Tissue transcriptional programs stratify Crohn's disease by therapeutic response and clinical outcomes.

Crohn's disease is biologically heterogeneous, and current clinical classifications poorly predict treatment response or disease progression. The molecular programs that drive clinical outcomes in Crohn's disease remain poorly defined. We generated and analyzed whole-transcriptome RNA-sequencing data from non-inflamed colonic biopsies of 101 well-characterized Crohn's disease patients. We performed weighted gene co-expression network analysis and identified 15 transcriptional programs that stratified Crohn's disease independent of conventional clinical classification. We then tested associations between these programs and clinical outcomes, including primary and secondary treatment failure, surgical burden, and perianal disease. A neutrophil activation program enriched for CD69 expression was strongly associated with both primary and secondary treatment failure, identifying a mucosal immune phenotype of therapeutic resistance. A fibro-proliferative program centered on SERPINE1 expression correlated with higher cumulative surgical burden, implicating tissue remodeling pathways in progressive disease. We also discovered an antimicrobial program, marked by elevated DEFA5 and DEFA6, in colonic mucosa; this signature was enriched in patients with treatment failure and validated by DEFA5 immunofluorescence. A distinct program uniquely associated with perianal disease highlights the molecular features of this severe phenotype that are not captured by standard clinical metrics. In conclusion, colonic transcriptional programs identify biologically meaningful disease states in Crohn's disease that associate with treatment failure, surgical risk, and perianal involvement. These findings provide a molecular basis for prognostic biomarkers and targeted therapeutic stratification in Crohn's disease.