Abstract

Our knowledge of species and functional composition of the human gut microbiome is rapidly increasing, but it is still based on very few cohorts and little is known about variation across the world. By combining 22 newly sequenced faecal metagenomes of individuals from four countries with previously published data sets, here we identify three robust clusters (referred to as enterotypes hereafter) that are not nation or continent specific. We also confirmed the enterotypes in two published, larger cohorts, indicating that intestinal microbiota variation is generally stratified, not continuous. This indicates further the existence of a limited number of well-balanced host–microbial symbiotic states that might respond differently to diet and drug intake. The enterotypes are mostly driven by species composition, but abundant molecular functions are not necessarily provided by abundant species, highlighting the importance of a functional analysis to understand microbial communities. Although individual host properties such as body mass index, age, or gender cannot explain the observed enterotypes, data-driven marker genes or functional modules can be identified for each of these host properties. For example, twelve genes significantly correlate with age and three functional modules with the body mass index, hinting at a diagnostic potential of microbial markers.

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Change history

  • Corrected online 08 June 2011

    An author was omitted. His name has been added to the HTML and PDF and described in the accompanying Corrigendum.

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Acknowledgements

The authors are grateful to C. Creevey, G. Falony and members of the Bork group at EMBL for discussions and assistance. We thank the EMBL IT core facility and Y. Yuan for managing the high-performance computing resources. The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013): MetaHIT, grant agreement HEALTH-F4-2007-201052, EMBL, the Lundbeck Foundation Centre for Applied Medical Genomics in Personalized Disease Prediction, Prevention and Care (LuCAMP), Novo Nordisk Foundation and the International Science and Technology Cooperation Project in China (0806). Obese/non-obese volunteers for the MicroObes study were recruited from the SU.VI.MAX cohort study coordinated by P. Galan and S. Hercberg, and metagenome sequencing was funded by Agence Nationale de la Recherche (ANR); volunteers for MicroAge study were recruited from the CROWNALIFE cohort study coordinated by S. Silvi and A. Cresci, and metagenome sequencing was funded by GenoScope. Ciberehd is funded by the Instituto de Salud Carlos III (Spain). J.R. is supported by the Institute for the encouragement of Scientific Research and Innovation of Brussels (ISRIB) and the Odysseus programme of the Fund for Scientific Research Flanders (FWO). We are thankful to the Human Microbiome Project for generating the reference genomes from human gut microbes and the International Human Microbiome Consortium for discussions and exchange of data.

Author information

Author notes

    • Manimozhiyan Arumugam
    •  & Jeroen Raes

    These authors contributed equally to this work.

Affiliations

  1. European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany

    • Manimozhiyan Arumugam
    • , Jeroen Raes
    • , Takuji Yamada
    • , Daniel R. Mende
    • , Gabriel R. Fernandes
    • , Julien Tap
    •  & Peer Bork
  2. VIB—Vrije Universiteit Brussel, 1050 Brussels, Belgium

    • Jeroen Raes
  3. Commissariat à l’Energie Atomique, Genoscope, 91000 Evry, France

    • Eric Pelletier
    • , Denis Le Paslier
    • , Thomas Bruls
    • , Julie Poulain
    • , Edgardo Ugarte
    •  & Jean Weissenbach
  4. Centre National de la Recherche Scientifique, UMR8030, 91000 Evry, France

    • Eric Pelletier
    • , Denis Le Paslier
    • , Thomas Bruls
    •  & Jean Weissenbach
  5. Université d'Evry Val d'Essone 91000 Evry, France

    • Eric Pelletier
    • , Denis Le Paslier
    • , Thomas Bruls
    •  & Jean Weissenbach
  6. Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, 31270-901 Belo Horizonte, Minas Gerais, Brazil

    • Gabriel R. Fernandes
  7. Institut National de la Recherche Agronomique, 78350 Jouy en Josas, France

