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

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 Crohn’s 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 AbstractIn 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. Competing Interest Statement B.S.B has received research grants from Merck, Mirador, Gilead, S.R.T. Therapeutics and served as a consultant for Abbvie, Merck, and Celltrion. The remaining authors declare that no conflict of interest exists. Footnotes This is an updated and improved manuscript version. Changes include update abstract, text, discussion, and figures.