Single-cell integration reveals metaplasia in inflammatory gut diseases

Amanda J. Oliver, Ni Huang, Raquel Bartolome-Casado, Ruoyan Li, Simon Koplev, Hogne R. Nilsen, Madelyn Moy, Batuhan Cakir, Krzysztof Polanski, Victoria Gudiño, Elisa Melón-Ardanaz, Dinithi Sumanaweera, Daniel Dimitrov, Lisa Marie Milchsack, Michael E. B. FitzPatrick, Nicholas M. Provine, Jacqueline M. Boccacino, Emma Dann, Alexander V. Predeus, Ken To, Martin Prete, Jonathan A. Chapman, Andrea C. Masi, Emily Stephenson, Justin Engelbert, Sebastian Lobentanzer, Shani Perera, Laura Richardson, Rakeshlal Kapuge, Anna Wilbrey-Clark, Claudia I. Semprich, Sophie Ellams, Catherine Tudor, Philomeena Joseph, Alba Garrido-Trigo, Ana M. Corraliza, Thomas R. W. Oliver, C. Elizabeth Hook, Kylie R. James, Krishnaa T. Mahbubani, Kourosh Saeb-Parsy, Matthias Zilbauer, Julio Saez-Rodriguez, Marte Lie Høivik, Espen S. Bækkevold, Christopher J. Stewart, Janet E. Berrington, Kerstin B. Meyer, Paul Klenerman, Azucena Salas, Muzlifah Haniffa, Frode L. Jahnsen, Rasa Elmentaite and Sarah A. Teichmann ()
Additional contact information
Amanda J. Oliver: Wellcome Genome Campus
Ni Huang: Wellcome Genome Campus
Raquel Bartolome-Casado: Wellcome Genome Campus
Ruoyan Li: Wellcome Genome Campus
Simon Koplev: Wellcome Genome Campus
Hogne R. Nilsen: University of Oslo and Oslo University Hospital–Rikshospitalet
Madelyn Moy: Wellcome Genome Campus
Batuhan Cakir: Wellcome Genome Campus
Krzysztof Polanski: Wellcome Genome Campus
Victoria Gudiño: Hospital Clínic
Elisa Melón-Ardanaz: Hospital Clínic
Dinithi Sumanaweera: Wellcome Genome Campus
Daniel Dimitrov: Bioquant
Lisa Marie Milchsack: Wellcome Genome Campus
Michael E. B. FitzPatrick: University of Oxford
Nicholas M. Provine: University of Oxford
Jacqueline M. Boccacino: Wellcome Genome Campus
Emma Dann: Wellcome Genome Campus
Alexander V. Predeus: Wellcome Genome Campus
Ken To: Wellcome Genome Campus
Martin Prete: Wellcome Genome Campus
Jonathan A. Chapman: Newcastle University
Andrea C. Masi: Newcastle University
Emily Stephenson: Wellcome Genome Campus
Justin Engelbert: Wellcome Genome Campus
Sebastian Lobentanzer: Bioquant
Shani Perera: Wellcome Genome Campus
Laura Richardson: Wellcome Genome Campus
Rakeshlal Kapuge: Wellcome Genome Campus
Anna Wilbrey-Clark: Wellcome Genome Campus
Claudia I. Semprich: Wellcome Genome Campus
Sophie Ellams: Wellcome Genome Campus
Catherine Tudor: Wellcome Genome Campus
Philomeena Joseph: Wellcome Genome Campus
Alba Garrido-Trigo: Hospital Clínic
Ana M. Corraliza: Hospital Clínic
Thomas R. W. Oliver: Cambridge University Hospitals
C. Elizabeth Hook: University of Cambridge
Kylie R. James: Translational Genomics, Garvan Institute of Medical Research
Krishnaa T. Mahbubani: University of Cambridge
Kourosh Saeb-Parsy: University of Cambridge
Matthias Zilbauer: University of Cambridge
Julio Saez-Rodriguez: Bioquant
Marte Lie Høivik: Oslo University Hospital
Espen S. Bækkevold: University of Oslo and Oslo University Hospital–Rikshospitalet
Christopher J. Stewart: Newcastle University
Janet E. Berrington: Newcastle University
Kerstin B. Meyer: Wellcome Genome Campus
Paul Klenerman: University of Oxford
Azucena Salas: Hospital Clínic
Muzlifah Haniffa: Wellcome Genome Campus
Frode L. Jahnsen: University of Oslo and Oslo University Hospital–Rikshospitalet
Rasa Elmentaite: Wellcome Genome Campus
Sarah A. Teichmann: Wellcome Genome Campus

Nature, 2024, vol. 635, issue 8039, 699-707

Abstract: Abstract The gastrointestinal tract is a multi-organ system crucial for efficient nutrient uptake and barrier immunity. Advances in genomics and a surge in gastrointestinal diseases1,2 has fuelled efforts to catalogue cells constituting gastrointestinal tissues in health and disease3. Here we present systematic integration of 25 single-cell RNA sequencing datasets spanning the entire healthy gastrointestinal tract in development and in adulthood. We uniformly processed 385 samples from 189 healthy controls using a newly developed automated quality control approach (scAutoQC), leading to a healthy reference atlas with approximately 1.1 million cells and 136 fine-grained cell states. We anchor 12 gastrointestinal disease datasets spanning gastrointestinal cancers, coeliac disease, ulcerative colitis and Crohn’s disease to this reference. Utilizing this 1.6 million cell resource (gutcellatlas.org), we discover epithelial cell metaplasia originating from stem cells in intestinal inflammatory diseases with transcriptional similarity to cells found in pyloric and Brunner’s glands. Although previously linked to mucosal healing4, we now implicate pyloric gland metaplastic cells in inflammation through recruitment of immune cells including T cells and neutrophils. Overall, we describe inflammation-induced changes in stem cells that alter mucosal tissue architecture and promote further inflammation, a concept applicable to other tissues and diseases.

Date: 2024
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DOI: 10.1038/s41586-024-07571-1

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