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:

Immune adaptations that maintain homeostasis with the intestinal microbiota

An Erratum to this article was published on 07 April 2015

This article has been updated

Key Points

  • The human intestine contains 100 trillion bacteria that make essential contributions to human metabolism and establish symbiotic relationships with their hosts. However, these organisms pose an ongoing threat of invasion owing to their enormous numbers.

  • The intestinal immune system has evolved unique immune adaptations that allow it to manage its high bacterial load. These immune mechanisms work together to ensure that commensal bacteria rarely breach the intestinal barrier and that any that do invade are killed rapidly and do not penetrate to systemic sites.

  • A key element of the mammalian intestinal strategy for maintaining homeostasis with the microbiota is to minimize contact between luminal microorganisms and the intestinal epithelial cell surface. This is accomplished by enhancing the physical barrier through the production of mucus, antimicrobial proteins and IgA.

  • A second layer of intestinal immune protection relies on the rapid detection and killing of bacteria that penetrate the epithelial cell surface. This occurs by several immune mechanisms, including bacterial uptake and phagocytosis by innate immune cells and a complex set of T cell-mediated responses.

  • A third immune barrier is presented by the mesenteric lymph nodes, which constitute an immune 'firewall' limiting penetration by commensal microorganisms to the systemic immune system. This allows induction of adaptive immune responses to resident bacteria to be confined to the mucosal immune compartment.

  • An increasing amount of evidence suggests that inflammatory bowel disease (IBD) arises from dysregulated control of host–microorganism interactions. In support of this hypothesis, several IBD risk alleles compromise intestinal immune mechanisms that maintain homeostasis with the microbiota.

Abstract

Humans harbour nearly 100 trillion intestinal bacteria that are essential for health. Millions of years of co-evolution have moulded this human–microorganism interaction into a symbiotic relationship in which gut bacteria make essential contributions to human nutrient metabolism and in return occupy a nutrient-rich environment. Although intestinal microorganisms carry out essential functions for their hosts, they pose a constant threat of invasion owing to their sheer numbers and the large intestinal surface area. In this Review, we discuss the unique adaptations of the intestinal immune system that maintain homeostatic interactions with a diverse resident microbiota.

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

Access options

Buy this article

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

Figure 1: Immune mechanisms that limit bacteria–epithelial cell interactions.
Figure 2: Regulation of antimicrobial protein expression.
Figure 3: Production of IgA directed against intestinal bacteria.
Figure 4: CD4+ T cell subset differentiation.
Figure 5: Regulatory networks for intestinal CD4+ T cells.

Similar content being viewed by others

Change history

  • 07 April 2015

    In figure 4 of the original article, the cytokines that promote the differentiation of T helper 2 (TH2) cells and TH17 cells were included in the wrong order. This has now been corrected in the online HTML and PDF versions of the article. Nature Reviews Immunology apologizes for this error.

References

  1. Mathers, C. D., Boerma, T. & Ma Fat, D. Global and regional causes of death. Br. Med. Bull. 92, 7–32 (2009).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. 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 

  4. Martens, E. C., Chiang, H. C. & Gordon, J. I. Mucosal glycan foraging enhances fitness and transmission of a saccharolytic human gut bacterial symbiont. Cell Host Microbe 4, 447–457 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ley, R. E., Lozupone, C. A., Hamady, M., Knight, R. & Gordon, J. I. Worlds within worlds: evolution of the vertebrate gut microbiota. Nature Rev. Microbiol. 6, 776–788 (2008).

    Article  CAS  Google Scholar 

  6. Xu, J. & Gordon, J. I. Inaugural article: honor thy symbionts. Proc. Natl Acad. Sci. USA 100, 10452–10459 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hooper, L. V. et al. Molecular analysis of commensal host-microbial relationships in the intestine. Science 291, 881–884 (2001). This paper shows that commensal bacteria manipulate host cell functions and widely influence host biology, revealing the essential nature of the interactions between resident microorganisms and their mammalian hosts.

