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A Roadmap for the Human Gut Cell Atlas

Nature Reviews Gastroenterology & Hepatology volume 20, pages 597–614 (2023)Cite this article

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Abstract

The number of studies investigating the human gastrointestinal tract using various single-cell profiling methods has increased substantially in the past few years. Although this increase provides a unique opportunity for the generation of the first comprehensive Human Gut Cell Atlas (HGCA), there remains a range of major challenges ahead. Above all, the ultimate success will largely depend on a structured and coordinated approach that aligns global efforts undertaken by a large number of research groups. In this Roadmap, we discuss a comprehensive forward-thinking direction for the generation of the HGCA on behalf of the Gut Biological Network of the Human Cell Atlas. Based on the consensus opinion of experts from across the globe, we outline the main requirements for the first complete HGCA by summarizing existing data sets and highlighting anatomical regions and/or tissues with limited coverage. We provide recommendations for future studies and discuss key methodologies and the importance of integrating the healthy gut atlas with related diseases and gut organoids. Importantly, we critically overview the computational tools available and provide recommendations to overcome key challenges.

Key points

  • The number of studies applying single-cell sequencing methods to human intestinal tissue has been rapidly increasing, providing a unique opportunity to generate a complete map of the human intestine.

  • Generation of the Human Gut Cell Atlas (HGCA) requires the coordinated efforts of groups across the globe and the integration of various data sets followed by their computational analyses.

  • This article provides a roadmap for the generation of the HGCA based on the expertise and recommendations of the Gut Biological Network of the Human Cell Atlas.

  • The HGCA will provide a unique and highly valuable reference map enhancing research in intestinal health and disease.

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Fig. 1: Profiling the human gastrointestinal tract.
Fig. 2: Summary of main tissue types and sampling strategies available.
Fig. 3: Template metadata for gut-related single-cell studies.
Fig. 4: Data integration, processing and analysing strategies.
Fig. 5: Current applications for the Human Gut Cell Atlas Common Coordinate Framework.
Fig. 6: HGCA in health and disease.

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Acknowledgements

This publication is part of the Human Cell Atlas (HCA) www.humancellatlas.org/publications. The HCA initiative receives funding from The Wellcome Trust, the UK Research and Innovation Medical Research Council, EU Horizon 2020, INSERM (HuDeCA), and the Knut and Alice Wallenberg and Erling-Persson foundations. We thank the HCA Executive Office for their support. The Gut Cell Atlas is organized by The Leona M. and Harry B. Helmsley Charitable Trust and provides funding for members in the form of project grants. M.Z. was supported by an MRC New Investigator research grant (MR/T001917/1) and a project grant from the Great Ormond Street Hospital Children’s Charity, Sparks (V4519); K.S.L. was supported by NIDDK R01DK103831, and The Helmsley Trust — G-1903-03793. S.T.M. received funding from National Institutes of Health USA R01DK115806 and P30DK034987. T.S. was supported by the Japanese Science and Technology (JST) FOREST and the Japanese Society for the Promotion of Science (JSPS) (21K18272). L.A.C. and K.T.W. were supported by The Helmsley Charitable Trust — G-1903-03793. K.T.W. was also supported by NIDDK R01DK128200. L.A.C. was supported by a Veterans Affairs Merit Award 1I01BX004366. M.K. was supported by the National Research Foundation, South Africa grant no: 129356.

Author information

Author notes

  1. These authors jointly supervised this work: Matthias Zilbauer, Kylie R. James, Mandeep Kaur, Sebastian Pott, Zhixin Li & Albert Burger.

Authors and Affiliations

  1. Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK

    Matthias Zilbauer, Francesca Perrone & Alexander D. Ross

  2. University Department of Paediatrics, University of Cambridge, Cambridge, UK

    Matthias Zilbauer, Francesca Perrone & Alexander D. Ross

  3. Department of Paediatric Gastroenterology, Hepatology and Nutrition, Cambridge University Hospitals, Cambridge, UK

    Matthias Zilbauer

  4. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia

    Kylie R. James

  5. School of Biomedical Sciences, University of New South Wales, Sydney, NSW, Australia

    Kylie R. James

  6. School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg, South Africa

    Mandeep Kaur

  7. Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA

    Sebastian Pott & Ran Zhou

  8. Dana-Farber Cancer Institute, Boston, MA, USA

    Zhixin Li

  9. Department of Computer Science, Heriot-watt University, Edinburgh, UK

    Albert Burger

  10. Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Jay R. Thiagarajah & Jose Ordovas-Montanes

