Abstract
Background: Pregnancy is often described as an immune-tolerant state, and a disease modulatory role for pregnancy on inflammatory bowel disease (IBD) has been suggested. The direct effect of estrogen and progesterone on the intestinal epithelial barrier is underexplored. We investigated the direct consequences of these pregnancy hormones on barrier cells and their function. Methods: We used IBD patient-derived inflammatory organoid models and 2D cell lines models. Epithelial barrier function was analyzed by measuring transepithelial electrical resistance; wound closure was determined by scratch assay; and cell viability was measured by MTT assays. Pro-inflammatory cytokine production was determined by enzyme-linked immunosorbent assays. Molecular modulation of endoplasmic reticulum (ER) stress induced by tunicamycin was studied by western blot analysis of the ER stress markers GRP78, CHOP and p-IRE1. Results: Progesterone and estrogen improved wound healing and epithelial barrier function in intestinal epithelial cells via upregulation of tight junction proteins. Furthermore, these sex hormones significantly reduced ER-stress and reduce pro-inflammatory cytokine production in intestinal epithelial models. Conclusion: Our study shows that estrogen and progesterone alleviate ER stress, decrease pro-inflammatory cytokine production, stimulate wound healing, and increase barrier function of epithelial cells. Combined, these data suggest that pregnancy hormones can have beneficial effects on disease activity by positively modulating the intestinal epithelial lining.
Highlights
Inflammatory bowel disease (IBD), consisting of Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic debilitating disease
One of the treatment goals in inflammatory bowel disease (IBD) is achievement of mucosal healing, as this is associated with reduced relapse rates and better quality of life [28]
We first investigated the effect of sex hormones on wound healing of epithelial barriers
Summary
Inflammatory bowel disease (IBD), consisting of Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic debilitating disease. While immunological parameters have been extensively studied in the context of pregnancy, an underexplored avenue of investigation is the direct effect of estrogen and progesterone on the epithelial barrier. This barrier is the intestine’s first line of defense against invading bacteria. In IBD patients, the epithelial lining is weakened and, less resistant to pathogens This “leaky gut” process is mainly caused by immune cells producing inflammatory cytokines, such as IFNG an TNFα [17,18] and is worsened during active disease, when there is an additional reduction in tight junctions which regulate epithelial permeability [19]. We employed human colonic adenocarcinoma cell lines (Caco, HCT116, T84) and organoids from human colon biopsies as model systems to study epithelial barrier function, production of cytokines, and ER stress modulation in response to sex hormones
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