    • Julien Tap
    • , Jean-Michel Batto
    • , Marion Leclerc
    • , Florence Levenez
    • , Nicolas Pons
    • , Joel Doré
    •  & S. Dusko Ehrlich
  8. Center for Biological Sequence Analysis, Technical University of Denmark, DK-2800 Lyngby, Denmark

    • Marcelo Bertalan
    • , Laurent Gautier
    • , H. Bjørn Nielsen
    • , Thomas Sicheritz-Ponten
    •  & Søren Brunak
  9. Digestive System Research Unit, University Hospital Vall d’Hebron, Ciberehd, 08035 Barcelona, Spain

    • Natalia Borruel
    • , Francesc Casellas
    • , Chaysavanh Manichanh
    •  & Francisco Guarner
  10. Barcelona Supercomputing Center, Jordi Girona 31, 08034 Barcelona, Spain

    • Leyden Fernandez
    •  & David Torrents
  11. Marie Krogh Center for Metabolic Research, Section of Metabolic Genetics, Faculty of Health Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark

    • Torben Hansen
    • , Trine Nielsen
    •  & Oluf Pedersen
  12. Faculty of Health Sciences, University of Southern Denmark, DK-5000 Odense, Denmark

    • Torben Hansen
  13. Computational Biology Laboratory Bld, The University of Tokyo Kashiwa Campus, Kashiwa-no-ha 5-1-5, Kashiwa, Chiba, 277-8561, Japan

    • Masahira Hattori
  14. Division of Bioenvironmental Science, Frontier Science Research Center, University of Miyazaki, 5200 Kiyotake, Miyazaki 889-1692, Japan

    • Tetsuya Hayashi
  15. Laboratory of Microbiology, Wageningen University, 6710BA Ede, The Netherlands

    • Michiel Kleerebezem
    • , Sebastian Tims
    • , Erwin G. Zoetendal
    •  & Willem M. de Vos
  16. Tokyo Institute of Technology, Graduate School of Bioscience and Biotechnology, Department of Biological Information, 4259 Nagatsuta-cho, Midori-ku, Yokohama-shi, Kanagawa Pref. 226-8501, Japan

    • Ken Kurokawa
  17. BGI-Shenzhen, Shenzhen 518083, China

    • Junjie Qin
    •  & Jun Wang
  18. Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, DK-2800 Lyngby, Denmark

    • Thomas Sicheritz-Ponten
  19. Institució Catalana de Recerca i Estudis Avançats (ICREA), Pg. Lluís Companys 23, 08010 Barcelona, Spain

    • David Torrents
  20. Department of Biology, University of Copenhagen, DK-2200 Copenhagen, Denmark

    • Jun Wang
  21. Institute of Biomedical Science, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark

    • Oluf Pedersen
  22. Hagedorn Research Institute, DK-2820 Gentofte, Denmark

    • Oluf Pedersen
  23. Faculty of Health Sciences, University of Aarhus, DK-8000 Aarhus, Denmark

    • Oluf Pedersen
  24. University of Helsinki, FI-00014 Helsinki, Finland

    • Willem M. de Vos
  25. Max Delbrück Centre for Molecular Medicine, D-13092 Berlin, Germany

    • Peer Bork
  26. Digestive System Research Unit, University Hospital Vall d’Hebron, Ciberehd, 08035 Barcelona, Spain.

    • María Antolín
    • , Antonio Torrejon
    •  & Encarna Varela
  27. Commissariat à l’Energie Atomique, Genoscope, 91000 Evry, France.

    • François Artiguenave
    •  & Raquel Melo Minardi
  28. Institut National de la Recherche Agronomique, 78350 Jouy en Josas, France.