    Article  CAS  PubMed  Google Scholar 

  8. 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 

  9. Stappenbeck, T. S., Hooper, L. V. & Gordon, J. I. Developmental regulation of intestinal angiogenesis by indigenous microbes via Paneth cells. Proc. Natl Acad. Sci. USA 99, 15451–15455 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. He, B. et al. Intestinal bacteria trigger T cell-independent immunoglobulin A2 class switching by inducing epithelial-cell secretion of the cytokine APRIL. Immunity 26, 812–826 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Ivanov, I. I. et al. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 4, 337–349 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hall, J. A. et al. Commensal DNA limits regulatory T cell conversion and is a natural adjuvant of intestinal immune responses. Immunity 29, 637–649 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Stecher, B. et al. Comparison of Salmonella enterica serovar Typhimurium colitis in germfree mice and mice pretreated with streptomycin. Infect. Immun. 73, 3228–3241 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Klare, I., Werner, G. & Witte, W. Enterococci. Habitats, infections, virulence factors, resistances to antibiotics, transfer of resistance determinants. Contrib. Microbiol. 8, 108–122 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Benson, A., Pifer, R., Behrendt, C. L., Hooper, L. V. & Yarovinsky, F. Gut commensal bacteria direct a protective immune response against Toxoplasma gondii. Cell Host Microbe 6, 187–196 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kuwahara, T. et al. Genomic analysis of Bacteroides fragilis reveals extensive DNA inversions regulating cell surface adaptation. Proc. Natl Acad. Sci. USA 101, 14919–14924 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Johansson, M. E. et al. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc. Natl Acad. Sci. USA 105, 15064–15069 (2008). This paper clearly visualizes the spatial relationships between the microbiota and the intestinal epithelial cell surface, and it shows that mucus glycoproteins are essential for limiting direct contact between luminal bacteria and epithelial cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Van der Sluis, M. et al. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 131, 117–129 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Celli, J. P. et al. Helicobacter pylori moves through mucus by reducing mucin viscoelasticity. Proc. Natl Acad. Sci. USA 106, 14321–14326 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Guerry, P. Campylobacter flagella: not just for motility. Trends Microbiol. 15, 456–461 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Flo, T. H. et al. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 432, 917–921 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Putsep, K. et al. Germ-free and colonized mice generate the same products from enteric prodefensins. J. Biol. Chem. 275, 40478–40482 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Brandl, K., Plitas, G., Schnabl, B., Dematteo, R. P. & Pamer, E. G. MyD88-mediated signals induce the bactericidal lectin RegIIIγ and protect mice against intestinal Listeria monocytogenes infection. J. Exp. Med. 204, 1891–1900 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Vaishnava, S., Behrendt, C. L., Ismail, A. S., Eckmann, L. & Hooper, L. V. Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc. Natl Acad. Sci. USA 105, 20858–20863 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kobayashi, K. S. et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307, 731–734 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Meyer-Hoffert, U. et al. Secreted enteric antimicrobial activity localizes to the mucus surface layer. Gut 57, 764–771 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Boneca, I. G. et al. A critical role for peptidoglycan N-deacetylation in Listeria evasion from the host innate immune system. Proc. Natl Acad. Sci. USA 104, 997–1002 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Guo, L. et al. Lipid A acylation and bacterial resistance against vertebrate antimicrobial peptides. Cell 95, 189–198 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Raffatellu, M. et al. Lipocalin-2 resistance confers an advantage to Salmonella enterica serotype Typhimurium for growth and survival in the inflamed intestine. Cell Host Microbe 5, 476–486 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Suzuki, K. et al. Aberrant expansion of segmented filamentous bacteria in IgA-deficient gut. Proc. Natl Acad. Sci. USA 101, 1981–1986 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Macpherson, A. J. et al. A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science 288, 2222–2226 (2000).

    Article  CAS  PubMed  Google Scholar 

  33. Macpherson, A. J. & Uhr, T. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 303, 1662–1665 (2004). This study shows that DCs harbouring live commensal bacteria are restricted to the mucosal immune compartment by mesenteric lymph nodes, which thus function as an immune firewall that limits systemic penetration of commensal bacteria.

