Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Genomic approaches to studying the human microbiota

Nature volume 489, pages 250–256 (2012)Cite this article

Subjects

Abstract

The human body is colonized by a vast array of microbes, which form communities of bacteria, viruses and microbial eukaryotes that are specific to each anatomical environment. Every community must be studied as a whole because many organisms have never been cultured independently, and this poses formidable challenges. The advent of next-generation DNA sequencing has allowed more sophisticated analysis and sampling of these complex systems by culture-independent methods. These methods are revealing differences in community structure between anatomical sites, between individuals, and between healthy and diseased states, and are transforming our view of human biology.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Data and analysis workflow for microbiome analysis.

Similar content being viewed by others

References

  1. Backhed, F., Ley, R. E., Sonnenburg, J. L., Peterson, D. A. & Gordon, J. I. Host–bacterial mutualism in the human intestine. Science 307, 1915–1920 (2005).

    Article  ADS  Google Scholar 

  2. Foxman, B., Goldberg, D., Murdock, C., Xi, C. & Gilsdorf, J. R. Conceptualizing human microbiota: from multicelled organ to ecological community. Interdiscip. Perspect. Infect. Dis. 2008, 613979 (2008).

    Article  Google Scholar 

  3. Possemiers, S., Bolca, S., Verstraete, W. & Heyerick, A. The intestinal microbiome: a separate organ inside the body with the metabolic potential to influence the bioactivity of botanicals. Fitoterapia 82, 53–66 (2011).

    Article  CAS  Google Scholar 

  4. Shanahan, F. The host–microbe interface within the gut. Best Pract. Res. Clin. Gastroenterol. 16, 915–931 (2002).

    Article  Google Scholar 

  5. Bruls, T. & Weissenbach, J. The human metagenome: our other genome? Hum. Mol. Genet. 20, R142–R148 (2011).

    Article  CAS  Google Scholar 

  6. Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010). This paper presents initial findings on the gut microbiome from the MetaHIT project.

    Article  CAS  Google Scholar 

  7. Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012). This paper presents analysis of data from the HMP.

  8. Stein, J. L., Marsh, T. L., Wu, K. Y., Shizuya, H. & DeLong, E. F. Characterization of uncultivated prokaryotes: isolation and analysis of a 40-kilobase-pair genome fragment from a planktonic marine archaeon. J. Bacteriol. 178, 591–599 (1996).

    Article  CAS  Google Scholar 

  9. Vergin, K. L. et al. Screening of a fosmid library of marine environmental genomic DNA fragments reveals four clones related to members of the order Planctomycetales. Appl. Environ. Microbiol. 64, 3075–3078 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Olsen, G. J., Lane, D. J., Giovannoni, S. J., Pace, N. R. & Stahl, D. A. Microbial ecology and evolution: a ribosomal RNA approach. Annu. Rev. Microbiol. 40, 337–365 (1986).

    Article  CAS  Google Scholar 

  11. Manichanh, C. et al. Reduced diversity of faecal microbiota in Crohn's disease revealed by a metagenomic approach. Gut 55, 205–211 (2006).

    Article  CAS  Google Scholar 

  12. Fredricks, D. N., Fiedler, T. L. & Marrazzo, J. M. Molecular identification of bacteria associated with bacterial vaginosis. N. Engl. J. Med. 353, 1899–1911 (2005).

    Article  CAS  Google Scholar 

  13. Flint, H. J., Bayer, E. A., Rincon, M. T., Lamed, R. & White, B. A. Polysaccharide utilization by gut bacteria: potential for new insights from genomic analysis. Nature Rev. Microbiol. 6, 121–131 (2008).

    Article  CAS  Google Scholar 

  14. Srikanth, C. V. & McCormick, B. A. Interactions of the intestinal epithelium with the pathogen and the indigenous microbiota: a three-way crosstalk. Interdiscip. Perspect. Infect. Dis. 2008, 626827 (2008).

