Integrated Metabolomics and Gut Microbiome Analysis Reveal the Role of Demethylzeylasteral in Alleviating Ulcerative Colitis in Mice

Demethylzeylasteral (DMLL) is a natural compound isolated from the root of the herbal plant <i>Tripterygium wilfordii</i> Hook. F. It exhibits various pharmacological activities, yet the therapeutic effects against ulcerative colitis (UC) remain poorly understood. In this study, multiomics analysis revealed that DMLL alleviated DSS-induced experimental colitis by reconstructing gut microbiota and improving metabolic dysbiosis. The Bacteroidota phylum and genera of <i>norank_f_Muribaculaceae</i> and <i>Ruminococcus</i> with beneficial potential for UC were the major gut flora influenced by DMLL treatment. In terms of microbiota-derived metabolites, DMLL primarily enriched tryptophan metabolites, secondary bile acids, and nicotinamide. These compounds possess anti-inflammatory activity and protective effects for intestinal epithelial barrier, subsequently altered metabolic pathways, and improved impaired host gut homeostasis. In addition, we found significantly elevated levels of indolelactic acid (ILA) in the cecum of colitis mice and showed a strong positive correlation with UC symptoms, whereas serum levels of ILA were remarkably reduced and exhibited a negative association with UC, suggesting its dual role in colitis. Importantly, DMLL treatment effectively restored ILA levels in both the cecum and the systemic circulation. These findings provide novel mechanistic insights into the anticolitis effect of DMLL in mice, highlighting the crucial role of gut microbiota in its therapeutic action.