Epithelial inflammatory memory in ulcerative colitis: molecular mechanisms and translational implications

Ulcerative colitis (UC) can relapse after clinical and endoscopic remission, raising the question of whether previously inflamed epithelium retains altered responsiveness. Patient-derived colonic organoids and lineage-resolved colitis models show that inflammation-associated chromatin accessibility can persist after removal of the original environment and influence subsequent epithelial behavior. Basal inflammatory transcription, however, can return toward normal during organoid expansion. These observations distinguish ongoing inflammatory output from latent regulatory competence; transcriptomic normalization alone neither establishes nor excludes functional memory. Differences between paired colonic regions and persistence across molecular layers support spatial and molecular heterogeneity. Exposure history, treatment, and patient characteristics are plausible modifiers whose independent contributions remain unresolved. This Review focuses on the evidence for epithelial inflammatory memory in UC and its implications for regeneration and mucosal healing. We examine how stem and regenerative lineages could retain prior experience, with emphasis on enhancer accessibility and the supporting evidence for histone, DNA-methylation, and metabolic mechanisms. Persistent epithelial states are distinguished from continued niche stimulation, reversible adaptation, fixed injury, and somatic clonal selection. Altered recall can accelerate repair while coexisting with deficient differentiation, barrier function, or regenerative reserve, making functional recovery more informative than inflammatory output alone. Translational opportunities include targeted biopsy assays linked to organoid recall, longitudinal sampling during remission, and interventions that restore mature epithelial function. Stepwise assay validation and treatment testing could connect these mechanisms to clinical outcomes, although no epithelial memory assay or memory-directed therapy is currently validated for routine UC care.