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.

  • Opinion
  • Published:

The keystone-pathogen hypothesis

Nature Reviews Microbiology volume 10, pages 717–725 (2012)Cite this article

Subjects

Abstract

Recent studies have highlighted the importance of the human microbiome in health and disease. However, for the most part the mechanisms by which the microbiome mediates disease, or protection from it, remain poorly understood. The keystone-pathogen hypothesis holds that certain low-abundance microbial pathogens can orchestrate inflammatory disease by remodelling a normally benign microbiota into a dysbiotic one. In this Opinion article, we critically assess the available literature that supports this hypothesis, which may provide a novel conceptual basis for the development of targeted diagnostics and treatments for complex dysbiotic diseases.

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: 'Keystone pathogens' versus dominant pathogens.
Figure 2: Porphyromonas gingivalis-induced dysbiosis and periodontal disease.
Figure 3: The 'alpha-bug' hypothesis in colon cancer.

Similar content being viewed by others

References

  1. Paine, R. T. A note on trophic complexity and community stability. Am. Nat. 103, 91–93 (1969).

    Article  Google Scholar 

  2. Power, M. E. et al. Challenges in the quest for keystones. Bioscience 46, 609–620 (1996).

    Article  Google Scholar 

  3. Estes, J. A. & Palmisano, J. F. Sea otters: their role in structuring nearshore communities. Science 185, 1058–1060 (1974).

    Article  CAS  PubMed  Google Scholar 

  4. Paine, R. T. Food web complexity and cpecies diversity. Am. Nat. 100, 65–75 (1966).

    Article  Google Scholar 

  5. Maloy, K. J. & Powrie, F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 474, 298–306 (2011).

    Article  CAS  PubMed  Google Scholar 

  6. Nell, S., Suerbaum, S. & Josenhans, C. The impact of the microbiota on the pathogenesis of IBD: lessons from mouse infection models. Nature Rev. Microbiol. 8, 564–577 (2010).

    Article  CAS  Google Scholar 

  7. Littman, D. R. & Pamer, E. G. Role of the commensal microbiota in normal and pathogenic host immune responses. Cell Host Microbe 10, 311–323 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Artis, D. Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut. Nature Rev. Immunol. 8, 411–420 (2008).

    Article  CAS  Google Scholar 

  9. Darveau, R. P. Periodontitis: a polymicrobial disruption of host homeostasis. Nature Rev. Microbiol. 8, 481–490 (2010).

    Article  CAS  Google Scholar 

  10. 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 

  11. Stecher, B. et al. Salmonella enterica serovar Typhimurium exploits inflammation to compete with the intestinal microbiota. PLoS Biol. 5, 2177–2189 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Pihlstrom, B. L., Michalowicz, B. S. & Johnson, N. W. Periodontal diseases. Lancet 366, 1809–1820 (2005).

    Article  PubMed  Google Scholar 

  13. Genco, R. J. & Van Dyke, T. E. Prevention: reducing the risk of CVD in patients with periodontitis. Nature Rev. Cardiol. 7, 479–480 (2010).

    Article  Google Scholar 

  14. Lundberg, K., Wegner, N., Yucel-Lindberg, T. & Venables, P. J. Periodontitis in RA-the citrullinated enolase connection. Nature Rev. Rheumatol. 6, 727–730 (2010).

    Article  CAS  Google Scholar 

  15. Lalla, E. & Papapanou, P. N. Diabetes mellitus and periodontitis: a tale of two common interrelated diseases. Nature Rev. Endocrinol. 7, 738–748 (2011).

    Article  CAS  Google Scholar 

  16. Gaffen, S. L. & Hajishengallis, G. A new inflammatory cytokine on the block: re-thinking periodontal disease and the Th1/Th2 paradigm in the context of Th17 cells and IL-17. J. Dent. Res. 87, 817–828 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. Eskan, M. A. et al. The leukocyte integrin antagonist Del-1 inhibits IL-17-mediated inflammatory bone loss. Nature Immunol. 13, 465–473 (2012).

    Article  CAS  Google Scholar 

  18. Moore, W. E. et al. Bacteriology of severe periodontitis in young adult humans. Infect. Immun. 38, 1137–1148 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Socransky, S. S. Microbiology of periodontal disease – present status and future considerations. J. Periodontol. 48, 497–504 (1977).

