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.

  • Article
  • Published:

A microbial symbiosis factor prevents intestinal inflammatory disease

Abstract

Humans are colonized by multitudes of commensal organisms representing members of five of the six kingdoms of life; however, our gastrointestinal tract provides residence to both beneficial and potentially pathogenic microorganisms. Imbalances in the composition of the bacterial microbiota, known as dysbiosis, are postulated to be a major factor in human disorders such as inflammatory bowel disease. We report here that the prominent human symbiont Bacteroides fragilis protects animals from experimental colitis induced by Helicobacter hepaticus, a commensal bacterium with pathogenic potential. This beneficial activity requires a single microbial molecule (polysaccharide A, PSA). In animals harbouring B. fragilis not expressing PSA, H. hepaticus colonization leads to disease and pro-inflammatory cytokine production in colonic tissues. Purified PSA administered to animals is required to suppress pro-inflammatory interleukin-17 production by intestinal immune cells and also inhibits in vitro reactions in cell cultures. Furthermore, PSA protects from inflammatory disease through a functional requirement for interleukin-10-producing CD4+ T cells. These results show that molecules of the bacterial microbiota can mediate the critical balance between health and disease. Harnessing the immunomodulatory capacity of symbiosis factors such as PSA might potentially provide therapeutics for human inflammatory disorders on the basis of entirely novel biological principles.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: B. fragilis colonization requires PSA for protection from experimental colitis.
Figure 2: Purified PSA protects against experimental colitis.
Figure 3: Intestinal immune responses are modulated by a beneficial bacterial molecule.
Figure 4: PSA induces Il10 expression in TNBS-treated animals and inhibits TNF-α production in primary cultured cells through IL-10 production.
Figure 5: IL-10 is required for PSA-mediated protection from intestinal inflammation and experimental colitis.

Similar content being viewed by others

References

  1. Poxton, I. R., Brown, R., Sawyerr, A. & Ferguson, A. Mucosa-associated bacterial flora of the human colon. J. Med. Microbiol. 46, 85–91 (1997)

    Article  CAS  Google Scholar 

  2. Sellon, R. K. et al. Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice. Infect. Immun. 66, 5224–5231 (1998)

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Elson, C. O. Commensal bacteria as targets in Crohn’s disease. Gastroenterology 119, 254–257 (2000)

    Article  CAS  Google Scholar 

  4. Sartor, R. B. Mechanisms of disease: pathogenesis of Crohn’s disease and ulcerative colitis. Nature Clin. Pract. Gastroenterol. Hepatol. 3, 390–407 (2006)

    Article  CAS  Google Scholar 

  5. Videla, S. et al. Role of intestinal microflora in chronic inflammation and ulceration of the rat colon. Gut 35, 1090–1097 (1994)

    Article  CAS  Google Scholar 

  6. Taurog, J. D. et al. The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J. Exp. Med. 180, 2359–2364 (1994)

    Article  CAS  Google Scholar 

  7. Kullberg, M. C. et al. Induction of colitis by a CD4+ T cell clone specific for a bacterial epitope. Proc. Natl Acad. Sci. USA 100, 15830–15835 (2003)

    Article  CAS  ADS  Google Scholar 

  8. O’Hara, A. M. & Shanahan, F. The gut flora as a forgotten organ. EMBO Rep. 7, 688–693 (2006)

    Article  Google Scholar 

  9. Frank, D. N. et al. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc. Natl Acad. Sci. USA 104, 13780–13785 (2007)

    Article  CAS  ADS  Google Scholar 

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

    Article  CAS  ADS  Google Scholar 

  11. Ley, R. E., Peterson, D. A. & Gordon, J. I. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 124, 837–848 (2006)

    Article  CAS  Google Scholar 

  12. Smith, K., McCoy, K. D. & Macpherson, A. J. Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Semin. Immunol. 19, 59–69 (2006)

    Article  Google Scholar 

  13. Mazmanian, S. K., Liu, C. H., Tzianabos, A. O. & Kasper, D. L. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122, 107–118 (2005)

    Article  CAS  Google Scholar 

  14. Pamer, E. G. Immune responses to commensal and environmental microbes. Nature Immunol. 8, 1173–1178 (2007)

    Article  CAS  Google Scholar 

  15. Dethlefsen, L., McFall-Ngai, M. & Relman, D. A. An ecological and evolutionary perspective on human–microbe mutualism and disease. Nature 449, 811–818 (2007)

    Article  CAS  ADS  Google Scholar 

  16. Bell, E. B. Function of CD4 T cell subsets in vivo: expression of CD45R isoforms. Semin. Immunol. 4, 43–50 (1992)

    CAS  PubMed  Google Scholar 

  17. Izcue, A., Coombes, J. L. & Powrie, F. Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation. Immunol. Rev. 212, 256–271 (2006)

    Article  CAS  Google Scholar 

  18. Maloy, K. J. et al. CD4+CD25+ TR cells suppress innate immune pathology through cytokine-dependent mechanisms. J. Exp. Med. 197, 111–119 (2003)

