Baseline mucosal transcriptomic endotypes stratify healing capacity and biologic therapy outcomes in ulcerative colitis: an integrative multi-cohort study
Year: 2026
Type: article
Abstract: Background Numerous baseline mucosal transcriptomic signatures have been proposed to stratify therapeutic outcomes in ulcerative colitis (UC), but cross-cohort transferability is frequently undermined by platform heterogeneity, endpoint/timepoint differences, and drug-specific biases. The resulting lack of a biologic-agnostic molecular baseline has limited clinical translation and prospective trial design. Methods We integratively re-analyzed endpoint-linked baseline mucosal transcriptomes from seven public UC GEO series (778 unique baseline samples), with three additional public accessions used for disease-activity and contextual analyses. The primary response/healing synthesis used five study slices spanning anti-TNF, anti-integrin, and etrolizumab-treated cohorts. Unsupervised decomposition identified baseline endotypes, and endotype-outcome associations were estimated within each cohort (OR per 1-SD increase) and summarized by random-effects cross-cohort pooling with heterogeneity reporting, rank/seed sensitivity analyses, endpoint-restricted summaries, and negative controls. Results Across five primary response/healing study slices, an epithelial barrier endotype (EPITHELIAL_BARRIER/NMF_C3) was associated with higher odds of response/healing (random-effects cross-cohort pooling OR = 3.171, 95% CI 1.491–6.744), whereas macrophage-inflammation and lymphoid/complement-stromal axes (MACROPHAGE_INFLAMMATION/NMF_C1 and LYMPHOID_COMPLEMENT_STROMAL/NMF_C2) were associated with lower odds of response/healing (OR = 0.359, 0.175–0.735; OR = 0.378, 0.220–0.651). The epithelial estimate was largest in GSE73661 but remained significant in the five-study leave-one-out summary after excluding that cohort (OR = 2.547, 95% CI 1.271–5.105). Cross-mechanism evaluation included UNIFI ustekinumab week-8 mucosal healing (UST arm n = 358; EPITHELIAL_BARRIER OR = 4.483, 2.263–8.881) and directionally consistent effects in etrolizumab. Endotype axes were supported by independent single-cell localization (FDR = 0.0026). Treatment-interaction tests were imprecise and did not establish drug-class-specific prediction. In cohort-heldout prediction, AUC ranged from 0.717 to 0.758, but calibration was variable. A network-based therapeutic prioritization was enriched for UC-approved agents (AUC = 0.741; permutation p = 6.0 × 10 − 4 ) and is presented as hypothesis-generating. Conclusion Baseline mucosal endotypes stratify healing capacity and therapeutic outcomes across public cohorts, with orthogonal support from single-cell localization. These findings support prospective evaluation as biologic-agnostic outcome stratifiers rather than established drug-specific predictive biomarkers.
Source: Frontiers in Pharmacology
Authors: Wenbiao Chen, Shiyong Zeng
Institution: Quanzhou Medical College
Language: English
Topic: Inflammatory Bowel Disease
Subfield: Gastroenterology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7223287045