Peer-reviewedCC BYNature Genetics
Single-cell RNA sequencing of terminal ileal biopsies identifies signatures of Crohn’s disease pathogenesis
9 affiliations
- 1Wellcome Sanger Institute, Hinxton, UK
- 2Open Targets, Hinxton, UK
- 3Centre for Inflammation Research, Queens Medical Research institute, University of Edinburgh, Edinburgh, UK
- 4Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, UK
- 5Sanofi R&D, Cambridge, UK
- 6Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, UK. [email protected]
- 7Open Targets, Hinxton, UK. [email protected]
- 8Open Targets, Hinxton, UK. [email protected]
- 9Wellcome Sanger Institute, Hinxton, UK. [email protected]
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.
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BibTeX
@article{krzak2026singlecell,
title = {{Single-cell RNA sequencing of terminal ileal biopsies identifies signatures of Crohn’s disease pathogenesis}},
author = {Monika Krzak and Tobi Alegbe and D. Leland Taylor and Gareth‐Rhys Jones and Mennatallah Ghouraba and Michelle Strickland and Bradley T. Harris and Reem Satti and Kenneth Arestang and Lucia Ramirez-Navarro and Nilanga Nishad and Kimberly Ai Xian Cheam and Marcus Tutert and Matiss Ozols and Guillaume G. Noell and Leonard Steven and Moritz Jakob Przybilla and Ciro Ramírez-Suástegui and Eleonora Khabirova and Tong Deng and Hanna Najgebauer and Velislava N. Petrova and Carla P. Jones and Noor Wana and Hu Xueqi May and Jason Skelton and Jasmin Ostermayer and Yong Gu and Wendy Garri and Biljana Brezina and Charry Queen Caballes and Daniele Corridoni and Miles Parkes and Vivek Iyer and Cristina Cotobal and Rebecca E. McIntyre and Tim Raine and Carl A. Anderson},
journal = {Nature Genetics},
year = {2026},
month = jun,
doi = {10.1038/s41588-026-02634-7},
url = {https://doi.org/10.1038/s41588-026-02634-7},
note = {CC BY},
}
RIS
TY - JOUR
TI - Single-cell RNA sequencing of terminal ileal biopsies identifies signatures of Crohn’s disease pathogenesis
AU - Monika Krzak
AU - Tobi Alegbe
AU - D. Leland Taylor
AU - Gareth‐Rhys Jones
AU - Mennatallah Ghouraba
AU - Michelle Strickland
AU - Bradley T. Harris
AU - Reem Satti
AU - Kenneth Arestang
AU - Lucia Ramirez-Navarro
AU - Nilanga Nishad
AU - Kimberly Ai Xian Cheam
AU - Marcus Tutert
AU - Matiss Ozols
AU - Guillaume G. Noell
AU - Leonard Steven
AU - Moritz Jakob Przybilla
AU - Ciro Ramírez-Suástegui
AU - Eleonora Khabirova
AU - Tong Deng
AU - Hanna Najgebauer
AU - Velislava N. Petrova
AU - Carla P. Jones
AU - Noor Wana
AU - Hu Xueqi May
AU - Jason Skelton
AU - Jasmin Ostermayer
AU - Yong Gu
AU - Wendy Garri
AU - Biljana Brezina
AU - Charry Queen Caballes
AU - Daniele Corridoni
AU - Miles Parkes
AU - Vivek Iyer
AU - Cristina Cotobal
AU - Rebecca E. McIntyre
AU - Tim Raine
AU - Carl A. Anderson
PY - 2026
DA - 2026/06/15
JO - Nature Genetics
DO - 10.1038/s41588-026-02634-7
UR - https://doi.org/10.1038/s41588-026-02634-7
AB - 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.
SN - 1061-4036
SN - 1546-1718
ER -