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:

Intestinal homeostasis and its breakdown in inflammatory bowel disease

Abstract

Intestinal homeostasis depends on complex interactions between the microbiota, the intestinal epithelium and the host immune system. Diverse regulatory mechanisms cooperate to maintain intestinal homeostasis, and a breakdown in these pathways may precipitate the chronic inflammatory pathology found in inflammatory bowel disease. It is now evident that immune effector modules that drive intestinal inflammation are conserved across innate and adaptive leukocytes and can be controlled by host regulatory cells. Recent evidence suggests that several factors may tip the balance between homeostasis and intestinal inflammation, presenting future challenges for the development of new therapies for inflammatory bowel disease.

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: Bacterial sensing and cellular stress pathways in intestinal homeostasis.
Figure 2: Conserved innate and adaptive immune effector modules in the gut.
Figure 3: A multihit model of IBD pathogenesis.

Similar content being viewed by others

References

  1. Kaser, A., Zeissig, S. & Blumberg, R. S. Inflammatory bowel disease. Annu. Rev. Immunol. 28, 573–621 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hill, D. A. & Artis, D. Intestinal bacteria and the regulation of immune cell homeostasis. Annu. Rev. Immunol. 28, 623–667 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  Google Scholar 

  4. Hooper, L. V. & Macpherson, A. J. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nature Rev. Immunol. 10, 159–169 (2010).

    CAS  Google Scholar 

  5. Koslowski, M. J., Beisner, J., Stange, E. F. & Wehkamp, J. Innate antimicrobial host defense in small intestinal Crohn's disease. Int. J. Med. Microbiol. 300, 34–40 (2010).

    CAS  PubMed  Google Scholar 

  6. 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).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  7. 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).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  8. Deretic, V. & Levine, B. Autophagy, immunity, and microbial adaptations. Cell Host Microbe 5, 527–549 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Kaser, A., Martinez-Naves, E. & Blumberg, R. S. Endoplasmic reticulum stress: implications for inflammatory bowel disease pathogenesis. Curr. Opin. Gastroenterol. 26, 318–326 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 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). This report links ER stress in IECs to the development of intestinal inflammation in both mice and humans.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Taylor, B. C. et al. TSLP regulates intestinal immunity and inflammation in mouse models of helminth infection and colitis. J. Exp. Med. 206, 655–667 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Abreu, M. T. Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nature Rev. Immunol. 10, 131–144 (2010).

    CAS  Google Scholar 

  13. Fagarasan, S., Kawamoto, S., Kanagawa, O. & Suzuki, K. Adaptive immune regulation in the gut: T cell-dependent and T cell-independent IgA synthesis. Annu. Rev. Immunol. 28, 243–273 (2010).

    CAS  PubMed  Google Scholar 

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

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  15. Asquith, M. J., Boulard, O., Powrie, F. & Maloy, K. J. Pathogenic and protective roles of MyD88 in leukocytes and epithelial cells in mouse models of inflammatory bowel disease. Gastroenterology 139, 519–529 (2010).

    CAS  PubMed  Google Scholar 

  16. Cario, E. Toll-like receptors in inflammatory bowel diseases: a decade later. Inflamm. Bowel Dis. 16, 1583–1597 (2010).

    PubMed  Google Scholar 

  17. Strober, W., Murray, P. J., Kitani, A. & Watanabe, T. Signalling pathways and molecular interactions of NOD1 and NOD2. Nature Rev. Immunol. 6, 9–20 (2006).

    CAS  Google Scholar 

  18. Chen, G. Y., Shaw, M. H., Redondo, G. & Nunez, G. The innate immune receptor Nod1 protects the intestine from inflammation-induced tumorigenesis. Cancer Res. 68, 10060–10067 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Dupaul-Chicoine, J. et al. Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases. Immunity 32, 367–378 (2010).

    CAS  PubMed  Google Scholar 

  20. Zaki, M. H. et al. The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity 32, 379–391 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Allen, I. C. et al. The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. J. Exp. Med. 207, 1045–1056 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Schroder, K. & Tschopp, J. The inflammasomes. Cell 140, 821–832 (2010).

    CAS  PubMed  Google Scholar 

  23. Siegmund, B. Interleukin-18 in intestinal inflammation: friend and foe? Immunity 32, 300–302 (2010).

    CAS  PubMed  Google Scholar 

  24. Salcedo, R. et al. MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18. J. Exp. Med. 207, 1625–1636 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Feng, T., Wang, L., Schoeb, T. R., Elson, C. O. & Cong, Y. Microbiota innate stimulation is a prerequisite for T cell spontaneous proliferation and induction of experimental colitis. J. Exp. Med. 207, 1321–1332 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Asquith, M. & Powrie, F. An innately dangerous balancing act: intestinal homeostasis, inflammation, and colitis-associated cancer. J. Exp. Med. 207, 1573–1577 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Saleh, M. & Trinchieri, G. Innate immune mechanisms of colitis and colitis-associated colorectal cancer. Nature Rev. Immunol. 11, 9–20 (2011).

