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Region-specific immune regulation determines differential response to JAK1 inhibition in Crohn's disease ex vivo

Klaudia Maria Grieger1,2,3, Susann Dehmel1,2,3, Valerie Schröder1,2,3

  • 1Department for Preclinical Pharmacology, Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, 30625, Germany.

Journal of Crohn'S & Colitis
|July 30, 2026
PubMed

Insights

Filgotinib effectively treated colon inflammation in Crohn's disease (CD) patients but showed limited efficacy in the ileum. This suggests region-specific therapies are needed for inflammatory bowel disease (IBD).

Area of Science:

  • Gastroenterology
  • Immunology
  • Pharmacology

Background:

  • Crohn's disease (CD) presents therapeutic challenges due to limited options and varied patient responses.
  • Filgotinib, a JAK1 inhibitor, showed promise in ulcerative colitis but lacked consistent efficacy in CD, with unclear reasons.

Purpose of the Study:

  • To investigate the region-specific efficacy of filgotinib in Crohn's disease using an ex vivo model.
  • To explore the mechanistic basis for filgotinib's differential response in the ileum versus colon of CD patients.

Main Methods:

  • Utilized an immunocompetent ex vivo model of precision-cut intestinal slices (PCIS) from CD patients.
  • Analyzed region-specific responses (ileal vs. colonic) to filgotinib, including T cell activation, cytokine profiles, oxidative stress, and STAT signaling.

Main Results:

  • Colonic CD PCIS showed high T cell activation, sensitive to filgotinib, with suppressed Th1/Th17 cytokines, oxidative stress, and STAT signaling.
  • Ileal CD PCIS displayed innate and Th17-driven inflammation, with reduced sensitivity to JAK1 inhibition by filgotinib.

Conclusions:

  • Differential drug responses in ileal versus colonic tissues may explain filgotinib's variable efficacy in CD clinical trials.
  • Precision-cut intestinal slices (PCIS) serve as a valuable human-relevant model for studying region-specific drug responses in inflammatory bowel disease (IBD).
  • Therapies tailored to specific gut segments are crucial for effectively managing inflammatory bowel disease (IBD).
Keywords:
ex vivoCrohn’s diseaseT cellfilgotinibimmunityprecision-cut intestinal slices

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