Sophora moorcroftiana Seeds Ethanol Extract Against Metabolic Dysfunction-Associated Steatotic Liver Disease in Mice by Modulating Gut Microbiota Dysbiosis, SCFAs, and Related Inflammation.

Despite the traditional application of Sophora moorcroftiana (Benth.) Baker seeds for liver disorders, the capacity of its 70% ethanol extract (SMS) to alleviate metabolic dysfunction-associated steatotic liver disease (MASLD) and the underlying gut-liver axis mechanisms remain unclear. In this study, a high-fat diet (HFD)-induced MASLD mouse model was established to investigate the protective effects of SMS and its regulatory role in the interplay among gut microbiota, short-chain fatty acids (SCFAs), and inflammation. Serum, intestinal, and hepatic samples were collected to evaluate inflammatory responses, intestinal barrier integrity, and hepatic lipid metabolism. Gut microbiota composition and SCFA profiles were analyzed using 16S rRNA sequencing and metabolomics. In LPS-stimulated Caco-2 cells, SMS reduced inflammatory cytokines and TLR4/MyD88/NF-κB-associated signaling. The results demonstrated that SMS markedly alleviated hepatic steatosis by reducing triglyceride synthesis and hepatocellular lipid accumulation. In addition, SMS promoted the proliferation of beneficial bacteria, including Bifidobacterium and Akkermansia, and increased the production of SCFAs, particularly butyrate. SMS also restored intestinal barrier integrity through upregulation of Occludin and Claudin-1, thereby reducing circulating lipopolysaccharide (LPS) levels. Furthermore, SMS attenuated inflammation by inhibiting activation of the TLR4/NF-κB signaling pathway. Collectively, these findings demonstrate that SMS alleviates MASLD through coordinated modulation of gut microbiota composition, SCFA metabolism, intestinal barrier function, and inflammatory responses, highlighting its potential as a therapeutic strategy targeting the gut-liver axis.