Dysregulation of gut microbiota exacerbates LPS-induced endometritis by producing succinate in mice

Abstract

Abstract There is increasing evidence suggesting a connection between the gut microbiota and female reproductive diseases, including endometritis. Endometritis not only poses higher health risks to women but also incurs significant economic costs in animals. However, the impact of gut inflammation on the gut microbiota and its role in the development of endometritis is still uncertain. This study aimed to investigate the effects of intestinal microbiota on LPS-induced endometritis in mice. Our findings demonstrate that DSS-induced intestinal inflammation can worsen LPS-induced endometritis in mice, and this effect is dependent on the gut microbiota, as the use of antibiotics to deplete the gut microbiota eliminates this protective effect. Similarly, fecal microbiota transplantation (FMT) from DSS-treated mice (DF) to recipient mice exacerbates LPS-induced endometritis. Furthermore, the depletion of DSS and DF leads to increased levels of fecal succinate compared to controls. Additionally, treatment with succinic acid aggravates LPS-induced endometritis in mice. Mechanistically, depletion of DSS treatment resulted in disruption of the gut barrier and an imbalance of succinate-producing and succinate-consuming bacteria. This imbalance led to the massive production, blood transport, and accumulation of succinate in the uterus via the gut-uterus axis. Consequently, the uterine injury was exacerbated through intestinal succinate, which exacerbates uterine injury by SUCNR 1-dependent promotion of NF-κB activation. Overall, our findings suggest that dysbiosis of the gut microbiota exacerbates LPS-induced endometritis in mice by gut microbiota producing succinate. This identifies gut-derived succinate as a novel target for treating critical endometritis. Furthermore, it indicates that targeting the gut microbiota and its metabolism could be a potential strategy for intervention in endometritis and other infectious diseases.