Hyperoside, a dietary flavonoid, protects against endometritis <i>via</i> gut microbiota-dependent production of hydroxyphenyllactic acid and the gut–uterus axis

Endometritis, primarily caused by <i>Escherichia coli</i> (<i>E. coli</i>) infection, poses significant therapeutic challenges due to rising antibiotic resistance. The associated pro-inflammatory cytokines cause persistent endometrial damage, thereby leading to infertility, pregnancy loss, and other gynecological complications, which impose substantial long-term medical and socioeconomic burdens. Hyperoside, a flavonol glycoside abundant in various common fruits (<i>e.g.</i>, hawthorn) and vegetables, exhibits significant anti-inflammatory activity, highlighting its potential as a functional food or nutraceutical. Our present study firstly demonstrated that hyperoside could alleviate <i>E. coli</i>-induced endometritis in mice through a gut-uterus axis mechanism. Specifically, hyperoside remodeled the gut microbiota by enriching beneficial genera, such as <i>Lactobacillus</i> and <i>Prevotella</i>, which subsequently elevated the production of the metabolite hydroxyphenyllactic acid (HPLA). Crucially, antibiotic treatment and fecal microbiota transplantation (FMT) experiments further confirmed that gut microbiota restructuring was essential for the anti-endometritic effect of hyperoside. Mechanistically, HPLA enters systemic circulation and targets uterine tissue, where it is directly bound to TLR4 to suppress the activation of the TLR4/NF-κB pathway and then the release of inflammatory cytokines. The present study provides the first systematic evidence of the gut-uterus axis, establishing microbiota-derived HPLA as a key effector against <i>E. coli</i>-induced endometritis, offering a novel nutritional intervention strategy for inflammatory reproductive disorders.