Single-cell and spatial transcriptomics of stricturing Crohn’s disease highlights a fibrosis-associated network

Lingjia Kong, Sathish Subramanian, Åsa Segerstolpe, Vy Tran, Angela R. Shih, Grace T. Carter, Hiroko Kunitake, Shaina W. Twardus, Jasmine Li, Shivam Gandhi, Marco E. Kaper, Christy Cauley, Eric J. Chen, Caroline B. M. Porter, Toni M. Delorey, Liliana Bordeianou, Rocco Ricciardi, Ashwin N. Ananthakrishnan, Helena Lau, Daniel B. Graham, Richard Hodin, Jacques Deguine, Christopher S. Smillie, Ramnik J. Xavier

Published in Nature Genetics, 2025

Fibrosis is a major complication of Crohn’s disease (CD) marked by excess deposition of extracellular matrix, leading to stricturing and functional impairment. As mechanistic characterization and therapeutic options are lacking, we paired single-cell and spatial transcriptomics in 61 samples from 21 CD and 10 non-IBD patients. Intestinal strictures were characterized by increased immune cells, including IgG+ plasma cells, CCR7-hi CD4+ T cells, and inflammatory fibroblasts. Spatial transcriptomics showed that key subsets colocalize within diseased tissues and identified additional populations such as interstitial cells of Cajal and enteric neurons. Further, we mapped gene expression onto intestinal biogeography, finding that known genetic risk loci are enriched within discrete spatial modules, defined by the presence of inflammatory fibroblasts and lymphoid follicles. Altogether, our datasets chart the key transcriptomic and cellular networks in stricturing CD and highlight the spatial organization of multicellular genetic risk factors.