    Article  CAS  Google Scholar 

  15. Jakobsson, H. E. et al. Short-term antibiotic treatment has differing long-term impacts on the human throat and gut microbiome. PLoS ONE 5, e9836 (2010).

    Article  ADS  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  Google Scholar 

  17. Miller, C. P., Bohnhoff, M. & Rifkind, D. The effect of an antibiotic on the susceptibility of the mouse's intestinal tract to Salmonella infection. Trans. Am. Clin. Climatol. Assoc. 68, 51–55 (1956).

    PubMed  Google Scholar 

  18. Sekirov, I. et al. Antibiotic-induced perturbations of the intestinal microbiota alter host susceptibility to enteric infection. Infect. Immun. 76, 4726–4736 (2008).

    Article  CAS  Google Scholar 

  19. Croswell, A., Amir, E., Teggatz, P., Barman, M. & Salzman, N. H. Prolonged impact of antibiotics on intestinal microbial ecology and susceptibility to enteric Salmonella infection. Infect. Immun. 77, 2741–2753 (2009).

    Article  CAS  Google Scholar 

  20. Mulligan, M. E. Epidemiology of Clostridium difficile-induced intestinal disease. Clin. Infect. Dis. 6, S222–S228 (1984).

    Article  Google Scholar 

  21. Jarchum, I. & Pamer, E. G. Regulation of innate and adaptive immunity by the commensal microbiota. Curr. Opin. Immunol. 23, 353–360 (2011).

    Article  CAS  Google Scholar 

  22. Marsland, B. J. Regulation of inflammatory responses by the commensal microbiota. Thorax 67, 93–94 (2012).

    Article  Google Scholar 

  23. Wang, Z. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57–63 (2011).

    Article  ADS  CAS  Google Scholar 

  24. Gough, E., Shaikh, H. & Manges, A. R. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin. Infect. Dis. 53, 994–1002 (2011).

    Article  Google Scholar 

  25. Brandt, L. J. & Reddy, S. S. Fecal microbiota transplantation for recurrent clostridium difficile infection. J. Clin. Gastroenterol. 45, S159–S167 (2011).

    Article  Google Scholar 

  26. D'Onofrio, A. et al. Siderophores from neighboring organisms promote the growth of uncultured bacteria. Chem. Biol. 17, 254–264 (2010).

    Article  CAS  Google Scholar 

  27. Human Microbiome Jumpstart Reference Strains Consortium. A catalog of reference genomes from the human microbiome. Science 328, 994–999 (2010). This paper presents methods and analysis for large-scale production of reference genome sequences from human-microbiome organisms.

  28. Gans, J., Wolinsky, M. & Dunbar, J. Computational improvements reveal great bacterial diversity and high metal toxicity in soil. Science 309, 1387–1390 (2005).

    Article  ADS  CAS  Google Scholar 

  29. Nelson, T. A. et al. PhyloChip microarray analysis reveals altered gastrointestinal microbial communities in a rat model of colonic hypersensitivity. Neurogastroenterol. Motil. 23, 169–177 (2011).

    Article  CAS  Google Scholar 

  30. Bent, S. J. et al. Measuring species richness based on microbial community fingerprints: the emperor has no clothes. Appl. Environ. Microbiol. 73, 2399–2401 (2007).

    Article  CAS  Google Scholar 

  31. Sogin, M. L. et al. Microbial diversity in the deep sea and the underexplored “rare biosphere”. Proc. Natl Acad. Sci. USA 103, 12115–12120 (2006).

    Article  ADS  CAS  Google Scholar 

  32. The NIH HMP Working Group et al. The NIH Human Microbiome Project. Genome Res. 19, 2317–2323 (2009).

  33. Human Microbiome Project Consortium. A framework for human microbiome research. Nature 486, 215–221 (2012). This paper describes the data sets and resources of the HMP.

