Single-Cell RNA Sequencing of Terminal Ileal Biopsies Identifies Signatures of Crohn's Disease Pathogenesis.
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Krzak, Monika
(Contact person)
- Alegbe, Tobi
- Taylor, Leland D
- Rhys-Jones, Gareth
- Ghouraba, Mennatallah H
- Strickland, Michelle
- Harris, Bradley T
- Satti, Reem
- Arestang, Kenneth
- Ramirez-Navarro, Lucia
- Nishad, Nilanga
- Cheam, Kimberly Ai Xian
- Tutert, Marcus
- Ozols, Matiss
- Noell, Guillaume
- Leonard, Steven
- Przybilla, Moritz J
- Velislava, Petrova
- Jones, Carla P
- Wana, Noor
- Hu, May Xueqi
- Skelton, Jason
- Ostermayer, Jasmin
- Gu, Yong
- Garri, Wendy
- Brezina, Biljana
- Caballes, Charry Queen
- Corridoni, Daniele
- Parkes, Miles
- Iyer, Vivek
- Cotobal, Cristina
- McIntyre, Rebecca E
- Raine, Tim
- Anderson, Carl A
Description
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, the largest single-cell RNA sequencing (scRNA-seq) dataset of terminal ileal biopsies, profiling over 1.1 million cells from 111 CD patients and 232 healthy controls. This resource integrates discovery and replication cohorts for robust identification of CD-associated cell types, genes, and pathways. We uncovered epithelial changes marked by interferon-driven MHC-I upregulation, persisting in progenitors after macroscopic inflammation resolution. ITGA4+ macrophages were identified as key inflammatory drivers, showing enriched JAK/STAT signaling and cytokine expression (IL-6, IL-12, 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 new insights into disease mechanisms and therapeutic opportunities.
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