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Background The classification of IBD into ulcerative colitis (UC) and Crohn’s disease (CD) is based on clinicopathological criteria established in the 20th century. Whether this binary reflects underlying molecular biology remains unresolved. We aimed to discover data-driven molecular subtypes of IBD through unsupervised transcriptomic integration across independent cohorts.Methods Colonic biopsy gene expression profiles from four GEO cohorts (GSE75214, GSE179285, GSE16879, GSE36807; n=616; UC=215, CD=303, Control=98) were integrated following probe-to-gene mapping, cross-platform harmonisation, and ComBat batch correction. Consensus clustering was applied to the top 5,000 most variable genes across k=2-8, with optimal cluster number determined by the Proportion of Ambiguous Clustering (PAC) score. Subtypes were characterised by differential expression, MSigDB Hallmark pathway enrichment, and immune cell deconvolution. Treatment response prediction was validated using pre-treatment samples from GSE16879 (n=61).Results Consensus clustering identified three robust molecular subtypes (optimal k=3, PAC=0.026), designated C1-Metabolic-Absorptive, C2-Hypoxia-Metabolic, and C3-Inflammatory-EMT ( IDDF2026-ABS-0219 Figure 1. Molecular subtypes). Subtype membership did not correspond to clinical diagnosis: C2 comprised 45% CD and 35% UC with no molecular distinction between diagnoses (IDDF2026-ABS-0219 Figure 2. Clinical diagnosis). C1 was enriched for lipid metabolism and bile acid pathways (APOB, APOC3, MTTP; p=2×10−12), C2 for hypoxia and glycolysis with preserved epithelial integrity (AQP8, CLDN8; p=1×10−7), and C3 for TNF/NF-κB, IL-17, and epithelial-mesenchymal transition (MMP1/3/7, S100A8; EMT p=4×10−32) (IDDF2026-ABS-0219 Figure 3. Disease composition per subtype). Immune deconvolution revealed C3 as pan-immune activated with the highest plasma cell infiltration (z=0.98) and M1 macrophage polarisation (z=0.77), while C2 showed uniformly low immune infiltration consistent with a mucosal healing phenotype (IDDF2026-ABS-0219 Figure 4. Immune cell deconvolution per molecular subtype). Molecular subtype significantly predicted infliximab response independent of diagnosis (χ2=13.8, p=0.001): C2 achieved 92% response versus 29% in C3 and 47% in C1 (IDDF2026-ABS-0219 Figure 5. Infliximab response per subtype).Conclusions Unsupervised transcriptomic integration across 616 IBD biopsies reveals three molecular subtypes that transcend the UC/CD dichotomy. Subtype membership predicts anti-TNF response more accurately than clinical diagnosis, with the pan-immune C3 subtype showing primary resistance likely driven by TNF-independent IL-17 and humoral mechanisms. These findings challenge the clinical utility of the UC/CD binary and support a molecular reclassification framework for IBD precision medicine.Abstract IDDF2026-ABS-0219 Figure 1Abstract IDDF2026-ABS-0219 Figure 2Abstract IDDF2026-ABS-0219 Figure 4Abstract IDDF2026-ABS-0219 Figure 3Abstract IDDF2026-ABS-0219 Figure 5