    CAS  Google Scholar 

  28. Round, J. L. & Mazmanian, S. K. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc. Natl Acad. Sci. USA 107, 12204–12209 (2010).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  29. Richardson, W. M. et al. Nucleotide-binding oligomerization domain-2 inhibits Toll-like receptor-4 signaling in the intestinal epithelium. Gastroenterology 139, 904–917 (2010).

    CAS  PubMed  Google Scholar 

  30. Travassos, L. H. et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nature Immunol. 11, 55–62 (2010).

    CAS  Google Scholar 

  31. Cooney, R. et al. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nature Med. 16, 90–97 (2010).

    CAS  PubMed  Google Scholar 

  32. Saitoh, T. et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production. Nature 456, 264–268 (2008). References 31 and 32 describe a link between key Crohn's disease susceptibility factors by showing that NOD2 can stimulate autophagy and that this constitutes an important bacterial handling mechanism.

    ADS  CAS  PubMed  Google Scholar 

  33. Zhou, R., Yazdi, A. S., Menu, P. & Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221–225 (2011).

    ADS  CAS  PubMed  Google Scholar 

  34. Martinon, F., Chen, X., Lee, A. H. & Glimcher, L. H. TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nature Immunol. 11, 411–418 (2010).

    CAS  Google Scholar 

  35. Melmed, G. Y. & Targan, S. R. Future biologic targets for IBD: potentials and pitfalls. Nature Rev. Gastroenterol. Hepatol. 7, 110–117 (2010).

    Google Scholar 

  36. Maloy, K. J. & Kullberg, M. C. IL-23 and Th17 cytokines in intestinal homeostasis. Mucosal Immunol. 1, 339–349 (2008).

    CAS  PubMed  Google Scholar 

  37. Kamada, N. et al. Unique CD14+ intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-γ axis. J. Clin. Invest. 118, 2269–2280 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Goodall, J. C. et al. Endoplasmic reticulum stress-induced transcription factor, CHOP, is crucial for dendritic cell IL-23 expression. Proc. Natl Acad. Sci. USA 107, 17698–17703 (2010).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ahern, P. P. et al. Interleukin-23 drives intestinal inflammation through direct activity on T cells. Immunity 33, 279–288 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Leppkes, M. et al. RORγ-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. Gastroenterology 136, 257–267 (2009).

    CAS  PubMed  Google Scholar 

  41. Cosmi, L. et al. Human interleukin 17-producing cells originate from a CD161+CD4+ T cell precursor. J. Exp. Med. 205, 1903–1916 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Kleinschek, M. A. et al. Circulating and gut-resident human Th17 cells express CD161 and promote intestinal inflammation. J. Exp. Med. 206, 525–534 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Yang, X. O. et al. Regulation of inflammatory responses by IL-17F. J. Exp. Med. 205, 1063–1075 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Chaudhry, A. et al. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science 326, 986–991 (2009).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  45. Buonocore, S. et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464, 1371–1375 (2010).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  46. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 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). References 47 and 48 document a strong link between segmented filamentous bacteria colonization and T H 17 cells and, together with reference 80, provide compelling evidence that colonization with distinct types of commensal bacterium results in the accumulation of different effector T cells in the intestine.

    CAS  PubMed  Google Scholar 

  49. Wolk, K., Witte, E., Witte, K., Warszawska, K. & Sabat, R. Biology of interleukin-22. Semin. Immunopathol. 32, 17–31 (2010).

    CAS  PubMed  Google Scholar 

  50. Pickert, G. et al. STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J. Exp. Med. 206, 1465–1472 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Sonnenberg, G. F. et al. Pathological versus protective functions of IL-22 in airway inflammation are regulated by IL-17A. J. Exp. Med. 207, 1293–1305 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Chung, Y. et al. Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity 30, 576–587 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Ng, J. et al. Clostridium difficile toxin-induced inflammation and intestinal injury are mediated by the inflammasome. Gastroenterology 139, 542–552.e3 (2010).

    CAS  PubMed  Google Scholar 

  54. Muller, A. J. et al. The S. Typhimurium effector SopE induces caspase-1 activation in stromal cells to initiate gut inflammation. Cell Host Microbe 6, 125–136 (2009).

    CAS  PubMed  Google Scholar 

  55. Colonna, M. Interleukin-22-producing natural killer cells and lymphoid tissue inducer-like cells in mucosal immunity. Immunity 31, 15–23 (2009).