    • Hervé M. Blottiere
    • , Mathieu Almeida
    • , Antonella Cultrone
    • , Christine Delorme
    • , Rozenn Dervyn
    • , Maarten van de Guchte
    • , Eric Guedon
    • , Florence Haimet
    • , Alexandre Jamet
    • , Catherine Juste
    • , Ghalia Kaci
    • , Omar Lakhdari
    • , Severine Layec
    • , Karine Le Roux
    • , Emmanuelle Maguin
    • , Pierre Renault
    • , Nicolas Sanchez
    • , Gaetana Vandemeulebrouck
    •  & Yohanan Winogradsky
  29. UCB Pharma SA, 28046 Madrid, Spain.

    • Carlos Cara
  30. Danone Research, 91120 Palaiseau, France.

    • Christian Chervaux
    • , Gérard Denariaz
    • , Johan van Hylckama-Vlieg
    • , Jan Knol
    •  & Raish Oozeer
  31. European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.

    • Konrad U. Foerstner
    • , Wolfgang Huber
    • , Shinichi Sunagawa
    •  & Georg Zeller
  32. Heidelberger Strasse 24, 64285 Darmstadt, Germany.

    • Konrad U. Foerstner
  33. Center for Biological Sequence Analysis, Technical University of Denmark, DK-2800 Kongens Lyngby, Denmark.

    • Carsten Friss
  34. Institute of Genetics and Molecular and Cellular Biology, CNRS, INSERM, University of Strasbourg, 67404 Illkrich, France.

    • Jean Muller
  35. The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.

    • Julian Parkhill
    •  & Keith Turner
  36. Istituto Europeo di Oncologia, 20100 Milan, Italy.

    • Maria Rescigno
  37. Institut Mérieux, 17 rue Burgelat, 69002 Lyon, France.

    • Christian Brechot
    • , Alexandre Mérieux
    •  & Christine M'rini
  38. Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen, Denmark.

    • Karsten Kristiansen

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Contributions

All authors are members of the Metagenomics of the Human Intestinal Tract (MetaHIT) Consortium. Jun W., F.G., O.P., W.M.d.V., S.B., J.D., Jean W., S.D.E. and P.B. managed the project. N.B., F.C., T.H., C.M. and T. N. performed clinical analyses. M.L. and F.L. performed DNA extraction. E.P., D.L.P., T.B., J.P. and E.U. performed DNA sequencing. M.A., J.R., S.D.E. and P.B. designed the analyses. M.A., J.R., T.Y., D.R.M., G.R.F., J.T., J.-M.B., M.B., L.F., L.G., M.K., H.B.N., N.P., J.Q., T.S.-P., S.T., D.T., E.G.Z., S.D.E. and P.B. performed the analyses. M.A., J.R., P.B. and S.D.E. wrote the manuscript. M.H., T.H., K.K. and the MetaHIT Consortium members contributed to the design and execution of the study.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to S. Dusko Ehrlich or Peer Bork.

Raw Sanger read data from the European faecal metagenomes have been deposited in the NCBI Trace Archive with the following project identifiers: MH6 (33049), MH13 (33053), MH12 (33055), MH30 (33057), CD1 (33059), CD2 (33061), UC4 (33113), UC6 (33063), NO1 (33305), NO3 (33307), NO4 (33309), NO8 (33311), OB2 (33313), OB1 (38231), OB6 (38233), OB8 (45929), A (63073), B (63075), C (63077), D (63079), E (63081), G (63083). Contigs, genes and annotations are available to download from http://www.bork.embl.de/Docu/Arumugam_et_al_2011/.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    The file contains Supplementary Methods, Supplementary Notes and Supplementary References. A minor error in Supplementary Information section 2.2 was corrected on 02 June 2011.

  2. 2.

    Supplementary Figures

    This file contains Supplementary Figures 1-27 with legends.

  3. 3.

    Supplementary Tables

    The file contains Supplementary Tables 1 - 2 and 4 - 24 (see separate file for Supplementary Table 3).

  4. 4.

    Supplementary Table 3

    The file contains Supplementary Table 3.

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