  34. Lazarevic, V. et al. Metagenomic study of the oral microbiota by Illumina high-throughput sequencing. J. Microbiol. Methods 79, 266–271 (2009).

    Article  CAS  Google Scholar 

  35. Claesson, M. J. et al. Comparison of two next-generation sequencing technologies for resolving highly complex microbiota composition using tandem variable 16S rRNA gene regions. Nucleic Acids Res. 38, e200 (2010).

    Article  Google Scholar 

  36. Gloor, G. B. et al. Microbiome profiling by Illumina sequencing of combinatorial sequence-tagged PCR products. PLoS ONE 5, e15406 (2010).

    Article  ADS  Google Scholar 

  37. Hummelen, R. et al. Deep sequencing of the vaginal microbiota of women with HIV. PLoS ONE 5, e12078 (2010).

    Article  ADS  Google Scholar 

  38. Zubrzycki, L. & Spaulding, E. H. Studies on the stability of the normal human fecal flora. J. Bacteriol. 83, 968–974 (1962).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Luckey, T. D. Introduction to intestinal microecology. Am. J. Clin. Nutr. 25, 1292–1294 (1972).

    Article  CAS  Google Scholar 

  40. Arumugam, M. et al. Enterotypes of the human gut microbiome. Nature 473, 174–180 (2011).

    Article  CAS  Google Scholar 

  41. Martin, J. et al. Optimizing read mapping to reference genomes to determine composition and species prevalence in microbial communities. PloS ONE 7, e36427 (2012).

    Article  ADS  CAS  Google Scholar 

  42. Wu, G. D. et al. Linking long-term dietary patterns with gut microbial enterotypes. Science 334, 105–108 (2011).

    Article  ADS  CAS  Google Scholar 

  43. Ravel, J. et al. Vaginal microbiome of reproductive-age women. Proc. Natl Acad. Sci. USA 108, S4680–S4687 (2011).

    Article  ADS  Google Scholar 

  44. Proctor, L. M. The Human Microbiome Project in 2011 and beyond. Cell Host Microbe 10, 287–291 (2011).

    Article  CAS  Google Scholar 

  45. DOE Joint Genome Institute. A Genomic Encyclopedia of Bacteria and Archaea. http://www.jgi.doe.gov/programs/GEBA/ (US Department of Energy, 2012).

  46. Parfrey, L. W., Walters, W. A. & Knight, R. Microbial eukaryotes in the human microbiome: ecology, evolution, and future directions. Front. Microbiol. 2, 153 (2011).

    Article  Google Scholar 

  47. Wylie, K. M., Weinstock, G. M. & Storch, G. A. Emerging view of the human virome. Transl. Res. http://dx.doi.org/10.1016/j.trsl.2012.03.006 (24 April 2012).

  48. Breitbart, M. et al. Metagenomic analyses of an uncultured viral community from human feces. J. Bacteriol. 185, 6220–6223 (2003).

    Article  CAS  Google Scholar 

  49. Palacios, G. et al. Panmicrobial oligonucleotide array for diagnosis of infectious diseases. Emerg. Infect. Dis. 13, 73–81 (2007).

    Article  CAS  Google Scholar 

  50. Wang, D. et al. Viral discovery and sequence recovery using DNA microarrays. PLoS Biol. 1, E2 (2003).

    Article  Google Scholar 

  51. Casas, V. & Rohwer, F. Phage metagenomics. Methods Enzymol. 421, 259–268 (2007).

    Article  CAS  Google Scholar 

  52. Allander, T. et al. Cloning of a human parvovirus by molecular screening of respiratory tract samples. Proc. Natl Acad. Sci. USA 102, 12891–12896 (2005).

    Article  ADS  CAS  Google Scholar 

  53. Finkbeiner, S. R. et al. Metagenomic analysis of human diarrhea: viral detection and discovery. PLoS Pathogens. 4, e1000011 (2008).