    Article  CAS  PubMed  Google Scholar 

  20. Holt, S. C., Ebersole, J., Felton, J., Brunsvold, M. & Kornman, K. S. Implantation of Bacteroides gingivalis in nonhuman primates initiates progression of periodontitis. Science 239, 55–57 (1988).

    Article  CAS  PubMed  Google Scholar 

  21. Holt, S. C. & Ebersole, J. L. Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia: the “red complex”, a prototype polybacterial pathogenic consortium in periodontitis. Periodontol. 2000 38, 72–122 (2005).

    Article  PubMed  Google Scholar 

  22. Socransky, S. S., Haffajee, A. D., Cugini, M. A., Smith, C. & Kent, R. L. Jr. Microbial complexes in subgingival plaque. J. Clin. Periodontol. 25, 134–144 (1998).

    Article  CAS  PubMed  Google Scholar 

  23. Hajishengallis, G. & Lambris, J. D. Microbial manipulation of receptor crosstalk in innate immunity. Nature Rev. Immunol. 11, 187–200 (2011).

    Article  CAS  Google Scholar 

  24. Darveau, R. P. The oral microbial consortium's interaction with the periodontal innate defense system. DNA Cell Biol. 28, 389–395 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hajishengallis, G. et al. Low-abundance biofilm species orchestrates inflammatory periodontal disease through the commensal microbiota and complement. Cell Host Microbe 10, 497–506 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang, M. et al. Microbial hijacking of complement–Toll-like receptor crosstalk. Sci. Signal. 3, ra11 (2010).

    PubMed  PubMed Central  Google Scholar 

  27. Liang, S. et al. The C5a receptor impairs IL-12-dependent clearance of Porphyromonas gingivalis and is required for induction of periodontal bone loss. J. Immunol. 186, 869–877 (2011).

    Article  CAS  PubMed  Google Scholar 

  28. Darveau, R. P., Belton, C. M., Reife, R. A. & Lamont, R. J. Local chemokine paralysis, a novel pathogenic mechanism for Porphyromonas gingivalis. Infect. Immun. 66, 1660–1665 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Madianos, P. N., Papapanou, P. N. & Sandros, J. Porphyromonas gingivalis infection of oral epithelium inhibits neutrophil transepithelial migration. Infect. Immun. 65, 3983–3990 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Bainbridge, B. et al. Role of Porphyromonas gingivalis phosphoserine phosphatase enzyme SerB in inflammation, immune response, and induction of alveolar bone resorption in rats. Infect. Immun. 78, 4560–4569 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Frias-Lopez, J. & Duran-Pinedo, A. Effect of periodontal pathogens on the metatranscriptome of a healthy multispecies biofilm model. J. Bacteriol. 194, 2082–2095 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hasturk, H. et al. Resolvin E1 regulates inflammation at the cellular and tissue level and restores tissue homeostasis in vivo. J. Immunol. 179, 7021–7029 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Page, R. C. et al. Immunization of Macaca fascicularis against experimental periodontitis using a vaccine containing cysteine proteases purified from Porphyromonas gingivalis. Oral Microbiol. Immunol. 22, 162–168 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Kumar, P. S. et al. Changes in periodontal health status are associated with bacterial community shifts as assessed by quantitative 16S cloning and sequencing. J. Clin. Microbiol. 44, 3665–3673 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Doungudomdacha, S., Rawlinson, A. & Douglas, C. W. Enumeration of Porphyromonas gingivalis, Prevotella intermedia and Actinobacillus actinomycetemcomitans in subgingival plaque samples by a quantitative-competitive PCR method. J. Med. Microbiol. 49, 861–874 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Chaves, E. S., Jeffcoat, M. K., Ryerson, C. C. & Snyder, B. Persistent bacterial colonization of Porphyromonas gingivalis, Prevotella intermedia, and Actinobacillus actinomycetemcomitans in periodontitis and its association with alveolar bone loss after 6 months of therapy. J. Clin. Periodontol. 27, 897–903 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Moore, W. E. et al. The microflora of periodontal sites showing active destructive progression. J. Clin. Periodontol. 18, 729–739 (1991).

    Article  CAS  PubMed  Google Scholar 

  38. Frank, D. N. & Pace, N. R. Gastrointestinal microbiology enters the metagenomics era. Curr. Opin. Gastroenterol. 24, 4–10 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. Chassaing, B. & Darfeuille-Michaud, A. The commensal microbiota and enteropathogens in the pathogenesis of inflammatory bowel diseases. Gastroenterology 140, 1720–1728 (2011).

