Sex differences in colonic inflammation are driven by epithelial-specific expression of estrogen receptor alpha

Inflammatory bowel disease (IBD) patients exhibit altered expression of nuclear estrogen receptors alpha and beta (ERa, ERb) and G-protein coupled estrogen receptor 1 (GPER1). We previously showed that deletion of ERa 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 ERa- and ERb-specific mechanisms contributing to intestinal epithelial function in males and females. Expression of ERa, ERb, and GPER1 was evaluated in colonocytes from wild-type (WT) male and female mice. Intestinal epithelial cell (IEC)-specific ERa and ERb knockout mice were developed and challenged with dextran sulfate sodium (DSS). Colonic organoids were used to identify estrogen-dependent and -independent effects on cellular growth, differentiation, and transcriptional regulation in WT, ERa-KO, and ERb-KO IECs. Colonic IECs showed significant expression of ERa, ERb, and GPER1 as well as Cyp19A1, which catalyzes production of 17b-estradiol (estrogen). Female mice lacking ERa specifically in colonic IECs showed protection from DSS-induced injury, whereas males showed increased pathology. Organoids derived from male ERa-KO mice showed enhanced proliferation and decreased expression of key functional genes even without exogenous estrogen; however, colonoids derived from female ERa-KO mice transcriptional analysis showed a protective gene signature. These findings reveal that deletion of ERa differentially contributes to enhanced barrier function and resistance to inflammation in females, but to dysfunctional hyper-proliferation in males. ERα signaling within IECs drives opposing sex-dependent effects on the development, regenerative capacity, and inflammatory susceptibility of the intestinal epithelium.