  11. Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University’, Chapel Hill, NC, USA

    Joseph Burclaff & Scott T. Magness

  12. Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Joseph Burclaff & Scott T. Magness

  13. Department of Pathology, Oslo University Hospital and University of Oslo, Oslo, Norway

    Frode L. Jahnsen, Raquel Bartolome-Casado & Espen S. Bækkevold

  14. University Department of Medical Genetics, University of Cambridge, Cambridge, UK

    Alexander D. Ross

  15. Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium

    Gianluca Matteoli, Nathalie Stakenborg & Guy Boeckxstaens

  16. Center for the Diagnostic and Therapeutic Endoscopy, School of Medicine, Keio University, Tokyo, Japan

    Tomohisa Sujino

  17. Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland

    Andreas Moor

  18. Wellcome Sanger Institute, Hinxton, UK

    Raquel Bartolome-Casado & Sarah A. Teichmann

  19. Department of Medicine, University of Chicago, Chicago, IL, USA

    Bingqing Xie

  20. Epithelial Biology Center and Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA

    Ken S. Lau

  21. Edinburgh IBD Unit, Western General Hospital, NHS Lothian, Edinburgh, UK

    Shahida Din

  22. Department of Computer Science and Engineering, University of Nebraska Lincoln, Lincoln, NE, USA

    Qiuming Yao

  23. Cold Spring Harbour Laboratory, Cold Spring Harbour, New York, NY, USA

    Semir Beyaz

  24. Division of Pathology, Centre for Comparative Pathology, Cancer Research UK Edinburgh Centre, Institute of Cancer and Genetics, University of Edinburgh, Edinburgh, UK

    Mark Arends

  25. Laboratory of Mucosal Biology, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium

    Alexandre Denadai-Souza

  26. Vanderbilt University Medical Center, Nashville, TN, USA

    Lori A. Coburn & Keith T. Wilson

  27. Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA

    Lori A. Coburn & Keith T. Wilson

  28. Department of Biological Sciences, Columbia University, New York, NY, USA

    Jellert T. Gaublomme

  29. University of Edinburgh, Edinburgh, UK

    Richard Baldock

  30. European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Genome Campus, Hinxton, UK

    Irene Papatheodorou

  31. Genentech, San Francisco, CA, USA

    Anna Hupalowska & Aviv Regev

  32. Theory of Condensed Matter Group, Cavendish Laboratory/Department of Physics, University of Cambridge, Cambridge, UK

    Sarah A. Teichmann

  33. Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA

    Aviv Regev

  34. Broad Institute and Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Ramnik J. Xavier

  35. MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK

    Alison Simmons

  36. Stanford University School of Medicine, Stanford, CA, USA

    Michael P. Snyder

Authors
  1. Matthias Zilbauer
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  2. Kylie R. James
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  3. Mandeep Kaur
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  4. Sebastian Pott
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  5. Zhixin Li
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  6. Albert Burger
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  18. Ran Zhou
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  19. Bingqing Xie
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  20. Ken S. Lau
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  21. Shahida Din
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Consortia

Gut Cell Atlas Consortium

  • Matthias Zilbauer
  • , Kylie R. James
  • , Sebastian Pott
  • , Albert Burger
  • , Nathalie Stakenborg
  • , Andreas Moor
  • , Ran Zhou
  • , Bingqing Xie
  • , Ken S. Lau
  • , Shahida Din
  • , Mark Arends
  • , Alexandre Denadai-Souza
  • , Lori A. Coburn
  • , Jellert T. Gaublomme
  • , Richard Baldock
  • , Irene Papatheodorou
  • , Guy Boeckxstaens
  • , Sarah A. Teichmann
  • , Ramnik J. Xavier
  •  & Keith T. Wilson

