Hyperoside alleviates Escherichia coli-induced endometritis through increasing gut microbiota-derived hydroxyphenyllactic acid via the gut-uterus axis

Endometritis, primarily triggered by Escherichia coli (E. coil) infection, poses therapeutic challenges due to antibiotic resistance. It has been widely recognized that endometritis impairs the reproductive performance of dairy cow and suppresses lactation through pro-inflammatory cytokines, ultimately reducing milk yield and inflicting substantial economic losses on the dairy industry. Our study firstly demonstrated that hyperoside, an active flavonoid from Cuscuta chinensis Lam, could alleviate E. coli-induced endometritis in mice through a gut-uterus axis mechanism. Hyperoside remodeled gut microbiota by enriching beneficial genera, such as Lactobacillus and [Prevotella]), which subsequently elevated production of the metabolite hydroxyphenyllactic acid (HPLA). HPLA enterd systemic circulation and targetd uterine tissue, where it directly bound TLR4 to suppress TLR4/NF-κB pathway and the release of inflammatory cytokines. Crucially, fecal microbiota transplantation further confirmed that gut microbiota restructuring was essential for the anti- endometritic effect of hyperoside, while exogenous HPLA administration played a decisive role. The present study provides the first systematic evidence of the gut-uterus axis, establishing microbiota-derived HPLA as the primary effector against E. coil-induced endometritis, offering novel therapeutic strategies for inflammatory reproductive disorders.