Abstract Background Presymptomatic ulcerative colitis (UC), defined as mucosal inflammation in the absence of clinical symptomatology and identified during routine colonoscopy, offers a unique window into the preclinical stages of the disease. Novel spatial transcriptomic (ST) technologies enable deep molecular and genetic characterization of tissue, providing high-resolution, spatially coherent data to study UC. We recruited 4 presymptomatic UC cases during colorectal cancer screening, 2 symptomatic UC patients pre-treatment, and 2 patients in stable remission. Using ST, we profiled intestinal mucosal tissues, examining transcriptomic alterations arising before clinical onset of UC. Methods We generated ST profiles from colon biopsies of 8 UC patients in different stages of the disease using Visium HD. Data processing and integration was performed with Seurat. Differential gene expression was assessed with DESeq2, and pathway enrichment with fGSEA. We applied the recent GSMap framework1 to characterize the alterations of genes associated with IBD genetic risk across regions and disease stages. Results Using the novel Visium HD platform, which enables single-cell–level ST profiling, we identified epithelial, immune, and stromal clusters across all samples (A). Notably, presymptomatic individuals showed the highest proportion of lymphoid follicles vs symptomatic or remission cohorts, together with an increase in activated immune cell populations, although levels remained below those of symptomatic cases. The most pronounced transcriptional differences emerged between presymptomatic and symptomatic samples, highlighting the substantial molecular shift that occurs as the disease becomes clinically apparent (B). Pathway analysis highlighted an early activation of TNFα and NFκB signalling pathways and interferon-α/γ responses in presymptomatic tissue. GsMap revealed that IBD risk variants localize to epithelial-enriched and adaptive immune clusters, with follicular lymphoid structures accumulating the highest genetic risk burden (C). Conclusion We demonstrate that presymptomatic UC tissue exhibits distinct cellular, transcriptional, genetic, and spatial features compared with symptomatic and remission stages. Molecular changes include evidence of immune activation in presymptomatic UC. Additionally several inflammatory pathways characteristic of symptomatic UC remain only partially engaged, providing a window of opportunity for therapeutic interventions. Spatial mapping of IBD genetic risk identifies adaptive immune niches as the sites where genetic susceptibility exerts its effect during the earliest stage. Together, these findings highlight the power of presymptomatic sampling to resolve the initial pathogenic events that shape UC development. Reference: 1. Song L, Chen W, Hou J, et al. Spatially resolved mapping of cells associated with human complex traits. Nature. 2025;641:932-941. Conflict of interest: Ms. Mateos, Beatriz: No conflict of interest Mehandru, Saurabh: Grant: Genentech, Brystol Myers Squib (BMS) Personal Fees: AbbVie, Adacyte, Alimentiv, Atticus, Brystol Myers Squib (BMS), Cabaletta, Georgia Immune, Merck, Novartis Rodríguez-Lago, Iago: Financial support for traveling and educational activities from or has served as an advisory board member for Abbvie, Adacyte, Alfasigma, Biogen, Chiesi, Faes Farma, Ferring, Fresenius Kabi, Galapagos, Johnson & Johnson, Eli Lilly, Mirum Pharmaceuticals, Merck, Pfizer, Roche, Takeda, and Tillotts Pharma. Research support from AbbVie. Supported by a research grant from Gobierno Vasco-Eusko Jaurlaritza (Grant No 2020111061 and 2023222006). M. Marigorta, Urko: None
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