Darutigenol alleviates colitis through Akkermansia muciniphila-driven intestinal proline synthesis

ABSTRACT:

Background: Gut microbiota dysbiosis is a critical contributor to the pathogenesis and progression of inflammatory bowel disease (IBD). Darutigenol (DL), a natural compound has demonstrated significant anti-inflammatory activity, but its low oral bioavailability limits its application. However, the therapeutic potential of this compound in colitis and whether it acts through microbiota-dependent mechanisms remain to be further explored.

Results: To identify the key gut microbial species and metabolites contributing to DL-mediated amelioration of DSS-induced colitis in mice, we conducted gut microbiota analysis, antibiotic intervention, and fecal microbiota transplantation (FMT). Furthermore, metabolomic and transcriptomic analyses, as well as the targeted administration of specific bacteria and metabolites were conducted to investigate the microbiota-dependent mechanisms through which DL mitigates the severity of murine colitis. The results demonstrated that DL ameliorates colitis by modulating the gut microbiota, particularly through enriching Akkermansia muciniphila (A. muciniphila) and promoting 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, proline supplementation exhibited a relieving effect on murine colitis by downregulating the IL-17 signaling pathway and its downstream signaling pathway. 

Conclusions: In summary, our findings reveal a novel therapeutic axis in which DL alleviates colitis via IDO1 inhibition-driven A. muciniphila expansion and proline-mediated immunoregulation, offering mechanistic insights for microbiota-targeted interventions of IBD.

INSTRUMENT(S): Liquid Chromatography MS - alternating - reverse phase

PROVIDER: MTBLS13054 | MetaboLights | 2025-09-27

REPOSITORIES: MetaboLights