Epithelial Barrier-Injury Transcriptomic Stratification Across Human IBD Mucosal Cohorts

Public mucosal transcriptomic datasets provide an opportunity to examine whether experimental epithelial barrier biology is reflected in human inflammatory bowel disease (IBD) endpoints. We constructed a prespecified barrier-injury transcriptomic score from an inositol polyphosphate multikinase-histone deacetylase 3-matrix metalloproteinase (MMP) barrier-biology gene set and epithelial junctional genes, then evaluated it across 10 public IBD mucosal transcriptomic cohorts (2172 scored biopsies) and an independent prospective adult cohort (GSE193677; 1162 participants). Adult cohorts were analyzed for mucosal healing, clinical remission, or treatment response; pediatric and early onset cohorts were analyzed separately. In UNIFI (GSE206285), a higher baseline score was inversely associated with week 8 mucosal healing (odds ratio [OR]: 0.56, 95% confidence interval [CI]: 0.45-0.71, p < 0.001). In GSE193677, the score was associated with IBD compared with control status (OR: 1.71, 95% CI: 1.45-2.02) and with endoscopic and histologic activity. The association was directionally consistent across biopsy-selection analyses and exceeded expression- and variance-matched random-gene estimates (empirical p = 0.034), while MMP and inflammatory comparators were at least as strong. Single-cell data localized the MMP module predominantly to stromal cells. These findings support retrospective transcriptomic stratification of mucosal injury states and define a barrier biology-motivated bulk mucosal readout shaped by stromal inflammatory remodeling in human tissue.