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Intestinal epithelial organoids (IEOs) preserve donor-specific genetics and architecture, offering a promising model, but their ability to replicate patient-specific epithelial inflammation remains undetermined. To directly compare in vivo epithelial transcriptional states with defined cytokine-induced responses in vitro, we analyzed patient-matched transcriptomics from laser microdissected inflamed and uninflamed colonic epithelium and IEOs derived from uninflamed biopsies of the same UC patients. IEOs were stimulated with UC-relevant cytokines (TNF, IFN\u03b3, IFN\u03bb1, or TNF\u2009+\u2009IFN\u03b3) or a cytokine cocktail (TNF, IL17, IL1\u03b2, IL22, Poly(I:C), IFN\u03b3). Key inflammatory genes were validated by immunoblotting and immunostaining. Cytokine-stimulated IEOs recapitulated key in vivo epithelial inflammation, including interferon signaling, antigen presentation, and unfolded protein response pathways. Among the tested conditions, TNF\u2009+\u2009IFN\u03b3 combination and the cytokine cocktail most closely replicated UC epithelial inflammation, with concordance for over 350 UC-relevant genes and protein-level validation of IRF1, ERAP2, NOS2, DUOX2 confirmed patient-dependent expression between inflamed epithelium and cytokine-stimulated IEOs. Our study shows that cytokine-stimulated IEOs provide a robust, personalized platform for modeling epithelial inflammation, enabling discovery of epithelial-specific disease mechanisms and therapeutic targets.<\/jats:p>","DOI":"10.1038\/s41598-026-54857-7","type":"journal-article","created":{"date-parts":[[2026,6,14]],"date-time":"2026-06-14T08:12:31Z","timestamp":1781424751000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Patient-matched transcriptomics of in vivo and in vitro colonic epithelium substantiate organoids as a translational model for ulcerative colitis"],"prefix":"10.1038","volume":"16","author":[{"given":"Gunnar Andreas Enerhaug","family":"Walaas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arun","family":"Sridhar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lusie Frostvoll","family":"Kuraas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siri","family":"S\u00e6terstad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda Yin","family":"Schioldborg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atle","family":"Van Beelen Granlund","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arne Kristian","family":"Sandvik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann Elisabet","family":"\u00d8stvik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingunn","family":"Bakke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torunn","family":"Bruland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,14]]},"reference":[{"issue":"10114","key":"54857_CR1","doi-asserted-by":"publisher","first-page":"2769","DOI":"10.1016\/S0140-6736(17)32448-0","volume":"390","author":"SC Ng","year":"2017","unstructured":"Ng, S. 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