Ulcerative 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.
Bibliographical noteFunding Information:
Funding: This research was funded by the National Agency of Research and Development ANID/ FONDECYT GRANTS 1170648 (M.A.H.), 11190990 (M.D.l.F.), 3190931 (G.L.), 3210367 (K.D.-C.), Proyecto Puente ICBM2021_ 570333 (M.A.H.); ANID/FONDAP15090007 (M.M.), Glucocorticoid hormone action 1ZIA ES090057 24; Apoptosis 1ZIA ES090079 24; Molecular genetics support to identify gene/environment interactions in disease 1ZIC ES102546 12 (J.A.C.); Intramural Research Program of National Institute of Environmental Health Sciences of the NIH (X.L.) (Z01 ES102205) and a scholarship from the Vice-Rector’s Office for Academic Affairs, Postgraduate and Postgraduate Department, Universidad de Chile (M.B.).
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- Colitis, Ulcerative/drug therapy
- Intestinal Mucosa/metabolism