Landskron, GlaubenDubois-Camacho, KarenOrellana-Serradell, OctavioDe la Fuente, MarjorieParada-Venegas, DanielaBitrán, MiritDíaz-Jiménez, DavidTang, ShuangCidlowski, John ALi, XiaolingMolina, HéctorGonzález, Carlos MSimian, DanielaLubascher, JaimePola, VictorMontecino, MartínBlokzijl, TjassoFaber, Klaas NicoGonzález, María-JulietaQuera, RodrigoHermoso, Marcela A2022-11-032022-11-032022-06-12Cells. 2022 Jun 12;11(12):1905. doi: 10.3390/cells11121905.2073-4409http://hdl.handle.net/20.500.12254/2589Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) and can be treated with glucocorticoids (GC), although some patients are unresponsive to this therapy. The transcription factor LRH-1/NR5A2 is critical to intestinal cortisol production (intestinal steroidogenesis), being reduced in UC patients. However, the relationship between LRH-1 expression and distribution with altered corticosteroid responses is unknown. To address this, we categorized UC patients by their steroid response. Here, we found that steroid-dependent and refractory patients presented reduced glucocorticoid receptor (GR)-mediated intestinal steroidogenesis compared to healthy individuals and responder patients, possibly related to increased colonic mucosa GR isoform beta (GRβ) content and cytoplasmic LRH-1 levels in epithelial and lamina propria cells. Interestingly, an intestinal epithelium-specific GR-induced knockout (GRiKO) dextran sodium sulfate (DSS)-colitis mice model presented decreased epithelial LRH-1 expression, whilst it increased in the lamina propria compared to DSS-treated control mice. Mechanistically, GR directly induced NR5A2 gene expression in CCD841CoN cells and human colonic organoids. Furthermore, GR bound to two glucocorticoid-response elements within the NR5A2 promoter in dexamethasone-stimulated CCD841CoN cells. We conclude that GR contributes to intestinal steroidogenesis by inducing LRH-1 in epithelial cells, suggesting LRH-1 as a potential marker for glucocorticoid-impaired response in UC. However, further studies with a larger patient cohort will be necessary to confirm role of LRH-1 as a therapeutic biomarker.en-USAtribución-NoComercial-CompartirIgual 3.0 Chile (CC BY-NC-SA 3.0 CL)Glucocorticoid receptorUlcerative colitisSteroid refractorinessSteroid dependencyArtículohttps://orcid.org/0000-0002-7953-6769https://doi.org/10.3390/cells11121905