    Article  CAS  PubMed  Google Scholar 

  34. Rescigno, M. et al. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nature Immunol. 2, 361–367 (2001).

    Article  CAS  Google Scholar 

  35. Niess, J. H. et al. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307, 254–258 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Fagarasan, S. & Honjo, T. Intestinal IgA synthesis: regulation of front-line body defences. Nature Rev. Immunol. 3, 63–72 (2003).

    Article  CAS  Google Scholar 

  37. Lee, S. H., Starkey, P. M. & Gordon, S. Quantitative analysis of total macrophage content in adult mouse tissues. Immunochemical studies with monoclonal antibody F4/80. J. Exp. Med. 161, 475–489 (1985).

    Article  CAS  PubMed  Google Scholar 

  38. Kelsall, B. Recent progress in understanding the phenotype and function of intestinal dendritic cells and macrophages. Mucosal Immunol. 1, 460–469 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Smythies, L. E. et al. Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity. J. Clin. Invest. 115, 66–75 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sansonetti, P. J. War and peace at mucosal surfaces. Nature Rev. Immunol. 4, 953–964 (2004).

    Article  CAS  Google Scholar 

  41. Macpherson, A. J., Geuking, M. B. & McCoy, K. D. Immune responses that adapt the intestinal mucosa to commensal intestinal bacteria. Immunology 115, 153–162 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Pull, S. L., Doherty, J. M., Mills, J. C., Gordon, J. I. & Stappenbeck, T. S. Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury. Proc. Natl Acad. Sci. USA 102, 99–104 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. 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  PubMed  Google Scholar 

  44. Shroff, K. E., Meslin, K. & Cebra, J. J. Commensal enteric bacteria engender a self-limiting humoral mucosal immune response while permanently colonizing the gut. Infect. Immun. 63, 3904–3913 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Benveniste, J., Lespinats, G. & Salomon, J. Serum and secretory IgA in axenic and holoxenic mice. J. Immunol. 107, 1656–1662 (1971).

    CAS  PubMed  Google Scholar 

  46. Guy-Grand, D. et al. Two gut intraepithelial CD8+ lymphocyte populations with different T cell receptors: a role for the gut epithelium in T cell differentiation. J. Exp. Med. 173, 471–481 (1991).

    Article  CAS  PubMed  Google Scholar 

  47. Macpherson, A. J. & Harris, N. L. Interactions between commensal intestinal bacteria and the immune system. Nature Rev. Immunol. 4, 478–485 (2004).

    Article  CAS  Google Scholar 

  48. Barnes, M. J. & Powrie, F. Regulatory T cells reinforce intestinal homeostasis. Immunity 31, 401–411 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  50. Shull, M. M. et al. Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease. Nature 359, 693–699 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Nedjic, J., Aichinger, M., Emmerich, J., Mizushima, N. & Klein, L. Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance. Nature 455, 396–400 (2008).

    Article  CAS  PubMed  Google Scholar 

  52. Powrie, F. et al. Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. Immunity 1, 553–562 (1994).

    Article  CAS  PubMed  Google Scholar 

  53. 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  PubMed  PubMed Central  Google Scholar 

  54. Asseman, C., Read, S. & Powrie, F. Colitogenic Th1 cells are present in the antigen-experienced T cell pool in normal mice: control by CD4+ regulatory T cells and IL-10. J. Immunol. 171, 971–978 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Li, M. O., Wan, Y. Y. & Flavell, R. A. T cell-produced transforming growth factor-β1 controls T cell tolerance and regulates Th1- and Th17-cell differentiation. Immunity 26, 579–591 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Cong, Y., Weaver, C. T., Lazenby, A. & Elson, C. O. Bacterial-reactive T regulatory cells inhibit pathogenic immune responses to the enteric flora. J. Immunol. 169, 6112–6119 (2002).

