and associated anxiety/depression-like behaviors is still unclear. Methods: This study investigated the protective effect of PAMK on NASH and associated anxiety/depression-like behaviors through a Western diet-induced NASH mice model. Results: showed that PAMK decreased the concentrations of liver TC, TG, and serum AST and ALT, improving glucose tolerance, and reducing liver steatosis and fibrosis. Moreover, the expression of liver IL-6, IL-1β, TNF-α, IL-18 and MCP-1 could be reduced by PAMK significantly. Additionally, PAMK decreased anxiety/depression-like behaviors and expression of IL-6, IL-1β, TNF-α, and MCP-1 in the hippocampus. 16S rRNA gene sequencing revealed that PAMK diminished the Firmicutes/Bacteroidetes ratio and abundance of Faecalibaculum_rodentium, and increased the abundance of Muribaculaceae. This might be related to gene abundance of Pentose, the glucuronate interconversions pathway and carbohydrate enzymes (GH1, GH4). Serum metabolomics suggested that PC (18:5e/2:0), PC (16:2e/2:0), Lysopc 20:4, PC (16:0/2:0), and LPC 19:0 upregulated significantly after PAMK intervention, together with the enrichment of carbon metabolism and Citrate cycle pathways specially. Conclusions: PAMK as a potential prebiotic ameliorated NASH and associated anxiety/depression-like behaviors in mice, probably by regulating Faecalibaculum_rodentium, carbohydrate enzymes and lipid metabolites.
