Regional partitioning of colorectal epithelial cells is altered in gastrointestinal disorders without overt inflammation

The intestinal epithelium integrates host- and environment-derived cues to coordinate barrier defense, nutrient absorption, and fluid homeostasis 1-3. Single-cell atlases have delineated key regional differences between the small and large intestines and revealed extensive epithelial rewiring in inflammatory gastrointestinal diseases. However, whether comparable epithelial alterations occur in the absence of active inflammation remains unknown. In particular, the epithelial landscape in functional gastrointestinal disorders, such as irritable bowel syndrome (IBS), as well as in symptomatic patients with Crohn’s disease (CD) in remission, has not been defined. Here, using integrated single-cell and spatial transcriptomics, we generate a high-resolution map of the human colorectal epithelium across health, IBS, and symptomatic CD remission. In healthy tissue, we identify robust regional partitioning within absorptive lineages, with the rectum exhibiting transcriptional programs biased towards chloride secretion. Strikingly, in IBS and symptomatic CD remission, we observe the emergence of ectopic epithelial programs despite the absence of overt inflammation. These include antigen-sampling microfold cells in the rectum of patients with IBS and two aberrant absorptive subsets in the ascending colon of symptomatic CD patients in remission, both transcriptionally enriched for antigen sampling and chloride secretory pathways. Together, these findings reveal previously unrecognized epithelial rewiring that emerges or persists in patients with debilitating gastrointestinal symptoms despite the absence of overt inflammation.