    CAS  PubMed  Google Scholar 

  56. Cua, D. J. & Tato, C. M. Innate IL-17-producing cells: the sentinels of the immune system. Nature Rev. Immunol. 10, 479–489 (2010).

    CAS  Google Scholar 

  57. Park, S. G. et al. T regulatory cells maintain intestinal homeostasis by suppressing γδ T cells. Immunity 33, 791–803 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Martin, B., Hirota, K., Cua, D. J., Stockinger, B. & Veldhoen, M. Interleukin-17-producing γδ T cells selectively expand in response to pathogen products and environmental signals. Immunity 31, 321–330 (2009).

    CAS  PubMed  Google Scholar 

  59. Sutton, C. E. et al. Interleukin-1 and IL-23 induce innate IL-17 production from γδ T cells, amplifying Th17 responses and autoimmunity. Immunity 31, 331–341 (2009).

    CAS  PubMed  Google Scholar 

  60. Spits, H. & Di Santo, J. P. The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nature Immunol. 12, 21–27 (2011).

    CAS  Google Scholar 

  61. Sawa, S. et al. Lineage relationship analysis of RORγ+ innate lymphoid cells. Science 330, 665–669 (2010).

    ADS  CAS  PubMed  Google Scholar 

  62. Sonnenberg, G. F., Monticelli, L. A., Elloso, M. M., Fouser, L. A. & Artis, D. CD4+ lymphoid tissue-inducer cells promote innate immunity in the gut. Immunity 34, 122–134 (2011). References 45 and 62 identify new populations of LTI-like ILCs that secrete T H 1 and T H 17 pro-inflammatory cytokines in response to IL-23, and these contribute to intestinal pathology and host defences against intestinal pathogenic bacteria.

    CAS  PubMed  Google Scholar 

  63. Moro, K. et al. Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells. Nature 463, 540–544 (2010).

    ADS  CAS  PubMed  Google Scholar 

  64. Saenz, S. A. et al. IL25 elicits a multipotent progenitor cell population that promotes TH2 cytokine responses. Nature 464, 1362–1366 (2010).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  65. Neill, D. R. et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464, 1367–1370 (2010). References 63–65 describe various ILC populations that secrete T H 2 cytokines (ILC type 2) in response to IL-25 and IL-33 and that can contribute to defence against intestinal helminth infection.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  66. Coombes, J. L. & Powrie, F. Dendritic cells in intestinal immune regulation. Nature Rev. Immunol. 8, 435–446 (2008).

    CAS  Google Scholar 

  67. Varol, C., Zigmond, E. & Jung, S. Securing the immune tightrope: mononuclear phagocytes in the intestinal lamina propria. Nature Rev. Immunol. 10, 415–426 (2010).

    CAS  Google Scholar 

  68. Varol, C. et al. Intestinal lamina propria dendritic cell subsets have different origin and functions. Immunity 31, 502–512 (2009).

    CAS  PubMed  Google Scholar 

  69. Bogunovic, M. et al. Origin of the lamina propria dendritic cell network. Immunity 31, 513–525 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Schulz, O. et al. Intestinal CD103+, but not CX3CR1+, antigen sampling cells migrate in lymph and serve classical dendritic cell functions. J. Exp. Med. 206, 3101–3114 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Niess, J. H. & Adler, G. Enteric flora expands gut lamina propria CX3CR1+ dendritic cells supporting inflammatory immune responses under normal and inflammatory conditions. J. Immunol. 184, 2026–2037 (2010).

    CAS  PubMed  Google Scholar 

  72. Manicassamy, S. et al. Activation of β-catenin in dendritic cells regulates immunity versus tolerance in the intestine. Science 329, 849–853 (2010).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  73. Laffont, S., Siddiqui, K. R. & Powrie, F. Intestinal inflammation abrogates the tolerogenic properties of MLN CD103+ dendritic cells. Eur. J. Immunol. 40, 1877–1883 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Smith, P. D. et al. Intestinal macrophages and response to microbial encroachment. Mucosal Immunol. 4, 31–42 (2011).

    PubMed  Google Scholar 

  75. Murai, M. et al. Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nature Immunol. 10, 1178–1184 (2009).

    CAS  Google Scholar 

  76. Hadis, U. et al. Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria. Immunity 34, 237–246 (2011). This study shows that oral tolerance requires homing and expansion of T reg cells in the intestine.

    CAS  PubMed  Google Scholar 

  77. Siddiqui, K. R., Laffont, S. & Powrie, F. E-cadherin marks a subset of inflammatory dendritic cells that promote T cell-mediated colitis. Immunity 32, 557–567 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Platt, A. M., Bain, C. C., Bordon, Y., Sester, D. P. & Mowat, A. M. An independent subset of TLR expressing CCR2-dependent macrophages promotes colonic inflammation. J. Immunol. 184, 6843–6854 (2010).

