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Enterotypes of the human gut microbiome

An Addendum to this article was published on 26 February 2014

A Corrigendum to this article was published on 08 June 2011

This article has been updated

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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Figure 1: Functional and phylogenetic profiles of human gut microbiome.
Figure 2: Phylogenetic differences between enterotypes.
Figure 3: Functional differences between enterotypes.
Figure 4: Correlations with host properties.

Change history

  • 08 June 2011

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

References

  1. Eckburg, P. B. et al. Diversity of the human intestinal microbial flora. Science 308, 1635–1638 (2005)

    PubMed  PubMed Central  ADS  Google Scholar 

  2. Hayashi, H., Sakamoto, M. & Benno, Y. Phylogenetic analysis of the human gut microbiota using 16S rDNA clone libraries and strictly anaerobic culture-based methods. Microbiol. Immunol. 46, 535–548 (2002)

    Article  CAS  PubMed  Google Scholar 

  3. Lay, C. et al. Colonic microbiota signatures across five northern European countries. Appl. Environ. Microbiol. 71, 4153–4155 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gill, S. R. et al. Metagenomic analysis of the human distal gut microbiome. Science 312, 1355–1359 (2006)

    Article  CAS  ADS  PubMed  PubMed Central  Google Scholar 

  5. Turnbaugh, P. J. et al. A core gut microbiome in obese and lean twins. Nature 457, 480–484 (2009)

    Article  CAS  ADS  PubMed  Google Scholar 

  6. Kurokawa, K. et al. Comparative metagenomics revealed commonly enriched gene sets in human gut microbiomes. DNA Res. 14, 169–181 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zoetendal, E. G., Rajilic-Stojanovic, M. & de Vos, W. M. High-throughput diversity and functionality analysis of the gastrointestinal tract microbiota. Gut 57, 1605–1615 (2008)

    Article  CAS  PubMed  Google Scholar 

  8. Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Raes, J. & Bork, P. Molecular eco-systems biology: towards an understanding of community function. Nature Rev. Microbiol. 6, 693–699 (2008)

    Article  CAS  Google Scholar 

  10. Nelson, K. E. et al. A catalog of reference genomes from the human microbiome. Science 328, 994–999 (2010)

    Article  CAS  PubMed  Google Scholar 

  11. MetaHIT Consortium . MetaHIT Draft Bacterial Genomes at the Sanger Institute. 〈http://www.sanger.ac.uk/resources/downloads/bacteria/metahit/〉 (9 July 2010)

    Google Scholar 

  12. Muller, J. et al. eggNOG v2.0: extending the evolutionary genealogy of genes with enhanced non-supervised orthologous groups, species and functional annotations. Nucleic Acids Res. 38, D190–D195 (2010)

    Article  CAS  ADS  PubMed  Google Scholar 

  13. Palmer, C., Bik, E. M., Digiulio, D. B., Relman, D. A. & Brown, P. O. Development of the human infant intestinal microbiota. PLoS Biol. 5, e177 (2007)

    Article  PubMed  PubMed Central  Google Scholar 

  14. Tap, J. et al. Towards the human intestinal microbiota phylogenetic core. Environ. Microbiol. 11, 2574–2584 (2009)

    Article  PubMed  Google Scholar 

  15. Jensen, L. J. et al. STRING 8—a global view on proteins and their functional interactions in 630 organisms. Nucleic Acids Res. 37, D412–D416 (2009)

    Article  CAS  PubMed  Google Scholar 

  16. Dethlefsen, L., Huse, S., Sogin, M. L. & Relman, D. A. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol. 6, e280 (2008)

    Article  PubMed  PubMed Central  Google Scholar 

  17. Walker, A. Say hello to our little friends. Nature Rev. Microbiol. 5, 572–573 (2007)

    Article  CAS  Google Scholar 

  18. Krogfelt, K. A. Bacterial adhesion: genetics, biogenesis, and role in pathogenesis of fimbrial adhesins of Escherichia coli . Rev. Infect. Dis. 13, 721–735 (1991)

    Article  CAS  PubMed  Google Scholar 

  19. Salonen, A. et al. Comparative analysis of fecal DNA extraction methods with phylogenetic microarray: effective recovery of bacterial and archaeal DNA using mechanical cell lysis. J. Microbiol. Methods 81, 127–134 (2010)

    Article  CAS  PubMed  Google Scholar 

  20. Rajilic-Stojanovic, M. et al. Development and application of the human intestinal tract chip, a phylogenetic microarray: analysis of universally conserved phylotypes in the abundant microbiota of young and elderly adults. Environ. Microbiol. 11, 1736–1751 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rousseeuw, P. J. Silhouettes: a graphical aid to the interpretation and validation of cluster analysis. J. Comput. Appl. Math. 20, 53–65 (1987)