Human Cell Atlas Gut Biological Network Consortium

  • Matthias Zilbauer
  • , Kylie R. James
  • , Mandeep Kaur
  • , Sebastian Pott
  • , Zhixin Li
  • , Albert Burger
  • , Jay R. Thiagarajah
  • , Joseph Burclaff
  • , Frode L. Jahnsen
  • , Francesca Perrone
  • , Alexander D. Ross
  • , Gianluca Matteoli
  • , Nathalie Stakenborg
  • , Tomohisa Sujino
  • , Andreas Moor
  • , Raquel Bartolome-Casado
  • , Espen S. Bækkevold
  • , Ran Zhou
  • , Bingqing Xie
  • , Ken S. Lau
  • , Shahida Din
  • , Scott T. Magness
  • , Qiuming Yao
  • , Semir Beyaz
  • , Mark Arends
  • , Alexandre Denadai-Souza
  • , Lori A. Coburn
  • , Jellert T. Gaublomme
  • , Richard Baldock
  • , Irene Papatheodorou
  • , Jose Ordovas-Montanes
  • , Guy Boeckxstaens
  • , Anna Hupalowska
  • , Sarah A. Teichmann
  • , Aviv Regev
  • , Ramnik J. Xavier
  • , Alison Simmons
  • , Michael P. Snyder
  •  & Keith T. Wilson

Contributions

M.Z., K.R.J., M.K., S.P., Z.L., A.B., J.R.T., J.B., F.L.J., F.P., A. Ross, N.S., R.B.C., E.S.B., R.Z., B.X., K.L., S.D., S.T.M., Q.Y., S.B., M.J.A., A.D-.S., L.C., J.G., R.B., I.P., J.O-.M., S.A.T., M.P.S. and K.T.W. researched data for the article. M.Z., K.R.J., M.K., S.P., Z.L., A.B., J.R.T., J.B., F.L.J., F.P., A. Ross, G.M., N.S., T.S., A.M., R.B.C., E.S.B., R.Z., B.X., K.L., S.D., S.T.M., Q.Y., S.B., M.J.A., A.D-.S., L.C., J.G., R.B., I.P., J.O-.M., G.E.B., A.H., S.A.T., A. Regev, R.J.X., M.P.S. and K.T.W. contributed substantially to discussion of the content. M.Z., K.R.J., M.K., S.P., Z.L., A.B., J.R.T., J.B., F.L.J., F.P., A. Ross, N.S., T.S., R.B.C., E.S.B., R.Z., B.X., K.L., S.D., S.T.M., Q.Y., S.B., M.J.A., A.D-.S., L.C., J.G., R.B., I.P., G.E.B., S.A.T., M.P.S. and K.T.W. wrote the article. M.Z., K.R.J., M.K., S.P., Z.L., A.B., J.R.T., J.B., F.L.J., F.P., A. Ross, G.M., T.S., A.M., R.B.C., E.S.B., R.Z., B.X., K.L., S.D., S.T.M., Q.Y., S.B., M.J.A., A.D-.S., L.C., J.G., R.B., I.P., J.O-.M., G.E.B., A.H., S.A.T., A. Regev, R.J.X., A.S., M.P.S. and K.T.W reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Matthias Zilbauer.

Ethics declarations

Competing interests

In the past 3 years, S.A.T. has consulted or been a member of scientific advisory boards at Roche, Genentech, Biogen, GlaxoSmithKline, Qiagen and ForeSite Labs and is an equity holder of Transition Bio. G.M. has received grant funding from Boehringer Ingelheim. A. Regev is a co-founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas, and was a SAB member of ThermoFisher Scientific, Syros Pharmaceuticals, Neogene Therapeutics and Asimov until 31 July 2020. Since 1 August 2020, A. Regev has been an employee of Genentech and has equity in Roche. A. Regev is an inventor on patents and patent applications filed at the Broad Institute related to single-cell genomics. The remaining authors declare no competing interests.

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Nature Reviews Reviews Gastroenterology & Hepatology thanks the anonymous reviewers for their contribution to the peer review of this work.

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Tabula Sapiens: https://tabula-sapiens-portal.ds.czbiohub.org

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Zilbauer, M., James, K.R., Kaur, M. et al. A Roadmap for the Human Gut Cell Atlas. Nat Rev Gastroenterol Hepatol 20, 597–614 (2023). https://doi.org/10.1038/s41575-023-00784-1

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