    CAS  PubMed  Google Scholar 

  79. Izcue, A., Coombes, J. L. & Powrie, F. Regulatory lymphocytes and intestinal inflammation. Annu. Rev. Immunol. 27, 313–338 (2009).

    CAS  PubMed  Google Scholar 

  80. Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011). This paper describes a link between Clostridium spp. and T reg cells in the gut and, together with references 47 and 48, provides compelling evidence that colonization with distinct commensal bacteria results in the accumulation of different effector T cells in the intestine.

    ADS  CAS  PubMed  Google Scholar 

  81. Littman, D. R. & Rudensky, A. Y. Th17 and regulatory T cells in mediating and restraining inflammation. Cell 140, 845–858 (2010).

    CAS  PubMed  Google Scholar 

  82. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Griseri, T., Asquith, M., Thompson, C. & Powrie, F. OX40 is required for regulatory T cell-mediated control of colitis. J. Exp. Med. 207, 699–709 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Oldenhove, G. et al. Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity 31, 772–786 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Li, M. O. & Flavell, R. A. Contextual regulation of inflammation: a duet by transforming growth factor-β and interleukin-10. Immunity 28, 468–476 (2008).

    PubMed  Google Scholar 

  86. Fantini, M. C. et al. Smad7 controls resistance of colitogenic T cells to regulatory T cell-mediated suppression. Gastroenterology 136, 1308–1316.e3 (2009).

    CAS  PubMed  Google Scholar 

  87. Pesu, M. et al. T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance. Nature 455, 246–250 (2008).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  88. Perruche, S. et al. CD3-specific antibody-induced immune tolerance involves transforming growth factor-β from phagocytes digesting apoptotic T cells. Nature Med. 14, 528–535 (2008).

    CAS  PubMed  Google Scholar 

  89. Torchinsky, M. B., Garaude, J., Martin, A. P. & Blander, J. M. Innate immune recognition of infected apoptotic cells directs TH17 cell differentiation. Nature 458, 78–82 (2009).

    ADS  CAS  PubMed  Google Scholar 

  90. Cong, Y., Feng, T., Fujihashi, K., Schoeb, T. R. & Elson, C. O. A dominant, coordinated T regulatory cell–IgA response to the intestinal microbiota. Proc. Natl Acad. Sci. USA 106, 19256–19261 (2009).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  91. Saraiva, M. & O'Garra, A. The regulation of IL-10 production by immune cells. Nature Rev. Immunol. 10, 170–181 (2010).

    CAS  Google Scholar 

  92. Glocker, E. O. et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N. Engl. J. Med. 361, 2033–2045 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Smith, A. M. et al. Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease. J. Exp. Med. 206, 1883–1897 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Winter, S. E. et al. Gut inflammation provides a respiratory electron acceptor for Salmonella. Nature 467, 426–429 (2010).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  95. Sartor, R. B. Microbial influences in inflammatory bowel diseases. Gastroenterology 134, 577–594 (2008).

    CAS  PubMed  Google Scholar 

  96. Frank, D. N. et al. Disease phenotype and genotype are associated with shifts in intestinal-associated microbiota in inflammatory bowel diseases. Inflamm. Bowel Dis. 17, 179–184 (2011).

    PubMed  Google Scholar 

  97. Willing, B. P. et al. A pyrosequencing study in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel disease phenotypes. Gastroenterology 139, 1844–1854.e1 (2010).

    PubMed  Google Scholar 

  98. Maslowski, K. M. & Mackay, C. R. Diet, gut microbiota and immune responses. Nature Immunol. 12, 5–9 (2011).

    CAS  Google Scholar 

  99. Cadwell, K. et al. Virus-plus-susceptibility gene interaction determines Crohn's disease gene Atg16L1 phenotypes in intestine. Cell 141, 1135–1145 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 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). References 99 and 100 provide illustrative examples of how several host and environmental factors may act together to precipitate chronic intestinal inflammation.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank M. Asquith, H. Uhlig, P. Ahern and M. Barnes for review and G. Song-Zhao and O. Harrison for help with the figures. We apologize to those whose work was not cited owing to space constraints. K.J.M. and F.P. are supported by grants from the Wellcome Trust, Cancer Research UK and the European Union (FP7, INFLAMMACARE).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Kevin J. Maloy or Fiona Powrie.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

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

Supplementary information

Supplementary References

This file contains a Supplementary Bibliography to the main paper. (PDF 261 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Maloy, K., Powrie, F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 474, 298–306 (2011). https://doi.org/10.1038/nature10208

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature10208

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