    Article  Google Scholar 

  22. Vanhoutte, T., Huys, G., Brandt, E., d & Swings, J. Temporal stability analysis of the microbiota in human feces by denaturing gradient gel electrophoresis using universal and group-specific 16S rRNA gene primers. FEMS Microbiol. Ecol. 48, 437–446 (2004)

    Article  CAS  PubMed  Google Scholar 

  23. Tannock, G. W. et al. Analysis of the fecal microflora of human subjects consuming a probiotic product containing Lactobacillus rhamnosus DR20. Appl. Environ. Microbiol. 66, 2578–2588 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Seksik, P. et al. Alterations of the dominant faecal bacterial groups in patients with Crohn’s disease of the colon. Gut 52, 237–242 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Costello, E. K. et al. Bacterial community variation in human body habitats across space and time. Science 326, 1694–1697 (2009)

    Article  CAS  ADS  PubMed  PubMed Central  Google Scholar 

  26. Martens, E. C., Koropatkin, N. M., Smith, T. J. & Gordon, J. I. Complex glycan catabolism by the human gut microbiota: the Bacteroidetes Sus-like paradigm. J. Biol. Chem. 284, 24673–24677 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wright, D. P., Rosendale, D. I. & Roberton, A. M. Prevotella enzymes involved in mucin oligosaccharide degradation and evidence for a small operon of genes expressed during growth on mucin. FEMS Microbiol. Lett. 190, 73–79 (2000)

    Article  CAS  PubMed  Google Scholar 

  28. Derrien, M., Vaughan, E. E., Plugge, C. M. & de Vos, W. M. Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium. Int. J. Syst. Evol. Microbiol. 54, 1469–1476 (2004)

    Article  CAS  PubMed  Google Scholar 

  29. Ley, R. E., Turnbaugh, P. J., Klein, S. & Gordon, J. I. Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022–1023 (2006)

    Article  CAS  ADS  PubMed  Google Scholar 

  30. Schwiertz, A. et al. Microbiota and SCFA in lean and overweight healthy subjects. Obesity 18, 190–195 (2009)

    Article  PubMed  Google Scholar 

  31. Woodmansey, E. J. Intestinal bacteria and ageing. J. Appl. Microbiol. 102, 1178–1186 (2007)

    Article  CAS  PubMed  Google Scholar 

  32. Kovacikova, G. & Skorupski, K. The alternative sigma factor σE plays an important role in intestinal survival and virulence in Vibrio cholerae . Infect. Immun. 70, 5355–5362 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Fujihashi, K. & Kiyono, H. Mucosal immunosenescence: new developments and vaccines to control infectious diseases. Trends Immunol. 30, 334–343 (2009)

    Article  CAS  PubMed  Google Scholar 

  34. Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006)

    Article  ADS  PubMed  Google Scholar 

  35. Raes, J., Korbel, J. O., Lercher, M. J., von Mering, C. & Bork, P. Prediction of effective genome size in metagenomic samples. Genome Biol. 8, R10 (2007)

    Article  PubMed  PubMed Central  Google Scholar 

  36. Gibson, G. R. et al. Alternative pathways for hydrogen disposal during fermentation in the human colon. Gut 31, 679–683 (1990)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Godon, J. J., Zumstein, E., Dabert, P., Habouzit, F. & Moletta, R. Molecular microbial diversity of an anaerobic digestor as determined by small-subunit rDNA sequence analysis. Appl. Environ. Microbiol. 63, 2802–2813 (1997)

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Arumugam, M., Harrington, E. D., Foerstner, K. U., Raes, J. & Bork, P. Smash Community: a metagenomic annotation and analysis tool. Bioinformatics 26, 2977–2978 (2010)

    Article  CAS  PubMed  Google Scholar 

  39. Wang, Q., Garrity, G. M., Tiedje, J. M. & Cole, J. R. Naive Bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy. Appl. Environ. Microbiol. 73, 5261–5267 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Gianoulis, T. A. et al. Quantifying environmental adaptation of metabolic pathways in metagenomics. Proc. Natl Acad. Sci. USA 106, 1374–1379 (2009)

    Article  CAS  ADS  PubMed  PubMed Central  Google Scholar 

Download references

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

Authors and Affiliations

Authors

Consortia

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.

Corresponding authors

Correspondence to S. Dusko Ehrlich or Peer Bork.

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Competing interests

The authors declare no competing financial interests.

Additional information

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

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. (PDF 769 kb)

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Supplementary Tables

The file contains Supplementary Tables 1 - 2 and 4 - 24 (see separate file for Supplementary Table 3). (PDF 520 kb)

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Arumugam, M., Raes, J., Pelletier, E. et al. Enterotypes of the human gut microbiome. Nature 473, 174–180 (2011). https://doi.org/10.1038/nature09944

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