    Article  CAS  Google Scholar 

  19. Cahill, R. J. et al. Inflammatory bowel disease: an immunity-mediated condition triggered by bacterial infection with Helicobacter hepaticus. Infect. Immun. 65, 3126–3131 (1997)

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Scheinin, T., Butler, D. M., Salway, F., Scallon, B. & Feldmann, M. Validation of the interleukin-10 knockout mouse model of colitis: antitumour necrosis factor-antibodies suppress the progression of colitis. Clin. Exp. Immunol. 133, 38–43 (2003)

    Article  CAS  Google Scholar 

  21. Kullberg, M. C. et al. Bacteria-triggered CD4+ T regulatory cells suppress Helicobacter hepaticus-induced colitis. J. Exp. Med. 196, 505–515 (2002)

    Article  CAS  Google Scholar 

  22. Bregenholt, S. Cells and cytokines in the pathogenesis of inflammatory bowel disease: new insights from mouse T cell transfer models. Exp. Clin. Immunogenet. 17, 115–129 (2000)

    Article  CAS  Google Scholar 

  23. Powrie, F. & Maloy, K. J. Immunology. Regulating the regulators. Science 299, 1030–1031 (2003)

    Article  CAS  Google Scholar 

  24. Xavier, R. & Podolsky, D. K. Commensal flora: wolf in sheep’s clothing. Gastroenterology 128, 1122–1126 (2005)

    Article  CAS  Google Scholar 

  25. Rutgeerts, P. et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 353, 2462–2476 (2005)

    Article  CAS  Google Scholar 

  26. Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S. & Medzhitov, R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118, 229–241 (2004)

    Article  CAS  Google Scholar 

  27. Kullberg, M. C. et al. IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. J. Exp. Med. 203, 2485–2494 (2006)

    Article  CAS  Google Scholar 

  28. Hue, S. et al. Interleukin-23 drives innate and T cell-mediated intestinal inflammation. J. Exp. Med. 203, 2473–2483 (2006)

    Article  CAS  Google Scholar 

  29. Tzianabos, A. O. et al. The capsular polysaccharide of Bacteroides fragilis comprises two ionically linked polysaccharides. J. Biol. Chem. 267, 18230–18235 (1992)

    CAS  PubMed  Google Scholar 

  30. Elson, C. O. et al. Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice. Gastroenterology 132, 2359–2370 (2007)

    Article  CAS  Google Scholar 

  31. Kuhn, R., Lohler, J., Rennick, D., Rajewsky, K. & Muller, W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75, 263–274 (1993)

    Article  CAS  Google Scholar 

  32. Asseman, C., Mauze, S., Leach, M. W., Coffman, R. L. & Powrie, F. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J. Exp. Med. 190, 995–1004 (1999)

    Article  CAS  Google Scholar 

  33. Groux, H. et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737–742 (1997)

    Article  CAS  ADS  Google Scholar 

  34. Strachan, D. P. Hay fever, hygiene, and household size. Br. Med. J. 299, 1259–1260 (1989)

    Article  CAS  Google Scholar 

  35. Bach, J. F. The effect of infections on susceptibility to autoimmune and allergic diseases. N. Engl. J. Med. 347, 911–920 (2002)

    Article  Google Scholar 

  36. Liu, C. H., Lee, S. M., Vanlare, J. M., Kasper, D. L. & Mazmanian, S. K. Regulation of surface architecture by symbiotic bacteria mediates host colonization. Proc. Natl Acad. Sci. USA 105, 3951–3956 (2008)

    Article  CAS  ADS  Google Scholar 

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

    Article  ADS  Google Scholar 

  38. Mazmanian, S. K. & Kasper, D. L. The love-hate relationship between bacterial polysaccharides and the host immune system. Nature Rev. Immunol. 6, 849–858 (2006)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank R. T. Bronson for discussions about histopathology; members of the Mazmanian laboratory for critical comments throughout the course of the work; and J. McCoy for editorial expertise. S.K.M. acknowledges a fellowship from the Helen Hay Whitney Foundation; J.L.R. acknowledges support from the Jane Coffin Childs Memorial Fund. This work was supported by funding from the NIH/NIAID (R01 AI039576) to D.L.K., and by grants from the Searle Scholars Program, the Damon Runyon Cancer Research Foundation, and the Crohn’s and Colitis Foundation of America to S.K.M.

Author Contributions S.K.M., J.L.R. and D.L.K. designed the research; S.K.M. and J.L.R. performed the research; S.K.M., J.L.R. and D.L.K. analysed the data and wrote the paper.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Sarkis K. Mazmanian or Dennis L. Kasper.

Supplementary information

Supplementray Information

The file contains Supplementary Figures 1 – 8 with Legends and Supplementary Methods with additional references. (PDF 248 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mazmanian, S., Round, J. & Kasper, D. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453, 620–625 (2008). https://doi.org/10.1038/nature07008

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature07008

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

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