Dimethyl Itaconate Alleviates Escherichia coli ‐Induced Endometritis Through the Guanosine‐CXCL14 Axis via Increasing the Abundance of norank_f_Muribaculaceae

Abstract Endometritis, a prevalent reproductive system disease with high incidence, leads to reproductive dysfunction in humans and animals, causing huge economic losses. Dimethyl itaconate (DI) has been demonstrated to exert protective effects in multiple inflammatory diseases. Nevertheless, the efficacy of DI in preventing endometritis and the role played by the gut microbiota remain unknown. In this study, it is found that DI ameliorated Escherichia coli ( E. coli) induced endometritis in mice. The protective effect is 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 reveals that DI promotes the multiplication of norank_f_Muribaculaceae in vivo, and supplementation of Muribaculum intestinale (DSM 28989), which belongs to the norank_f_Muribaculaceae genus, upregulates the level of guanosine in the uterus. Mechanistically, the protective effect of guanosine in endometritis is mediated by activating the expression of CXCL14 in uterine epithelial cells. Moreover, the antibody‐neutralizing experiment of CXCL14 eliminated this protective effect. In conclusion, this study elucidates the significant role of the gut microbiota and its metabolites in the protection of DI against endometritis, and provides new evidence for the regulation of distal organ by the gut microbiota.