Abstract Background and aims This project aims to elucidate how oestrogen influences intestinal barrier integrity, immune responses, and therapeutic outcomes in female patients with inflammatory bowel disease (IBD), using advanced patient-derived colonic organoid models (CPOs). Oestrogen regulates colonic permeability through the nuclear oestrogen receptors, ERβ and ERα, significantly affecting epithelial and immune function. Although these pathways are increasingly recognized as relevant in female IBD pathophysiology, the specific role of oestrogen remains largely unexplored. Methods CPOs derived from healthy female donors and female patients with ulcerative colitis and Crohn’s disease will be exposed to defined concentrations of 17β-oestradiol and inflammatory stimuli (cytokine cocktails or bacterial lysates). Cellular composition and phenotype will be characterized by flow cytometry, RNA sequencing, and immunostaining. The expression of ERα and ERβ will be assessed across donor and disease groups. To model immune–epithelial interactions, CPOs will be co-cultured with peripheral blood mononuclear cells (PBMCs) from female donors under both naïve and inflamed conditions. Barrier integrity will be evaluated using transepithelial electrical resistance (TEER), FITC-dextran permeability assays, and immunofluorescent staining for tight junction proteins. Cytokine secretion will be quantified through multiplex immunoassays, and transcriptomic profiling will identify oestrogen-responsive signalling pathways. To evaluate therapeutic response, co-cultures will be treated with clinically approved IBD therapies, including anti-TNF agents, JAK inhibitors, and anti-integrin antibodies, in the presence or absence of 17β-oestradiol. Treatment outcomes will be compared among CPOs groups. Anticipated impact This project is expected to identify key estrogen-responsive pathways involved in epithelial maintenance and immune regulation, and to clarify how it affects therapeutic efficacy. In the short term, it will improve our mechanistic understanding of the role of estrogen in IBD. In the medium to long term, it will support the development of personalized therapeutic strategies, offering more effective and tailored treatments for female diagnosed with IBD.
A Mora-Boza (Thu,) studied this question.