    Article  CAS  PubMed  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).

    Article  CAS  PubMed  Google Scholar 

  58. Gaboriau-Routhiau, V. et al. The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31, 677–689 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Neurath, M. F. et al. The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn's disease. J. Exp. Med. 195, 1129–1143 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 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  PubMed  Google Scholar 

  61. 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 

  62. Becker, C. et al. Constitutive p40 promoter activation and IL-23 production in the terminal ileum mediated by dendritic cells. J. Clin. Invest. 112, 693–706 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Gautreaux, M. D., Gelder, F. B., Deitch, E. A. & Berg, R. D. Adoptive transfer of T lymphocytes to T-cell-depleted mice inhibits Escherichia coli translocation from the gastrointestinal tract. Infect. Immun. 63, 3827–3834 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Weaver, C. T., Harrington, L. E., Mangan, P. R., Gavrieli, M. & Murphy, K. M. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24, 677–688 (2006).

    Article  CAS  PubMed  Google Scholar 

  65. Lee, Y. K., Mukasa, R., Hatton, R. D. & Weaver, C. T. Developmental plasticity of Th17 and Treg cells. Curr. Opin. Immunol. 21, 274–280 (2009).

    Article  CAS  PubMed  Google Scholar 

  66. Lee, Y. K. et al. Late developmental plasticity in the T helper 17 lineage. Immunity 30, 92–107 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 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  PubMed  PubMed Central  Google Scholar 

  68. 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  PubMed  PubMed Central  Google Scholar 

  69. 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  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Boismenu, R. & Havran, W. L. Modulation of epithelial cell growth by intraepithelial γδ T cells. Science 266, 1253–1255 (1994).

    Article  CAS  PubMed  Google Scholar 

  72. Chen, Y., Chou, K., Fuchs, E., Havran, W. L. & Boismenu, R. Protection of the intestinal mucosa by intraepithelial γδ T cells. Proc. Natl Acad. Sci. USA 99, 14338–14343 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Groh, V., Steinle, A., Bauer, S. & Spies, T. Recognition of stress-induced MHC molecules by intestinal epithelial γδ T cells. Science 279, 1737–1740 (1998).

    Article  CAS  PubMed  Google Scholar 

  74. Suemizu, H. et al. A basolateral sorting motif in the MICA cytoplasmic tail. Proc. Natl Acad. Sci. USA 99, 2971–2976 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ismail, A. S., Behrendt, C. L. & Hooper, L. V. Reciprocal interactions between commensal bacteria and γδ intraepithelial lymphocytes during mucosal injury. J. Immunol. 182, 3047–3054 (2009).

    Article  CAS  PubMed  Google Scholar 

  76. Poussier, P., Ning, T., Banerjee, D. & Julius, M. A unique subset of self-specific intraintestinal T cells maintains gut integrity. J. Exp. Med. 195, 1491–1497 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Sanos, S. L. et al. RORγt and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nature Immunol. 10, 83–91 (2009).

    Article  CAS  Google Scholar 

  78. Zheng, Y. et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nature Med. 14, 282–289 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Shiloh, M. U. et al. Phenotype of mice and macrophages deficient in both phagocyte oxidase and inducible nitric oxide synthase. Immunity 10, 29–38 (1999). This study shows the essential role of microbicidal mechanisms in containing the commensal intestinal microbiota.

    Article  CAS  PubMed  Google Scholar 

  80. Sansonetti, P. Phagocytosis of bacterial pathogens: implications in the host response. Semin. Immunol. 13, 381–390 (2001).

    Article  CAS  PubMed  Google Scholar 

  81. Gowans, J. L. & Knight, E. J. The route of re-circulation of lymphocytes in the rat. Proc. R. Soc. Lond. B Biol. Sci. 159, 257–282 (1964).

    Article  CAS  PubMed  Google Scholar 

  82. Husband, A. J. & Gowans, J. L. The origin and antigen-dependent distribution of IgA-containing cells in the intestine. J. Exp. Med. 148, 1146–1160 (1978). This is a landmark study of the immune geography of the mucosal immune system, showing the dissemination of IgA+ plasma cells that have been induced in the intestinal mucosa through the lymph and blood.

