Intestinal Epithelial Memory: From Inflammatory Imprinting to Metabolite‐Shaped Immune Tolerance

ABSTRACT Intestinal epithelial cells are rapidly renewing barrier cells that maintain compartmentalization between the luminal environment and the mucosal immune system through epithelial transport, antimicrobial defense, secretory programs, and cytokine‐mediated communication. Emerging evidence suggests that the intestinal epithelium can also retain durable imprints of prior inflammatory, microbial, or metabolic exposures. We refer to this phenomenon as intestinal epithelial memory. This form of memory is likely encoded within stem and progenitor compartments through persistent changes in chromatin accessibility, transcriptional responsiveness, lineage specification, and cellular metabolism. In inflammatory bowel disease, epithelial memory may help explain persistent barrier dysfunction, relapse‐prone mucosa, and incomplete epithelial recovery after apparent inflammatory resolution. Human organoid studies show that intestinal stem cells from previously inflamed ulcerative colitis mucosa retain chromatin‐based inflammatory memory. Mouse colitis models further show that long‐lasting epigenetic imprints in colonic stem cells can generate repair‐primed states that promote tumor growth after oncogenic mutation. Microbiota‐derived metabolites may represent another class of epithelial memory‐shaping cues. This possibility is exemplified by emerging evidence that butyrate can induce sustained epithelial metabolic and epigenetic programs that influence downstream IL‐10 + CD4 + T cell responses to maintain intestinal immune tolerance. In this Review, we discuss intestinal epithelial memory as a bridge between inflammatory imprinting, epithelial plasticity, mucosal immune regulation, and intestinal disease progression. We propose that durable intestinal health may require not only suppression of active inflammation but also a deeper understanding of how epithelial memory is established, maintained, and potentially redirected.