Estradiol, but not progesterone, exacerbates DSS colitis together with altering epithelial function, and expanding inflammatory cell populations
The effects of female sex hormones, such as estradiol or progesterone, in intestinal inflammation have been investigated, but a lot remains unclear. Previously, there have been reports of both alleviating and aggravating effects by estrogen receptor activation in DSS colitis.  However, epidemiological studies have indicated an increased risk of inflammatory bowel disease by endogenous ovarian, as well as contraceptive hormones. Here, we studied the effects of both estradiol and progesterone in an acute colitis model, using sham-operated female mice or ovariectomized mice with weeks-long hormonal supplementation. We found that estradiol exposure repeatedly aggravated intestinal inflammation compared to hormone depletion by ovariectomy, while progesterone did not influence inflammatory status. Inflammatory immune cell populations expanded by estradiol exposure, with fewer Ly6C+ monocytes maturing to CX3CR1+ CD206+ anti-inflammatory macrophages and homeostatic ?dT cell counts. Further, the estrogen receptors were observed to be ubiquitously expressed in the colon, with some differences in expression patterns between receptor types. In the mucosa, ERa and ERß signals were strongest in the epithelium, while GPER was expressed in the lamina propria. Additionally, ERa was expressed in both Ly6C+ and CD206+ macrophages, as well as in T cells and B cells. GPER expression was observed only in Ly6C+ cells, possibly indicating a role of estrogen signalling in macrophage differentiation. Estradiol exposure also altered the expression of nearly 800 genes, with pathways associated with the antimicrobial response, immune cell activation, and metabolism. Together, these results strengthen the evidence of longer-term effects of estradiol as inflammatory, while experiments with short estradiol treatment have alleviated inflammation.
The effects of female sex hormones, such as estradiol or progesterone, in intestinal inflammation have been investigated, but a lot remains unclear. Previously, there have been reports of both alleviating and aggravating effects by estrogen receptor activation in DSS colitis.  However, epidemiological studies have indicated an increased risk of inflammatory bowel disease by endogenous ovarian, as well as contraceptive hormones. Here, we studied the effects of both estradiol and progesterone in an acute colitis model, using sham-operated female mice or ovariectomized mice with weeks-long hormonal supplementation. We found that estradiol exposure repeatedly aggravated intestinal inflammation compared to hormone depletion by ovariectomy, while progesterone did not influence inflammatory status. Inflammatory immune cell populations expanded by estradiol exposure, with fewer Ly6C+ monocytes maturing to CX3CR1+ CD206+ anti-inflammatory macrophages and homeostatic ?dT cell counts. Further, the estrogen receptors were observed to be ubiquitously expressed in the colon, with some differences in expression patterns between receptor types. In the mucosa, ERa and ERß signals were strongest in the epithelium, while GPER was expressed in the lamina propria. Additionally, ERa was expressed in both Ly6C+ and CD206+ macrophages, as well as in T cells and B cells. GPER expression was observed only in Ly6C+ cells, possibly indicating a role of estrogen signalling in macrophage differentiation. Estradiol exposure also altered the expression of nearly 800 genes, with pathways associated with the antimicrobial response, immune cell activation, and metabolism. Together, these results strengthen the evidence of longer-term effects of estradiol as inflammatory, while experiments with short estradiol treatment have alleviated inflammation.
University of Turku