    Article  PubMed  Google Scholar 

  40. Garrett, W. S. et al. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell 131, 33–45 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Garrett, W. S. et al. Enterobacteriaceae act in concert with the gut microbiota to induce spontaneous and maternally transmitted colitis. Cell Host Microbe 8, 292–300 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lupp, C. et al. Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae. Cell Host Microbe 2, 119–129 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Hoffmann, C. et al. Community-wide response of the gut microbiota to enteropathogenic Citrobacter rodentium infection revealed by deep sequencing. Infect. Immun. 77, 4668–4678 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bry, L., Brigl, M. & Brenner, M. B. CD4+-T-cell effector functions and costimulatory requirements essential for surviving mucosal infection with Citrobacter rodentium. Infect. Immun. 74, 673–681 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Vijay-Kumar, M. et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328, 228–231 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Rogers, A. B. & Fox, J. G. Inflammation and Cancer I. Rodent models of infectious gastrointestinal and liver cancer. Am. J. Physiol. Gastrointest. Liver Physiol. 286, G361–G366 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Uronis, J. M. et al. Modulation of the intestinal microbiota alters colitis-associated colorectal cancer susceptibility. PLoS ONE 4, e6026 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Azcarate-Peril, M. A., Sikes, M. & Bruno-Barcena, J. M. The intestinal microbiota, gastrointestinal environment and colorectal cancer: a putative role for probiotics in prevention of colorectal cancer? Am. J. Physiol. Gastrointest. Liver Physiol. 301, G401–G424 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hope, M. E., Hold, G. L., Kain, R. & El-Omar, E. M. Sporadic colorectal cancer – role of the commensal microbiota. FEMS Microbiol. Lett. 244, 1–7 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. Sears, C. L. & Pardoll, D. M. Perspective: alpha-bugs, their microbial partners, and the link to colon cancer. J. Infect. Dis. 203, 306–311 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Wu, S. et al. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nature Med. 15, 1016–1022 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. Holton, J. Enterotoxigenic Bacteroides fragilis. Curr. Infect. Dis. Rep. 10, 99–104 (2008).

    Article  PubMed  Google Scholar 

  54. Sears, C. L. Enterotoxigenic Bacteroides fragilis: a rogue among symbiotes. Clin. Microbiol. Rev. 22, 349–369 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yu, H., Kortylewski, M. & Pardoll, D. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nature Rev. Immunol. 7, 41–51 (2007).

    Article  CAS  Google Scholar 

  56. Round, J. L. et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332, 974–977 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Mazmanian, S. K., Round, J. L. & Kasper, D. L. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453, 620–625 (2008).

    CAS  PubMed  Google Scholar 

  58. Wu, S., Morin, P. J., Maouyo, D. & Sears, C. L. Bacteroides fragilis enterotoxin induces c-Myc expression and cellular proliferation. Gastroenterology 124, 392–400 (2003).

    Article  CAS  PubMed  Google Scholar 

  59. Kim, J. M. et al. Nuclear factor-κB activation pathway in intestinal epithelial cells is a major regulator of chemokine gene expression and neutrophil migration induced by Bacteroides fragilis enterotoxin. Clin. Exp. Immunol. 130, 59–66 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Tjalsma, H., Boleij, A., Marchesi, J. R. & Dutilh, B. E. A bacterial driver–passenger model for colorectal cancer: beyond the usual suspects. Nature Rev. Microbiol. 10, 575–582 (2012).

