IBD-related inflammatory memory and colorectal cancer: epigenetic mechanisms and microbiome interventions

Abstract

Colitis-associated cancer (CAC) develops within chronically inflamed mucosa and differs from sporadic colorectal cancer in its field effects, multifocality, and sequence of molecular events. In addition to ongoing inflammation and mutation, experimental studies indicate that epithelial, immune, and stromal compartments can retain altered states after an initiating inflammatory stimulus has subsided. In this review, inflammatory memory is used operationally for a persistent molecular, cellular, tissue, or microbial state that changes the response to a later challenge. This definition distinguishes epithelial epigenetic memory from trained innate immunity, adaptive lymphocyte memory or exhaustion, and chronic signaling that depends on continued stimulation. We synthesize evidence for persistent chromatin accessibility, histone modification, DNA methylation, enhancer activity and three-dimensional organization, epithelial plasticity, immune–stromal circuits, and microbiota-derived metabolites. These responses can support mucosal repair, but repeated activation within a genetically altered field may facilitate clonal expansion and tumor development. We also assess emerging methylation, circulating tumor DNA, stool DNA, single-cell, and spatial biomarkers and grade proposed interventions according to evidence from cell culture, organoids, animal models, human tissues, and clinical studies. Because chromatin- and microbiome-directed interventions remain largely preclinical, selective modulation of pathological persistence—not complete “memory erasure”—is the appropriate translational objective.