ArticleJournal of Crohn's & colitis2026
Region-specific immune regulation determines differential response to JAK1 inhibition in Crohn's disease ex vivo.
Article in Journal of Crohn's & colitis, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Crohn's disease (CD) remains a significant therapeutic challenge, with limited treatment options and heterogeneous clinical responses. The selective JAK1 inhibitor filgotinib has shown great potential in treating ulcerative colitis but failed to demonstrate consistent efficacy in CD, for reasons that remain unclear. Here, we address this gap using an immunocompetent ex vivo model of precision-cut intestinal slices (PCIS) from CD patients, allowing region-specific analysis of ileal and colonic responses. We reveal that colonic PCIS display strong T cell activation and are highly sensitive to filgotinib, with suppression of Th1/Th17 cytokines, oxidative stress, and STAT signaling ex vivo. In contrast, ileal PCIS exhibited predominantly innate and Th17-driven inflammation, and were less sensitive to JAK1 inhibition. These data provide a potential mechanistic explanation for the limited efficacy of filgotinib in CD clinical trials and established PCIS as a human-relevant ex vivo model for region-specific drug responses, underscoring the importance of developing therapies tailored to different segments of the gut in inflammatory bowel disease.
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