Dimethyl itaconate alleviates Escherichia coli-induced endometritis by activating the guanosine-CXCL14 axis via increasing the abundance of Muribaculaceae

Endometritis, a prevalent reproductive system disease with high incidence, leads to reproductive dysfunction and potential miscarriage in both humans and animals, impacting human health and the dairy industry, resulting in significant economic loss. Gut microbiota plays an important role in the pathogenesis of endometritis. However, the specific microbial and metabolic mediators participating in the pathogenesis remain to be identified. In this study, we found that the concentration of itaconate in the feces of mice increased after endometritis induced by Escherichia coli (E. coli) infection, suggesting a potential association between itaconate and inflammatory processes. Here, we investigated the specific role of dimethyl itaconate (DI), a derivative of itaconate with potent anti-inflammatory and immunomodulatory properties on endometritis. Oral administration of DI ameliorated the symptoms of E. coli-induced endometritis in mice. The protective effect was abolished by antibiotic-induced depletion of the gut microbiota, and fecal microbiota transplantation (FMT) from DI-treated mice to recipient mice ameliorated E. coli-induced endometritis. Integrative multiomics revealed that the addition of DI led to an enrichment of Muribaculaceae and the microbial purine metabolite guanosine in the feces. Muribaculum intestinale (DSM 28989), a bacterium of Muribaculaceae or guanosine supplementation alleviated E. coli-induced endometritis in mice. Mechanistically, DI promoted the multiplication of Muribaculaceae, and supplementation of M. intestinale upregulated the level of guanosine in the uterus. Transcriptome data and antibody-neutralizing experiment demonstrated the protective effect of guanosine in E. coli-induced endometritis was mediated by activating the expression of CXCL14 in uterine epithelial cells. In conclusion, our study elucidates the significant role of the gut microbiota and its metabolites in safeguarding the uterus against pathogen infections, providing substantiation for the regulation of distal organ by the gut microbiota, and establishing a basis for preventive measures against related diseases through the gut-X axis.