Stromal state plasticity defines risk and therapeutic opportunity in recalcitrant inflammatory bowel disease

Tindle, C.; Penrose, H. M.; Sinha, S.; Mullick, M.; Carpio-Perkins, K.; Hayashi, M.; Carpinelli, S. S.; Mclaren, E.; Hsieh, C.-C.; Zablan, K.; Le, H. N.; Neill, J.; Katkar, G. D.; Sandborn, W. J.; Boland, B.; Ghosh, P.

doi:10.64898/2026.05.01.720931

bioRxiv · 10.64898/2026.05.01.720931

Stromal state plasticity defines risk and therapeutic opportunity in recalcitrant inflammatory bowel disease

Tindle, C.·Penrose, H. M.·Sinha, S.·Mullick, M.·Carpio-Perkins, K.·Hayashi, M.·Carpinelli, S. S.·Mclaren, E.·Hsieh, C.-C.·Zablan, K.·Le, H. N.·Neill, J.·Katkar, G. D.·Sandborn, W. J.·Boland, B.·Ghosh, P.

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Abstract

Inflammatory bowel diseases (IBD) remain a relapsing, treatment-refractory disorder marked by progressive tissue injury and inflammation despite expanding immune-targeted therapies. We established a prospective cohort integrating stromal biobanking, functional phenotyping, cross-cohort benchmarking, and outcome modeling to define disease-anchored cellular states. Colonic myofibroblasts from 34 individuals spanning health, ulcerative colitis, and Crohns disease resolved into two dominant states: inflammatory (IMFs) and quiescent (QMFs) myofibroblasts. QMF predominance forecasted remission, whereas IMF predominance increased the odds of worsening endoscopic severity despite therapy escalation during follow-up by [~]4.6-fold, linking early stromal biology to clinical outcomes. Unlike QMFs, IMFs exhibited a senescence-associated secretory phenotype that impaired epithelial stemness, barrier integrity, and innate immune fitness. State-guided prioritization identified EDNRB-antagonism as a high-confidence stromal intervention, reversing pathogenic phenotypes across orthogonal assays and species. Outcome simulation positioned stromal-state reversibility by EDNRB-antagonism as a precision axis, reducing odds of recalcitrance by [~]96.4% and reframing treatment resistance as a reversible stromal state. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=185 HEIGHT=200 SRC="FIGDIR/small/720931v2_ufig1.gif" ALT="Figure 1"> View larger version (88K): org.highwire.dtl.DTLVardef@3b2c50org.highwire.dtl.DTLVardef@da5400org.highwire.dtl.DTLVardef@1c100c1org.highwire.dtl.DTLVardef@1882e1_HPS_FORMAT_FIGEXP M_FIG C_FIG In this work, Tindle et al. identify reversible stromal states that govern remission vs. recalcitrant outcomes in IBD and nominate precision reprogramming of pathogenic myofibroblasts as a new therapeutic strategy.

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Tindle, C., Penrose, H. M., Sinha, S., Mullick, M., Carpio-Perkins, K., Hayashi, M., Carpinelli, S. S., Mclaren, E., Hsieh, C.-C., Zablan, K., Le, H. N., Neill, J., Katkar, G. D., Sandborn, W. J., Boland, B., Ghosh, P.. 2026-05-06. Stromal state plasticity defines risk and therapeutic opportunity in recalcitrant inflammatory bowel disease. https://doi.org/10.64898/2026.05.01.720931

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