    Article  CAS  Google Scholar 

  61. Toprak, N. U. et al. A possible role of Bacteroides fragilis enterotoxin in the aetiology of colorectal cancer. Clin. Microbiol. Infect. 12, 782–786 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Kostic, A. D. et al. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Res. 22, 292–298 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Castellarin, M. et al. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res. 22, 299–306 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Maddocks, O. D., Short, A. J., Donnenberg, M. S., Bader, S. & Harrison, D. J. Attaching and effacing Escherichia coli downregulate DNA mismatch repair protein in vitro and are associated with colorectal adenocarcinomas in humans. PLoS ONE 4, e5517 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Martin, H. M. et al. Enhanced Escherichia coli adherence and invasion in Crohn's disease and colon cancer. Gastroenterology 127, 80–93 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Cuevas-Ramos, G. et al. Escherichia coli induces DNA damage in vivo and triggers genomic instability in mammalian cells. Proc. Natl Acad. Sci. USA 107, 11537–11542 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  68. Strocchi, A., Furne, J., Ellis, C. & Levitt, M. D. Methanogens outcompete sulphate reducing bacteria for H2 in the human colon. Gut 35, 1098–1101 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Samuel, B. S. et al. Genomic and metabolic adaptations of Methanobrevibacter smithii to the human gut. Proc. Natl Acad. Sci. USA 104, 10643–10648 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Samuel, B. S. & Gordon, J. I. A humanized gnotobiotic mouse model of host-archaeal-bacterial mutualism. Proc. Natl Acad. Sci. USA 103, 10011–10016 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Zhang, H. et al. Human gut microbiota in obesity and after gastric bypass. Proc. Natl Acad. Sci. USA 106, 2365–2370 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Armougom, F., Henry, M., Vialettes, B., Raccah, D. & Raoult, D. Monitoring bacterial community of human gut microbiota reveals an increase in Lactobacillus in obese patients and Methanogens in anorexic patients. PLoS ONE 4, e7125 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Kane, M. et al. Successful transmission of a retrovirus depends on the commensal microbiota. Science 334, 245–249 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Kuss, S. K. et al. Intestinal microbiota promote enteric virus replication and systemic pathogenesis. Science 334, 249–252 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Chow, J., Tang, H. & Mazmanian, S. K. Pathobionts of the gastrointestinal microbiota and inflammatory disease. Curr. Opin. Immunol. 23, 473–480 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Chow, J. & Mazmanian, S. K. A pathobiont of the microbiota balances host colonization and intestinal inflammation. Cell Host Microbe 7, 265–276 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Xu, J. et al. A genomic view of the human-Bacteroides thetaiotaomicron symbiosis. Science 299, 2074–2076 (2003).

    Article  CAS  PubMed  Google Scholar 

  79. Hooper, L. V., Midtvedt, T. & Gordon, J. I. How host-microbial interactions shape the nutrient environment of the mammalian intestine. Annu. Rev. Nutr. 22, 283–307 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Sonnenburg, J. L. et al. Glycan foraging in vivo by an intestine-adapted bacterial symbiont. Science 307, 1955–1959 (2005).

    Article  CAS  PubMed  Google Scholar 

  81. Hooper, L. V., Stappenbeck, T. S., Hong, C. V. & Gordon, J. I. Angiogenins: a new class of microbicidal proteins involved in innate immunity. Nature Immunol. 4, 269–273 (2003).

    Article  CAS  Google Scholar 

  82. Kelly, D. et al. Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-gamma; and RelA. Nature Immunol. 5, 104–112 (2004).

    Article  CAS  Google Scholar 

  83. 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  PubMed  CAS  Google Scholar 

  84. Davic, R. D. Linking keystone species and functional groups: a new operational definition of the keystone species concept. Conserv. Ecol. 7, r11 (2003).

    Article  Google Scholar 

  85. Simberloff, D. (ed.) Community and Ecosystem Impacts of Single-Species Extinctions (Princeton Univ. Press, 2003).

    Book  Google Scholar 

  86. Honda, K. Porphyromonas gingivalis sinks teeth into the oral microbiota and periodontal disease. Cell Host Microbe 10, 423–425 (2011).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Work in the authors' laboratories is supported by grants from the US National Institutes of Health (DE015254, DE018292, DE021580 and DE021685 to G.H.; DE18274 and DE012768 to R.P.D.) and the UK Medical Research Council (G0900408 to M.A.C.).

Author information

Authors and Affiliations

  1. George Hajishengallis is at the Department of Microbiology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania 19104, USA.,

    George Hajishengallis

  2. Richard P. Darveau is at the Department of Periodontics, School of Dentistry, University of Washington, Seattle, Washington 98195, USA.,

    Richard P. Darveau

  3. Michael A. Curtis is at the Centre for Immunology and Infectious Disease, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.,

    Michael A. Curtis

Authors
  1. George Hajishengallis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard P. Darveau
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael A. Curtis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to George Hajishengallis.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

George Hajishengallis's homepage

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hajishengallis, G., Darveau, R. & Curtis, M. The keystone-pathogen hypothesis. Nat Rev Microbiol 10, 717–725 (2012). https://doi.org/10.1038/nrmicro2873

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro2873

This article is cited by

Search

Advanced search

Quick links

Nature Briefing Microbiology

Sign up for the Nature Briefing: Microbiology newsletter — what matters in microbiology research, free to your inbox weekly.

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