{
  "abstract": "Background IBD molecular subtyping assumes stable transcriptomic phenotypes, yet whether molecular subtypes reflect fixed patient biology or dynamic inflammatory states remains unknown. We aimed to determine whether IBD molecular subtypes are stable across disease activity states and characterise the transcriptomic consequences of the active-to-inactive transition.Methods Disease activity annotations were available for 172 IBD samples from GSE75214 (UC=97, CD=75). Transcriptomic data from these and three additional GEO cohorts (GSE179285, GSE16879, GSE36807; total n=616) were integrated using ComBat batch correction. Unsupervised consensus clustering (k=3) identified three molecular subtypes: Metabolic-Absorptive (C1), Hypoxia-Metabolic (C2), and Inflammatory-EMT (C3). Subtype distribution was compared between active (n=133) and inactive (n=39) disease. Differential expression (Welch’s t-test, FDR<0.05, |log2FC|>0.3), MSigDB Hallmark pathway enrichment, a 47-gene Fibrosis Risk Score (FRS), and 13-cell-type Total Immune Burden Score (TIBS) were computed per activity state.Results The Inflammatory-EMT subtype (C3) was entirely activity-dependent. C3 comprised 59% of active IBD samples but 0% of inactive samples (active: 59% C3, 28% C1, 13% C2; inactive: 0% C3, 39% C1, 61% C2). The effect was most striking in UC, 85% of active UC samples were C3 versus 0% of inactive, which consolidated exclusively into C2. In CD, C3 comprised 27% of active samples and 0% of inactive, with inactive CD consolidating entirely into C1 (94%).FRS and TIBS were both significantly elevated in active versus inactive disease (FRS: 0.298 vs -0.529, p<0.0001; TIBS: 0.221 vs -0.475, p<0.0001). A total of 1,913 genes were differentially expressed, with active disease enriched for TNF-α/NF-κB signalling, EMT, Inflammatory Response, and Interferon Gamma Response (all p<4×10−23). Inactive disease showed no significantly better pathways (best p=0.064), indicating transcriptomic quiescence.Conclusions The Inflammatory-EMT subtype is not a stable patient trait but an activity-dependent state superimposed on two stable ground-state subtypes: C1 and C2. C3 represents the transcriptomic consequence of active mucosal inflammation, not an intrinsic patient phenotype. These findings reframe molecular subtyping clinically: C1 and C2 are targetable biological ground states, while C3 identifies the acute inflammatory layer amenable to conventional immunosuppression. The C2-to-C3 transition may represent the critical therapeutic window for preventing treatment-refractory disease.",
  "authors": [
    {
      "affiliations": [
        "New York Medical College, United States"
      ],
      "name": "Jeril Lasington"
    },
    {
      "affiliations": [
        "Rutgers University, United States"
      ],
      "name": "Lawin Steve Mathew Lasington"
    }
  ],
  "title": "IDDF2026-ABS-0161 The phantom subtype: challenging the assumption of stable molecular phenotypes in IBD",
  "uid": "aaec247b-d86e-5e5e-94be-06ef1e993b33"
}