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

ABSTRACT: Gut microbiota dysbiosis is associated with the occurrence and development of inflammatory bowel disease (IBD). Darutigenol (DL) is a natural compound with limited oral bioavailability, but has shown promise in the treatment of ulcerative colitis (UC). However, the precise mechanisms underlying its therapeutic effects remain incompletely understood. To identify the critical gut microbial species and microbial metabolites associated with the UC-protective effects of DL, we assessed its microbiota-dependent anti-UC effects through 16S rRNA sequencing, antibiotic treatment, and fecal microbiota transplantation. Metabolomics analysis, transcriptional analysis, and targeted bacteria/metabolites gavage were conducted to explore how DL regulates gut microbiota to reduce the severity of UC. The results showed that DL mainly promoted the synthesis of its metabolite proline by regulating the abundance of Akkermansia muciniphila (A. muciniphila), thereby exerting anti-UC effect. Interestingly, we discovered that DL could promote the growth of A. muciniphila in the gut by targeting IDO1. Additionally, proline supplementation exerts an anti-UC effect by downregulating the IL-17 signaling pathway. Together, our study demonstrated that DL promoted the growth of A. muciniphila by targeting IDO1 and stimulates proline production, thereby alleviating the symptoms of UC. These findings offer new insights into the anti-UC mechanisms driven by DL

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS10395 | MetaboLights | 2025-09-26

REPOSITORIES: MetaboLights

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Project description:Background and aims. The etiopathology of inflammatory bowel diseases is still poorly understood. To date, only few little data are available on the microbiota composition in ulcerative colitis (UC), representing a major subform of inflammatory bowel diseases. Currently, one of the main challenges is to unravel the interactions between genetics and environmental factors in the onset or during the progression and maintenance of the disease. The aim of the present study was to analyse twin pairs discordant for UC for both gut microbiota dysbiosis and host expression profiles at a mucosal level and to get insight into the functional genomic crosstalk between microbiota and mucosal epithelium in vivo. Methods. Biopsies were sampled from the sigmoid colon of both healthy and diseased siblings from UC discordant twin pairs but also from healthy twins. Microbiota profiles were assessed by 16S rDNA libraries while mRNA expression profiles were analysed from the same volunteers using Affymetrix microarrays. Results. UC patients showed a dysbiotic microbiota with lower diversity and more species belonging to Actinobacteria and Proteobacteria phyla. On the contrary, their healthy siblingsM-bM-^@M-^Y microbiota contained more bacteria from the Lachnospiracea and Ruminococcaceae family than did healthy individuals . Sixty-three host transcripts significantly correlated with bacterial genera in healthy individuals whereas only 43 and 32 correlated with bacteria in healthy and UC siblings from discordant pairs, respectively. Several transcripts related to oxidative and immune responses were differentially expressed between unaffected and UC siblings. Conclusion. A loss of crosstalk between gut microbiota and host was highlighted in UC patients. This defect was also striking in healthy siblings from discordant pairs, as was the lower biodiversity within the microbiota. Our results suggest disease-relevant interactions between host transcriptome and microbiota. Moreover, unusual aerobic bacteria were noticed in UC mucosal microbiota, whereas healthy siblings from discordant pairs had higher percentages of potentially beneficialusual commensal bacterial species. Paired samples (twins) were analyzed to obtain data independent of genetic variation

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

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