Sex Differences in Colonic Inflammation are Driven by Epithelial-Specific Expression of Estrogen Receptor Alpha.

BACKGROUND AND AIMS: Inflammatory bowel disease patients exhibit altered expression of nuclear estrogen receptors alpha and beta (ERα and ERβ) and G-protein coupled estrogen receptor 1 (GPER1). We previously showed that deletion of ERα protects against intestinal damage selectively in female mice; however, the mechanisms conferring sex-specific protection are poorly understood. The goal of this study was to compare ERα- and ERβ-specific mechanisms contributing to intestinal epithelial function in males and females. METHODS: Expression of ERα, ERβ, and GPER1 was evaluated in colonocytes from wild-type male and female mice. Intestinal epithelial cell (IEC)-specific ERα and ERβ knockout mice were developed and challenged with dextran sulfate sodium. Colonic organoids were used to identify estrogen-dependent and estrogen-independent effects on cellular growth, differentiation, and transcriptional regulation in wild-type, ERα-KO, and ERβ-KO IECs. RESULTS: Colonic IECs showed significant expression of ERα, ERβ, and GPER1 as well as Cyp19A1, which catalyzes production of 17β-estradiol (estrogen). Female mice lacking ERα specifically in colonic IECs showed protection from dextran sulfate sodium-induced injury, whereas males showed increased pathology. Organoids derived from male ERα-KO mice showed enhanced proliferation and decreased expression of key functional genes even without exogenous estrogen; however, colonoids derived from female ERα-KO mice showed a protective gene signature. These findings reveal that deletion of ERα contributes to differential effects in male and female IECs, contributing to females' resistance to intestinal injury and inflammation. CONCLUSION: ERα signaling within IECs drives opposing sex-dependent effects on the development, regenerative capacity, and inflammatory susceptibility of the intestinal epithelium.