    Article  Google Scholar 

  54. Breitbart, M. & Rohwer, F. Method for discovering novel DNA viruses in blood using viral particle selection and shotgun sequencing. Biotechniques 39, 729–736 (2005).

    Article  CAS  Google Scholar 

  55. Wylie, K. M., Mihindukulasuriya, K. A., Sodergren, E., Weinstock, G. M. & Storch, G. A. Sequence analysis of the human virome in febrile and afebrile children. PLoS ONE 7, e27735 (2012).

    Article  ADS  CAS  Google Scholar 

  56. Pride, D. T. et al. Evidence of a robust resident bacteriophage population revealed through analysis of the human salivary virome. ISME J. 6, 915–926 (2011).

    Article  Google Scholar 

  57. Minot, S., Grunberg, S., Wu, G. D., Lewis, J. D. & Bushman, F. D. Hypervariable loci in the human gut virome. Proc. Natl Acad. Sci. USA 109, 3962–3966 (2012).

    Article  ADS  CAS  Google Scholar 

  58. Breitbart, M. et al. Viral diversity and dynamics in an infant gut. Res. Microbiol. 159, 367–373 (2008).

    Article  CAS  Google Scholar 

  59. Minot, S. et al. The human gut virome: inter-individual variation and dynamic response to diet. Genome Res. 21, 1616–1625 (2011).

    Article  CAS  Google Scholar 

  60. Willner, D. & Furlan, M. Deciphering the role of phage in the cystic fibrosis airway. Virulence 1, 309–313 (2010).

    Article  Google Scholar 

  61. Lepage, P. et al. Dysbiosis in inflammatory bowel disease: a role for bacteriophages? Gut 57, 424–425 (2008).

    Article  CAS  Google Scholar 

  62. Kanehisa, M., Goto, S., Furumichi, M., Tanabe, M. & Hirakawa, M. KEGG for representation and analysis of molecular networks involving diseases and drugs. Nucleic Acids Res. 38, D355–D360 (2010).

    Article  CAS  Google Scholar 

  63. Abubucker, S. et al. Metabolic reconstruction for metagenomic data and its application to the human microbiome. PLoS Comput. Biol. 8, e1002358 (2012).

    Article  CAS  Google Scholar 

  64. Cantarel, B. L. et al. The Carbohydrate-Active EnZymes database (CAZy): an expert resource for glycogenomics. Nucleic Acids Res. 37, D233–D238 (2009).

    Article  CAS  Google Scholar 

  65. Cantarel, B. L., Lombard, V. & Henrissat, B. Complex carbohydrate utilization by the healthy human microbiome. PLoS ONE 7, e28742 (2012).

    Article  ADS  CAS  Google Scholar 

  66. Turnbaugh, P. J. & Gordon, J. I. The core gut microbiome, energy balance and obesity. J. Physiol. (Lond.) 587, 4153–4158 (2009).

    Article  CAS  Google Scholar 

  67. Raes, J., Foerstner, K. U. & Bork, P. Get the most out of your metagenome: computational analysis of environmental sequence data. Curr. Opin. Microbiol. 10, 490–498 (2007).

    Article  CAS  Google Scholar 

  68. Wooley, J. C., Godzik, A. & Friedberg, I. A primer on metagenomics. PLoS Comput. Biol. 6, e1000667 (2010).

    Article  ADS  Google Scholar 

  69. Edgar, R. C., Haas, B. J., Clemente, J. C., Quince, C. & Knight, R. UCHIME improves sensitivity and speed of chimera detection. Bioinformatics 27, 2194–2200 (2011).

    Article  CAS  Google Scholar 

  70. Haas, B. J. et al. Chimeric 16S rRNA sequence formation and detection in Sanger and 454-pyrosequenced PCR amplicons. Genome Res. 21, 494–504 (2011).

