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

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.

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.

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.

ERα signaling within IECs drives opposing sex-dependent effects on the development, regenerative capacity, and inflammatory susceptibility of the intestinal epithelium.