    Article  CAS  PubMed  Google Scholar 

  83. Pierce, N. F. & Gowans, J. L. Cellular kinetics of the intestinal immune response to cholera toxoid in rats. J. Exp. Med. 142, 1550–1563 (1975).

    Article  CAS  PubMed  Google Scholar 

  84. Nagl, M. et al. Phagocytosis and killing of bacteria by professional phagocytes and dendritic cells. Clin. Diagn. Lab. Immunol. 9, 1165–1168 (2002).

    PubMed  PubMed Central  Google Scholar 

  85. Konrad, A., Cong, Y., Duck, W., Borlaza, R. & Elson, C. O. Tight mucosal compartmentation of the murine immune response to antigens of the enteric microbiota. Gastroenterology 130, 2050–2059 (2006).

    Article  CAS  PubMed  Google Scholar 

  86. Slack, E. et al. Innate and adaptive immunity cooperate flexibly to maintain host-microbiota mutualism. Science 325, 617–620 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Swidsinski, A., Weber, J., Loening-Baucke, V., Hale, L. P. & Lochs, H. Spatial organization and composition of the mucosal flora in patients with inflammatory bowel disease. J. Clin. Microbiol. 43, 3380–3389 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Hugot, J. P. et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411, 599–603 (2001).

    CAS  PubMed  Google Scholar 

  89. Ogura, Y. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411, 603–606 (2001). References 88 and 89 show that NOD2 polymorphisms account for a proportion of the genetic risk of Crohn's disease. This was the first of a large number of linked genetic loci to be identified and the suspected dysregulation of host–microorganism mutualism as a cause of IBD was reinforced by the finding that NOD2 senses a bacterial cell wall component.

    Article  CAS  PubMed  Google Scholar 

  90. Wehkamp, J. et al. Reduced Paneth cell α-defensins in ileal Crohn's disease. Proc. Natl Acad. Sci. USA 102, 18129–18134 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Cadwell, K. et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 456, 259–263 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Kaser, A. et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 134, 743–756 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Garabedian, E. M., Roberts, L. J., McNevin, M. S. & Gordon, J. I. Examining the role of Paneth cells in the small intestine by lineage ablation in transgenic mice. J. Biol. Chem. 272, 23729–23740 (1997).

    Article  CAS  PubMed  Google Scholar 

  94. Chapel, H. et al. Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood 112, 277–286 (2008).

    Article  CAS  PubMed  Google Scholar 

  95. Notarangelo, L. et al. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee Meeting in Budapest, 2005. J. Allergy Clin. Immunol. 117, 883–896 (2006).

    Article  PubMed  Google Scholar 

  96. Casanova, J. L. & Abel, L. Primary immunodeficiencies: a field in its infancy. Science 317, 617–619 (2007).

    Article  CAS  PubMed  Google Scholar 

  97. Eckburg, P. B. et al. Diversity of the human intestinal microbial flora. Science 308, 1635–1638 (2005). This landmark study uses molecular profiling to reveal the diversity of the human microflora and establish the dominant bacterial phylotypes that inhabit the human gastrointestinal tract.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Ogura, Y. et al. Expression of NOD2 in Paneth cells: a possible link to Crohn's ileitis. Gut 52, 1591–1597 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Inohara, N. et al. Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease. J. Biol. Chem. 278, 5509–5512 (2003).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

L.V.H. thanks the students and colleagues from her laboratory for the many discussions that contributed to the ideas in this manuscript. Work in L.V.H.'s laboratory is supported by the Howard Hughes Medical Institute, the US National Institutes of Health (DK070855), the Burroughs Wellcome Foundation and the Crohn's and Colitis Foundation. A.M. acknowledges K. McCoy, E. Slack, S. Hapfelmeier, M. Stoehl and M. Geuking.

