Protective effect of Timosaponin AIII on Escherichia coli-induced endometritis in mice through inhibiting inflammatory response and regulating uterine microbiota structure

Abstract

Endometritis is a sort of general reproductive disease, which can lead to infertility in both humans and animals. Escherichia coli (E. coli) is recognised as the main bacterial etiology of endometritis among livestock and causes huge economic losses to dairy farming industry. Antibiotics are frequently used in the clinical treatment of endometritis; nevertheless, long-term use may result in adverse effects, including bacterial resistance and food safety concerns. TSAIII, one of the active pharmacological components of A. asphodeloides, has exhibited multiple biological activities, including anticancer, anti-angiogenesis, and anti-inflammatory properties. However, the protective effects of TSAIII in E. coli-challenged endometritis remain unclear. This study aimed to clarify the role of TSAIII in E. coli-induced endometritis in mice and elucidate its specific molecular mechanisms. In the present research, TSAIII treatment markedly alleviated the E. coli-induced uterine histopathological injury, and decreased myeloperoxidase (MPO) activity and pro-inflammatory cytokines levels in uterine tissue. Our results further demonstrated that TSAIII improved uterine epithelial barrier function by restoring the expressions of tight junction proteins. Furthermore, TSAIII administration noticeably suppressed the activation of the TLR4/NF-κB pathway and the NLRP3 inflammasome. Importantly, we found that TSAIII could regulate the uterine microbiota structure and composition in E. coli-induced mouse endometritis. In conclusion, these data demonstrate that treatment with TSAIII protects against E. coli-induced endometritis via modulating uterine microbiota composition, inhibiting TLR4/NF-κB pathway and NLRP3 inflammasome activation, in addition to improving uterine epithelial barrier function. Therefore, the results of this study provide a new therapeutic to potentially prevent endometritis.

Keywords: Endometritis; NLRP3; TLR4/NF-κB; Tight junction proteins; Timosaponin AIII; Uterine microbiota.