Monika Krzak, Tobi Alegbe, D. Leland Taylor, Gareth‐Rhys Jones, Mennatallah Ghouraba, Michelle Strickland, Bradley T. Harris, Reem Satti, Kenneth Arestang, Lucia Ramirez-Navarro, Nilanga Nishad, Kimberly Ai Xian Cheam, Marcus Tutert, Matiss Ozols, Guillaume Noell, Steven Leonard, Moritz J. Przybilla, Ciro Ramirez Suastegui, Eleonora Khabirova, Tong Deng, Hanna Najgebauer, Velislava Petrova, Carla P. Jones, Noor Wana, May Xueqi Hu, Jason Skelton, Jasmin Ostermayer, Yong Gu, Wendy Garri, Biljana Brezina, Charry Queen Caballes, Daniele Corridoni, Miles Parkes, Vivek Iyer, Cristina Cotobal, Rebecca E. McIntyre, Tim Raine, Carl A. Anderson
Abstract Crohn’s disease (CD) is a chronic inflammatory bowel disease exhibiting substantial heterogeneity in clinical presentation and response to therapy. To explore its molecular basis, we developed IBDverse, a large single-cell RNA sequencing (scRNA-seq) dataset of terminal ileal biopsies, profiling over 1.1 million cells from 111 patients with CD and 232 healthy controls. This resource integrates discovery and replication cohorts for the robust identification of CD-associated cell types, genes and pathways. We uncovered epithelial changes marked by interferon-driven upregulation of major histocompatibility complex class I molecules that persisted in progenitor cells after macroscopic inflammation resolution. ITGA4 + macrophages were identified as key inflammatory drivers, showing enriched JAK–STAT signaling and cytokine expression (interleukin-6 (IL-6), IL-12 and IL-23). Heritability analysis linked inflammatory monocytes and macrophages to CD susceptibility, implicating resident and recruited immune cells in pathogenesis. These findings establish a comprehensive cellular and molecular framework for CD, offering insights into disease mechanisms and therapeutic opportunities.