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Lora V. Hooper's homepage

Andrew J. Macpherson's homepage

Glossary

Microbiota

The microorganisms that are harboured by normal, healthy individuals. These microorganisms live in the digestive tract and at other body sites.

Sepsis

A systemic response to severe infection or tissue damage, leading to a hyperactive and unbalanced network of pro-inflammatory mediators. Vascular permeability, cardiac function and metabolic balance are affected, resulting in tissue necrosis, multi-organ failure and death.

Metagenome

All the genetic material present in a population of microorganisms, consisting of the genomes of many individual organisms.

Goblet cell

A mucus-producing cell found in the epithelial cell lining of the intestine and lungs.

Defensin

A class of antimicrobial peptide that has activity against Gram-positive and Gram-negative bacteria, fungi and viruses. α-defensins are produced by intestinal Paneth cells and neutrophils, and β-defensins are expressed by most epithelial cells.

C-type lectin

An animal receptor protein that binds to carbohydrates, frequently in a Ca2+-dependent manner. The binding activity of C-type lectins is based on the structure of the carbohydrate-recognition domain, which is highly conserved among members of this family.

Paneth cells

A specialized epithelial cell lineage that produces most of the antimicrobial proteins in the small intestine.

Peyer's patches

Groups of lymphoid nodules present in the small intestine (usually the ileum). They occur massed together on the intestinal wall, opposite the line of attachment of the mesentery. Peyer's patches consist of a dome area, B cell follicles and interfollicular T cell areas. High endothelial venules are present mainly in the interfollicular areas.

Lamina propria

Connective tissue that underlies the epithelium of the mucosa and contains various myeloid and lymphoid cells, including macrophages, dendritic cells, T cells and B cells.

Plasma cell

A non-dividing, terminally differentiated, immobile antibody-secreting cell of the B cell lineage.

Transcytosis

Process of transport of material across a cell monolayer by uptake on one side of the cell into a coated vesicle, which might then be sorted through the trans-Golgi network and transported to the opposite side of the cell.

Germ-free mouse

A mouse that is born and raised in isolators, without exposure to microorganisms.

Germinal centre

Located in peripheral lymphoid tissues (for example, the spleen), these structures are sites of B cell proliferation and selection for clones that produce antigen-specific antibodies of higher affinity.

Recombination-activating gene

(Rag). A gene expressed by developing lymphocytes. Mice that are deficient for either Rag1 or Rag2 fail to produce B or T cells owing to a developmental block in the gene rearrangement that is necessary for antigen receptor expression.

Severe combined immunodeficiency

(SCID). A phenotype of mice with a defect in DNA recombination. SCID mice lack B and T cells and do not reject tissue grafts from allogeneic and xenogeneic sources.

Intraepithelial CD8αα+ T cell

A type of T cell that is found in the intestinal epithelium. The CD8 molecule that they express is a homodimer of CD8α, rather than the CD8αβ heterodimer that is expressed by conventional CD8+ T cells in the lymph nodes. It has been proposed that these cells are self-reactive T cells that have regulatory properties.

Lymphoid-tissue inducer cell

(LTi cell). A cell that is present in developing lymph nodes, Peyer's patches and nasopharynx-associated lymphoid tissue. LTi cells are required for the development of these lymphoid organs and are characterized by expression of the transcription factor retinoic acid receptor-related orphan receptor-γt (RORγt), interleukin-7 receptor-α and lymphotoxin-α1β;2.

Specific pathogen-free (SPF) mice

Mice kept in specific vivarium conditions whereby a number of pathogens are excluded or eradicated from the colony. These animals are maintained in the absence of most of the known chronic and latent persistent pathogens. Although this enables better control of experimental conditions related to immunity and infection, it also sets apart such animal models from pathogen-exposed humans or non-human primates, whose immune systems are in constant contact with potential pathogens.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hooper, L., Macpherson, A. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat Rev Immunol 10, 159–169 (2010). https://doi.org/10.1038/nri2710

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2710

This article is cited by

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