Darutigenol alleviates experimental colitis via promoting Akkermansia muciniphila-mediated proline synthesis

Gut microbiota dysbiosis is a critical contributor to the pathogenesis and progression of inflammatory bowel disease (IBD). Darutigenol (DL), a natural compound with limited oral bioavailability, has shown potent anti-inflammatory properties. its therapeutic efficacy in colitis and the microbiota-dependent mechanisms remain unexplored. To identify key gut microbial species and metabolites contributing to DL-mediated amelioration of DSS-induced colitis in mice, we employed various methods, including 16S rRNA sequencing, antibiotic treatment, and fecal microbiota transplantation (FMT). Furthermore, metabolomic and transcriptomic analyses, as well as targeted administration of specific bacteria and metabolites, were conducted to explore the microbiota-dependent mechanisms by which DL mitigates murine colitis severity. Our findings showed that DL alleviates colitis by enriching Akkermansia muciniphila (A. muciniphila) in the gut microbiota and promotes the biosynthesis of its key metabolite, proline. Interestingly, DL was found to promote the growth of A. muciniphila in the gut by targeting indoleamine 2,3-dioxygenase 1 (IDO1). Additionally, supplementation with proline demonstrated relieving effect on murine colitis by downregulating the IL-17 signaling pathway its downstream signaling pathway. This study uncovers a novel therapeutic axis wherein DL ameliorates colitis via IDO1 inhibition-driven A. muciniphila expansion and subsequent proline-mediated immunoregulation, offering mechanistic insights for microbiota-targeted IBD interventions.