Identification and multimodal characterization of a specialized epithelial cell type associated with Crohn's Disease

Crohn’s disease (CD) is a complex chronic inflammatory disorder with both gastrointestinal and extra-intestinal manifestations associated immune dysregulation. Analyzing 202,359 cells from 170 specimens across 83 patients, we identified a distinct epithelial cell type in both terminal ileum and ascending colon (termed “LND”) with high expression of LCN2, NOS2, and DUOX2 and genes related to antimicrobial response and immunoregulation. LND cells, confirmed by in-situ RNA and protein imaging, were rare in non-IBD controls but significantly expanded in active CD. These cells actively interacted with immune cells and specifically expressed IBD/CD susceptibility genes, as demonstrated by multimodal data, suggesting a possible role in CD immunopathogenesis. Furthermore, we discovered early and late LND subpopulations with different origins and developmental potential. A higher ratio of late to early LND cells correlated with better response to anti-TNF treatment. These findings suggest a potential pathogenic role for LND cells in both Crohn’s ileitis and colitis.