Integrated metabolomics and gut microbiota analyses reveal the protective effects of matrine in ulcerative colitis

Background Ulcerative colitis (UC) is a chronic inflammatory bowel disease driven by gut microbial dysbiosis and metabolic dysfunction. Matrine, a natural alkaloid with anti-inflammatory properties, shows therapeutic potential; however, its mechanisms involving the coordinated modulation of bacteria, fungi, and host intestinal luminal metabolism remain unclear. Methods We evaluated the therapeutic efficacy of matrine using a dextran sulfate sodium (DSS)-induced murine model of ulcerative colitis. Disease severity was assessed via the disease activity index, colon length, and histopathology. Integrated multi-omics approaches, including metagenomics, ITS fungal sequencing, and untargeted metabolomics of intestinal luminal contents, were employed to systematically characterize the regulatory effects of matrine on gut bacteria, fungi, and metabolic profiles. Results Here, we demonstrated that oral matrine significantly alleviated disease severity in a DSS-induced UC mouse model, as evidenced by improved disease activity index, colon length, histopathology, and restoration of tight junction proteins. Integrated multiomics revealed that matrine restored bacterial homeostasis—suppressing Escherichia while enriching SCFAs-producing taxa (Muribaculum, Paramuribaculum, Clostridium). Metagenomic predictions revealed that matrine treatment reversed the model-induced suppression of carbohydrate metabolism and bile acid biosynthesis while upregulating depleted CAZy enzyme families, thereby correcting dysregulated metabolic functions in colitis. Furthermore, matrine rebalanced the mycobiota by normalizing the Ascomycota/Basidiomycota ratio. Intestinal luminal contents untargeted metabolomics identified 43 matrine-responsive metabolites, implicating correction of bile acid metabolism, attenuation of leukotriene-mediated inflammation, and reversal of acylcarnitine-driven epithelial energy disruption. Critically, pro-inflammatory metabolites correlated positively with Escherichia and negatively with beneficial symbionts. Conclusion Our findings established that matrine exerted protective effects in UC through a unified “microbiota–metabolism” axis, highlighting its promise as a multi-target therapeutic agent for UC.