    Article  CAS  Google Scholar 

  71. Jumpstart Consortium Human Microbiome Project Data Generation Working Group. Evaluation of 16S rDNA-based community profiling for human microbiome research. PLoS ONE 7, e39315 (2012).

  72. Schloss, P. D., Gevers, D. & Westcott, S. L. Reducing the effects of PCR amplification and sequencing artifacts on 16S rRNA-based studies. PLoS ONE 6, e27310 (2011).

    Article  ADS  CAS  Google Scholar 

  73. Wright, E. S., Yilmaz, L. S. & Noguera, D. R. DECIPHER, a search-based approach to chimera identification for 16S rRNA sequences. Appl. Environ. Microbiol. 78, 717–725 (2012).

    Article  CAS  Google Scholar 

  74. Lozupone, C., Lladser, M. E., Knights, D., Stombaugh, J. & Knight, R. UniFrac: an effective distance metric for microbial community comparison. ISME J. 5, 169–172 (2011).

    Article  Google Scholar 

  75. Schloss, P. D. et al. Introducing mothur: open-source, platform-independent, community-supported software for describing and comparing microbial communities. Appl. Environ. Microbiol. 75, 7537–7541 (2009).

    Article  CAS  Google Scholar 

  76. Caporaso, J. G. et al. Moving pictures of the human microbiome. Genome Biol. 12, R50 (2011).

    Article  Google Scholar 

  77. Angiuoli, S. V., White, J. R., Matalka, M., White, O. & Fricke, W. F. Resources and costs for microbial sequence analysis evaluated using virtual machines and cloud computing. PLoS ONE 6, e26624 (2011).

    Article  ADS  CAS  Google Scholar 

  78. Chitsaz, H. et al. Efficient de novo assembly of single-cell bacterial genomes from short-read data sets. Nature Biotechnol. 29, 915–921 (2011).

    Article  CAS  Google Scholar 

  79. Dichosa, A. E. et al. Artificial polyploidy improves bacterial single cell genome recovery. PLoS ONE 7, e37387 (2012).

    Article  ADS  CAS  Google Scholar 

  80. Benson, A. K. et al. Individuality in gut microbiota composition is a complex polygenic trait shaped by multiple environmental and host genetic factors. Proc. Natl Acad. Sci. USA 107, 18933–18938 (2010).

    Article  ADS  CAS  Google Scholar 

  81. Elinav, E. et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145, 745–757 (2011).

    Article  CAS  Google Scholar 

  82. Hooper, L. V., Littman, D. R. & Macpherson, A. J. Interactions between the microbiota and the immune system. Science 336, 1268–1273 (2012).

    Article  ADS  CAS  Google Scholar 

  83. Handelsman, J., Rondon, M. R., Brady, S. F., Clardy, J. & Goodman, R. M. Molecular biological access to the chemistry of unknown soil microbes: a new frontier for natural products. Chem. Biol. 5, R245–R249 (1998).

    Article  CAS  Google Scholar 

  84. Riesenfeld, C. S., Schloss, P. D. & Handelsman, J. Metagenomics: genomic analysis of microbial communities. Annu. Rev. Genet. 38, 525–552 (2004).

    Article  CAS  Google Scholar 

  85. Hooper, L. V. & Gordon, J. I. Commensal host–bacterial relationships in the gut. Science 292, 1115–1118 (2001).

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

The author gratefully acknowledges generous support from the National Institutes of Health.

Author information

Authors and Affiliations

  1. The Genome Institute, Washington University, 4444 Forest Park Avenue, Campus Box 8501, St. Louis, 63108, Missouri, USA

    George M. Weinstock

Authors
  1. George M. Weinstock
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to George M. Weinstock.

Ethics declarations

Competing interests

The author declares no competing financial interests.

Additional information

Reprints and permissions information is available at www.nature.com/reprints.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Weinstock, G. Genomic approaches to studying the human microbiota. Nature 489, 250–256 (2012). https://doi.org/10.1038/nature11553

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature11553

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing