Vaginal epithelial estrogen receptor α regulates vaginal pH without detectable changes in glycogen content or microbial diversity in mice

Abstract

Estrogen (E2) 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 E2-induced epithelial proliferation and cornification, and for the suppression of MUC1 expression. Here, using mice with conditional deletion of Esr1 in vaginal epithelial cells, called epithelial Esr1d/-, we extend these findings to demonstrate that epithelial ESR1 also regulates luminal pH without substantial changes in microbial diversity, and has no impact on total glycogen content in the vagina. Compared to control littermates, epithelial Esr1d/- mice showed elevated vaginal pH and a subtle 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 indicate that epithelial ESR1 may modulate vaginal homeostasis by regulating vaginal pH without detectable changes in alpha diversity in mice. This work provides an insight into understanding postmenopausal vaginal dysbiosis and suggests epithelial estrogen signaling as a potential therapeutic target for genitourinary syndrome of menopause.