Single-cell integration reveals metaplasia in inflammatory gut diseases
The gastrointestinal tract is a multi-organ system crucial for efficient nutrient uptake and barrier immunity. Advances in genomics and a surge in gastrointestinal diseases<sup>1,2</sup> has fuelled efforts to catalogue cells constituting gastrointestinal tissues in health and disease<sup>3</sup>. 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 healing<sup>4</sup>, 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.
Authors
- Michael Fitzpatrick (ORCID: https://orcid.org/0000-0003-2365-2012)
- Raquel Bartolomé-Casado (ORCID: https://orcid.org/0000-0002-8966-9047)
- Julio Sáez-Rodríguez (ORCID: https://orcid.org/0000-0002-8552-8976)
- Madelyn Moy (ORCID: https://orcid.org/0000-0003-1159-5049)
- Catherine Tudor (ORCID: https://orcid.org/0000-0003-2093-9683)
- Dinithi Sumanaweera (ORCID: https://orcid.org/0000-0003-4515-0988)
- Anna Wilbrey-Clark (ORCID: https://orcid.org/0000-0002-5399-7997)
- Sebastian Lobentanzer (ORCID: https://orcid.org/0000-0003-3399-6695)
- Matthias Zilbauer (ORCID: https://orcid.org/0000-0002-7272-0547)
- Ruoyan Li (ORCID: https://orcid.org/0000-0001-5337-9729)
- Nicholas M. Provine (ORCID: https://orcid.org/0000-0002-9694-2216)
- Krishnaa T. A. Mahbubani (ORCID: https://orcid.org/0000-0002-1327-2334)
- Sarah Amalia Teichmann (ORCID: https://orcid.org/0000-0002-6294-6366)
- Paul Klenerman (ORCID: https://orcid.org/0000-0003-4307-9161)
- Ken To (ORCID: https://orcid.org/0000-0001-9262-7190)
- Christopher James Stewart (ORCID: https://orcid.org/0000-0002-6033-338X)
- Elisa Melón-Ardanaz (ORCID: https://orcid.org/0000-0003-1838-5474)
- Marte Lie Høivik (ORCID: https://orcid.org/0000-0002-0104-465X)
- Azucena Salas (ORCID: https://orcid.org/0000-0003-4572-2907)
- Emily Stephenson (ORCID: https://orcid.org/0000-0002-4244-4019)
- Simon Koplev (ORCID: https://orcid.org/0000-0002-8586-5614)
- Kourosh Saeb‐Parsy (ORCID: https://orcid.org/0000-0002-0633-3696)
- Jacqueline Marcia Boccacino (ORCID: https://orcid.org/0000-0001-6813-5217)
- Hogne Røed Nilsen
- Jonathan A. Chapman (ORCID: https://orcid.org/0000-0003-1068-8278)
- A M Corraliza (ORCID: https://orcid.org/0000-0002-3067-7763)
- Laura Richardson (ORCID: https://orcid.org/0000-0002-8075-3816)
- Amanda J. Oliver (ORCID: https://orcid.org/0000-0003-1690-9027)
- Alexander V. Predeus (ORCID: https://orcid.org/0000-0002-2750-1599)
- Frode L. Jahnsen (ORCID: https://orcid.org/0000-0003-3843-7171)
- Victòria Gudiño (ORCID: https://orcid.org/0000-0003-1663-975X)
- Batuhan Çakır (ORCID: https://orcid.org/0000-0003-4513-606X)
- Thomas R. W. Oliver (ORCID: https://orcid.org/0000-0003-4306-0102)
- Janet Berrington (ORCID: https://orcid.org/0000-0002-6185-2843)
- Rasa Elmentaite (ORCID: https://orcid.org/0000-0001-7366-5466)
- Espen S. Bækkevold (ORCID: https://orcid.org/0000-0002-5890-9108)
- Muzlifah A. Haniffa (ORCID: https://orcid.org/0000-0002-3927-2084)
- Martin Prete (ORCID: https://orcid.org/0000-0002-5946-821X)
- Kylie R. James (ORCID: https://orcid.org/0000-0002-7107-0650)
- Claudia I. Semprich (ORCID: https://orcid.org/0000-0002-2446-9028)
- Rakeshlal Kapuge (ORCID: https://orcid.org/0009-0001-3394-0387)
- Alba Garrido-Trigo
- Shani Perera (ORCID: https://orcid.org/0000-0001-8021-2078)
- A Masi (ORCID: https://orcid.org/0000-0002-4714-9174)
- Ni Huang (ORCID: https://orcid.org/0000-0001-8849-038X)
- Emma Dann (ORCID: https://orcid.org/0000-0002-7400-7438)
- Daniel Dimitrov (ORCID: https://orcid.org/0000-0002-5197-2112)
- Krzysztof Polański (ORCID: https://orcid.org/0000-0002-2586-9576)
- Kerstin B. Meyer (ORCID: https://orcid.org/0000-0001-5906-1498)
- Justin Engelbert (ORCID: https://orcid.org/0000-0002-4255-9668)
- P. Joseph
- Lisa Marie Milchsack (ORCID: https://orcid.org/0009-0003-4284-5263)
- Sophie Ellams
- C. Elizabeth Hook (ORCID: https://orcid.org/0000-0002-0450-7656)
Institutions
- Oslo University Hospital (NO)
- The University of Texas MD Anderson Cancer Center (US)
- Garvan Institute of Medical Research (AU)
- University of Oslo (NO)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- Heidelberg University (DE)
- University of Cambridge (GB)
- Macmillan Cancer Support (GB)
- University Hospital Heidelberg (DE)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Wellcome Sanger Institute (GB)
- UNSW Sydney (AU)
- National Institute for Health and Care Research (GB)
- University of Oxford (GB)
- Medawar Building for Pathogen Research (GB)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (ES)
- NIHR Newcastle Biomedical Research Centre (GB)
- Oxford BioMedica (United Kingdom) (GB)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- Newcastle University (GB)
- Wellcome Trust (GB)
Publication Details
- Journal
- Nature
- Published
- 2024-11-20
- DOI
- https://doi.org/10.1038/s41586-024-07571-1
- Citations
- 63
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 14.50
Funders
- Medical Research Council