Estrogen (E2) has been shown to contribute to the maintenance of intestinal barrier function through signaling to estrogen receptor beta (ERb), a nuclear receptor highly expressed by colonic epithelial cells. Knock-out of ERb leads to enhanced experimental (DSS) colitis in mice, further suggesting a protective role for E2-ERb signaling in the intestine. Interestingly, despite having higher levels of circulating E2 than males, females exhibit increased frequency and severity of UC. Our goal is to examine the role of E2/ERb signaling in the context of sex-related differences in UC.Methods:
Eight to 12-week-old ERb-KO mice and age-matched ERb-WT mice (littermate controls) were fed 3% DSS in their drinking water for 5 days, with or without recovery time. Colon tissue and/or intestinal epithelial cells were harvested following DSS treatment and evaluated for clinical colitis, inflammatory cytokine/chemokine production, and intracellular signaling responses to E2. Colon tissue biopsies from male and female UC patients were also analyzed for gene expression of key cytokines/chemokines known to be regulated by E2 signaling.Results:
Colon tissues from female UC patients were found to express particularly elevated levels of mRNA specific for IL-6 and IL-17 compared to tissues from male UC patients and healthy controls. In addition, female UC patients' colon tissues expressed dysregulated ratios of ERa:ERb, with levels of ERa significantly higher than their male counterparts.' We examined sex-specific responses of ERb-KO mice to acute DSS challenge, observing that ERb-KO-female (ERb-KO-F) mice developed significantly worse clinical colitis than ERb-KO-M mice following 5 days of DSS. Colon tissue gene expression of IL-6 and IL-17 was similarly dysregulated in ERb-KO-F mice following DSS, with alterations in key intracellular signaling pathways (ERK1/2, MEK1/2) observed in ERb-KO-F intestinal epithelial cells following stimulation with E2.Conclusions:
Female UC patients express significantly elevated ratios of ERa:ERb compared to male patients, leading to preferential signaling through ERa rather than ERb. Using ERb-KO mice to simulate the preferential E2/ERa signaling observed in female patients, we found that reduced ERb expression leads to enhanced clinical colitis in female mice; increased expression of proinflammatory cytokine gene expression in female mice; and impairment of key signaling pathways downstream of E2-ER in female intestinal epithelial cells. Collectively, our results suggest that dysregulated E2/ERb signaling contributes to worse clinical colitis in females.