Vaginal epithelial estrogen receptor α coordinates glycogen deposition, microbial stability, and pH regulation in mice

Estrogen plays a central role in regulating the vaginal environment, but the specific contribution of epithelial estrogen receptor (ESR1) to microbial and biochemical homeostasis has not been fully defined. In our previous work, we showed that epithelial ESR1 is indispensable for estrogen-induced epithelial proliferation, cornification, and MUC1 expression. Here, using mice with conditional deletion of Esr1 in vaginal epithelial cells, called epithelial Esr1d/d, we extend these findings to demonstrate that epithelial ESR1 also regulates glycogen deposition, luminal pH, and microbial stability. Compared to control littermates, epithelial Esr1d/d mice reduced glycogen abundance, elevated vaginal pH, and a compositional shift in the vaginal microbiome, marked by enrichment of Comamonadaceae and loss of Lactobacillus species, without significant differences in alpha diversity. These changes parallel features of postmenopausal dysbiosis in women. Together, our findings identify epithelial ESR1 as a master regulator of multiple pathways that sustain vaginal homeostasis, integrating epithelial metabolism, barrier function, and host-microbe interactions. This work provides a mechanistic framework to understand postmenopausal vaginal dysbiosis and suggests epithelial estrogen signaling as a potential therapeutic target for genitourinary syndrome of menopause. Significance StatementThe vaginal environment is essential for reproductive and gynecologic health, yet the mechanisms by which estrogen shapes this niche remain incompletely understood. We show that epithelial estrogen receptor (ESR1) regulates glycogen deposition, luminal pH, and microbial composition in the murine vagina. Loss of epithelial ESR1 reduced glycogen and increased luminal pH without altering overall microbial diversity, but shifted community structure toward enrichment of Comamonadaceae, a family associated with neutral to mildly alkaline environments. These findings identify epithelial ESR1 as a key regulator of the metabolic and physicochemical conditions that maintain vaginal microbial balance and provide a mechanistic framework for understanding postmenopausal dysbiosis.