Epithelial dysfunction as a driver of symptoms in gastrointestinal disorders

Abstract The intestinal epithelium integrates host and environmental signals to regulate defense, absorption, and fluid balance 1-3. Single-cell atlases have unveiled regional specialization across the gut 4-6. Nevertheless, the colorectum, closely linked to chronic GI symptoms, remains underexplored. Debilitating symptoms such as altered bowel habits and abdominal pain hallmark irritable bowel syndrome and affect nearly half of Crohn’s disease patients in remission 7,8. Although these symptoms are attributed to neuromuscular dysfunction 9 or immune-driven nociceptor sensitization 10, the limited therapeutic benefit translated from this conceptual framework suggests additional drivers may contribute. Using single-cell and spatial transcriptomics, we map the human colorectal epithelium. In health, we uncover marked absorptive-cell heterogeneity between rectum and colon, with the rectum functioning as a chloride-secreting zone. In disease, we detect ectopic cell types, i.e. antigen-sampling microfold-cell expansion in the rectum of irritable bowel syndrome and two aberrant absorptive subsets in the ascending colon of symptomatic Crohn’s in remission, transcriptionally resembling rectal chloride-secreting cells. Finally, we reveal disruption of a novel enteroendocrine–neuronal analgesic pathway. These insights challenge prevailing symptom models, establish epithelial dysfunction as a central pathogenic mechanism, and suggest new epithelial-directed therapies.