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

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. IMF predominance at recruitment forecasted progressive disease, increasing odds of worsening endoscopic severity despite therapy escalation by [~]4.6 during follow-up, thereby linking early stromal biology to clinical endpoints. 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=194 HEIGHT=200 SRC="FIGDIR/small/720931v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@194d546org.highwire.dtl.DTLVardef@3e16a9org.highwire.dtl.DTLVardef@41dd7borg.highwire.dtl.DTLVardef@33b972_HPS_FORMAT_FIGEXP M_FIG C_FIG In this work, Tindle et al. identify reversible stromal states that govern recalcitrant IBD and nominate precision reprogramming of pathogenic myofibroblasts as a new therapeutic strategy.