Abstract Background and aims Intestinal fibrosis is present but under studied in Ulcerative colitis (UC), while Endoplasmic Reticulum stress proteins have been found associated with fibrosis in Crohn Disease. Our scientific aim is to better understand the impact and role of epithelium in intestinal fibrosis. Methods We have developed a model of apical-out organoids deriving from Ulcerative colitis patients intestinal stem cells, which present a pro-fibrogenic phenotype in response to transient Endoplasmic reticulum stress (ERS) induction1. These induce by paracrine action a fibroblast to myofiboblast transition (FMT). Deciphering the paracrine mediators and the molecular changes arising in such organoids compared to non-induced one not inducing FMT, will be evaluated by multi-Omic differential studies: secretomics, transcriptomics and proteomics. Afterwards, FMT assays will be used to confirm therapeutics targets using antibody blocking strategy as in (Vieujean et al, JCC 2021) 2. IBD tissues, plasma, likely stool, will be used to confirm candidate markers association with fibrosis features3. Our pro-fibrogenic organoid model will be treated with 5ASA or corticoids, or other drugs with epithelial action, to assess any beneficial effect for mitigating the pro-fibrogenic phenotype observed and probably involved in IBD intestinal fibrosis development. Anticipated impact We expect to increase our knowledge on epithelial cell response to ERS involvement, in relation to fibrosis development. This model not generating any inflammatory response while inducing paracrine FMT, might explain partly why intestinal fibrosis development does not require inflammation and may progress even if inflammation is controlled in IBD. Currently, no evidence points cytokine trigger in our model, but only ERS response factors, as eAGR2. The multi-omic differential analyses comparing samples from organoids with and without induced pro-fibrogenic phenotype should highlight fibrogenic paracrine factors promoting FMT, and point epithelial changes as potential therapeutic target (s) or biomarker (s), detectable in biopsy, plasma or stools. Tests on treatment acting on epithelium might alleviate ERS and/or ERS response, and might unveil potential process and pathways involved in fibrosis progression and independent of inflammation and immune component. References: 1. M. Stepniak et al. , “P0120 Study of the Implication of the Epithelium in the Development and Progression of Fibrosis in Ulcerative Colitis, ” J. Crohn’s Colitis, vol. 19, no. Supplement₁, pp. i502–i502, Jan. 2025, doi: 10. 1093/ecco-jcc/jjae190. 0294. 2. S. Vieujean et al. , “Potential Role of Epithelial Endoplasmic Reticulum Stress and Anterior Gradient Protein 2 Homolog in Crohn’s Disease Fibrosis, ” J. Crohn’s Colitis, Apr. 2021, doi: 10. 1093/ecco-jcc/jjab061. 3. I. O. Gordon et al. , “Fibrosis in ulcerative colitis is directly linked to severity and chronicity of mucosal inflammation, ” Aliment. Pharmacol. Ther. , vol. 47, no. 7, pp. 922–939, Apr. 2018, doi: 10. 1111/apt. 14526.
Stepniak et al. (Thu,) studied this question.