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We thank the donors and their families for donating tissue samples and enabling this research; the organizers and members of the Helmsley Consortium and Human Cell Atlas Gut Bionetwork for facilitating valuable discussions; K. Roberts for support and expertise with imaging; A. Oszlanczi for help on sample management; A. Wilk for administrative assistance; H. H. Uhlig and M. G. Friedrich for valuable discussions; L. Buer and K. Thorvaldsen Hagen for assistance with tissue blocks and AB-PAS staining; H. V. Holm for access to healthy terminal ileum; A. Maartens for manuscript proofreading; and the Cambridge Biorepository for Translational Medicine for access to tissue from deceased transplant organ donors. We acknowledge support from the Wellcome Sanger Cellular Genetics Informatics team, Spatial Genomics Platform (SGP) team, particularly M. Patel, and the Core DNA Pipelines and New Pipeline Group (NPG), especially S. Leonard. This work was made possible through collaboration between the Wellcome Sanger Institute, University of Oslo and Oslo University Hospital, IDIBAPS Hospital Clinic Barcelona, Newcastle University, Newcastle University NHS Foundation Trust, Cambridge University Hospitals NHS Foundation Trust, University of Cambridge and the University of Oxford. This work was financially supported by the Wellcome Trust (WT206194 to S.A.T.); the European Research Council (646794, ThDefine to S.A.T.); an MRC New Investigator research grant (MR/T001917/1 to M.Z.); and a project grant from the Great Ormond Street Hospital Children's Charity, Sparks (V4519 to M.Z.). A.M.C. and V.G. were funded by grant #2008-04050 from The Leona and Harry B. Helmsley Charitable Trust. R.B.-C. was funded by Grant 315307, Researcher Project/International Mobility Grant from the Research Council of Norway, and travel grant from the Per Brandtzaeg's Fund for Research in Mucosal Immunology. E.M.-A. is funded by grant RH042155 (RTI2018-096946-B-I00) from the Ministerio de Ciencia e Innovacion. P.K. is funded by Wellcome grant 222426/Z/21/Z. This study was supported by the NIHR Biomedical Research Centre, Oxford, by grant PID2021-123918OB-I00 from MCIN/AEI/10.13039/501100011033 and co-funded by "FEDER A way to make Europe", Barcelona. A.J.O. is supported by the RESPIRE4 Marie Sklodowska-Curie fellowship (grant agreement 847462). This research was funded in whole, or in part, by the Wellcome Trust (203151/Z/16/Z, 203151/A/16/Z) and the UKRI Medical Research Council (MC_PC_17230). For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. The views expressed in this paper are those of the authors and not necessarily those of the NHS, the NIHR, the Department of Health or the ERS, REA and EU. The illustrations in Figs. 1a, 3h and 5f and Extended Data Fig. 1a were created with BioRender (https://biorender.com); all other illustrations were made by R.E. and A.J.O. This publication is part of the Human Cell Atlas (https://www.humancellatlas.org/publications).

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Single-cell integration reveals metaplasia in inflammatory gut diseases

Publicated to:Nature. 635 (8039): 699-+ - 2024-11-21 635(8039), DOI: 10.1038/s41586-024-07571-1

Authors: Oliver, Amanda J; Huang, Ni; Bartolome-Casado, Raquel; Li, Ruoyan; Koplev, Simon; Nilsen, Hogne R; Moy, Madelyn; Cakir, Batuhan; Polanski, Krzysztof; Gudino, Victoria; Melon-Ardanaz, Elisa; Sumanaweera, Dinithi; Dimitrov, Daniel; Milchsack, Lisa Marie; FitzPatrick, Michael E B; Provine, Nicholas M; Boccacino, Jacqueline M; Dann, Emma; Predeus, Alexander, V; To, Ken; Prete, Martin; Chapman, Jonathan A; Masi, Andrea C; Stephenson, Emily; Engelbert, Justin; Lobentanzer, Sebastian; Perera, Shani; Richardson, Laura; Kapuge, Rakeshlal; Wilbrey-Clark, Anna; Semprich, Claudia, I; Ellams, Sophie; Tudor, Catherine; Joseph, Philomeena; Garrido-Trigo, Alba; Corraliza, Ana M; Oliver, Thomas R W; Hook, C Elizabeth; James, Kylie R; Mahbubani, Krishnaa T; Saeb-Parsy, Kourosh; Zilbauer, Matthias; Saez-Rodriguez, Julio; Hoivik, Marte Lie; Baekkevold, Espen S; Stewart, Christopher J; Berrington, Janet E; Meyer, Kerstin B; Klenerman, Paul; Salas, Azucena; Haniffa, Muzlifah; Jahnsen, Frode L; Elmentaite, Rasa; Teichmann, Sarah A

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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 diseases(1,2) has fuelled efforts to catalogue cells constituting gastrointestinal tissues in health and disease(3). 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(4), 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. The study provides a comprehensive transcriptomic atlas of the human gastrointestinal tract across the lifespan, highlighting inflammation-induced changes in epithelial stem cells that alter mucosal architecture and promote further inflammation.

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