Pre-Treatment with Estradiol, But not Progesterone, Exacerbates DSS Colitis: Dysregulated Innate Immunity and Impaired Epithelial Damage Response

Epidemiological data have indicated an increased risk of inflammatory bowel disease associated with the female sex and contraceptive hormones. However, in preclinical models of estradiol in colitis, results have been inconsistent, and both alleviating and aggravating effects have been reported. Previously, we suggested that the estrogen receptor α mediates inflammation in the colon. Here, we investigated the effects of estradiol and progesterone in dextran sulphate sodium-induced colitis, using sham-operated or ovariectomized female mice with or without hormonal supplementation initiated three weeks before inflammation. We found that sham-operated, or ovariectomized mice supplemented either with only estradiol or estradiol and progesterone exhibited more severe intestinal inflammation compared to ovariectomized mice at day 7 of colitis. Simultaneously, progesterone supplementation of ovariectomized mice did not affect the inflammatory status. Estrogen receptors were expressed in several different cell types of the colonic mucosa, although at low levels. The estrogen receptor α was observed in the epithelium as well as in mononuclear phagocytes and T and B cells. The estrogen receptor β was found in the epithelium, and the G protein-coupled estrogen receptor in the lamina propria and vessel structures. Further, hormone depletion increased homeostatic immune cells, while estradiol exposure altered the expression of 791 genes involved in pathways promoting the antimicrobial response, immune cell activation, and metabolism related to epithelial integrity. With our results, we are the first to present strong and detailed evidence of estradiol as an inflammatory agent in the colon of female mice when allowing the appearance of longer-term effects.