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:

Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function

Nature Reviews Immunology volume 10, pages 131–144 (2010)Cite this article

Subjects

An Erratum to this article was published on 01 March 2010

This article has been updated

Key Points

  • A single layer of intestinal epithelial cells (IECs) provides a physical barrier that separates trillions of commensal bacteria in the intestinal lumen from the underlying lamina propria and deeper intestinal layers. IECs express several Toll-like receptors (TLRs) including TLR1, TLR2, TLR4, TLR5 and TLR9.

  • Polarization of TLRs to the basolateral membrane of the IECs has been described for TLR4, TLR5 and TLR9 and decreases activation in response to luminal commensal bacteria. TLRs are also expressed by specific types of IEC within the crypt to villus axis, such as enteroendocrine cells, which respond to TLR activation by secreting somatostatin and cholecystokinin.

  • Activation of TLRs in IECs results in proliferation, restitution and protection against apoptosis. Following intestinal injury, TLR4 signalling through myeloid differentiation primary-response protein 88 (MYD88) results in the induction of cyclooxygenase 2 (COX2) expression and the production of prostaglandin E2 (PGE2) and amphiregulin, which is an epidermal growth factor family member.

  • TLRs regulate stem cell proliferation during injury by directing the recruitment of COX2-expressing mesenchymal stromal cells and macrophages, which produce trophic factors including PGE2 that stimulate stem cell proliferation.

  • Paneth cells are specialized epithelial cells located at the base of the small intestinal crypts that produce antimicrobial proteins and lectins. MYD88 signalling by Paneth cells is required for the expression of regenerating islet-derived protein 3γ (REG3γ), REG3β, CRP-ductin and resistin-like molecule-β (RELMβ). The absence of these lectins allows dissemination of intestinal pathogens.

  • Secretory IgA produced by lamina propria B cells protects against invasion of both commensal organisms and pathogens. TLR signalling by IECs leads to the production of cytokines such as a proliferation-inducing ligand (APRIL), which induce class switching to IgA2, a protease-resistant, T cell-independent isotype of IgA.

  • TLR signalling promotes the development of APC-dependent colorectal cancers and inflammation-associated colorectal cancers. Manipulating TLR signalling may have a beneficial effect in this setting.

Abstract

A single layer of epithelial cells lines the small and large intestines and functions as a barrier between commensal bacteria and the rest of the body. Ligation of Toll-like receptors (TLRs) on intestinal epithelial cells by bacterial products promotes epithelial cell proliferation, secretion of IgA into the gut lumen and expression of antimicrobial peptides. As described in this Review, this establishes a microorganism-induced programme of epithelial cell homeostasis and repair in the intestine. Dysregulation of this process can result in chronic inflammatory and over-exuberant repair responses, and it is associated with the development of colon cancer. Thus, dysregulated TLR signalling by intestinal epithelial cells may explain how colonic bacteria and inflammation promote colorectal cancer.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Anatomy of the intestinal immune system.
Figure 2: Polarized expression of Toll-like receptors by intestinal epithelial cells.
Figure 3: Toll-like receptors promote proliferation of intestinal epithelial cells.
Figure 4: The role of Toll-like receptors in epithelial barrier function.

Similar content being viewed by others

Change history

  • 02 February 2010

    In the version of the article initially published, figure 1 depicted Paneth cells at the base of the crypt in the colon. These cells should have been enterocytes. This has been corrected in the HTML and PDF versions of this article.

References

  1. Yen, T. H. & Wright, N. A. The gastrointestinal tract stem cell niche. Stem Cell Rev. 2, 203–212 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Jabri, B. & Ebert, E. Human CD8+ intraepithelial lymphocytes: a unique model to study the regulation of effector cytotoxic T lymphocytes in tissue. Immunol. Rev. 215, 202–214 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. 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 

  4. 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 

  5. Khan, M. A. et al. Toll-like receptor 4 contributes to colitis development but not to host defense during Citrobacter rodentium infection in mice. Infect. Immun. 74, 2522–2536 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lebeis, S. L., Bommarius, B., Parkos, C. A., Sherman, M. A. & Kalman, D. TLR signaling mediated by MyD88 is required for a protective innate immune response by neutrophils to Citrobacter rodentium. J. Immunol. 179, 566–577 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. 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 

  8. Cario, E. & Podolsky, D. K. Differential alteration in intestinal epithelial cell expression of Toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect. Immun. 68, 7010–7017 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Abreu, M. T. et al. Decreased expression of Toll-like receptor-4 and MD-2 correlates with intestinal epithelial cell protection against dysregulated proinflammatory gene expression in response to bacterial lipopolysaccharide. J. Immunol. 167, 1609–1616 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Otte, J. M., Cario, E. & Podolsky, D. K. Mechanisms of cross hyporesponsiveness to Toll-like receptor bacterial ligands in intestinal epithelial cells. Gastroenterology 126, 1054–1070 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Vamadevan, A. S. et al. Regulation of TLR4-associated MD-2 in intestinal epithelial cells: a comprehensive analysis. Innate Immun. 26 Aug 2009 (doi:10.1177/1753425909339231).

    Article  PubMed  Google Scholar 

  12. Abreu, M. T. et al. TLR4 and MD-2 expression is regulated by immune-mediated signals in human intestinal epithelial cells. J. Biol. Chem. 277, 20431–20437 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Pedersen, G., Andresen, L., Matthiessen, M. W., Rask-Madsen, J. & Brynskov, J. Expression of Toll-like receptor 9 and response to bacterial CpG oligodeoxynucleotides in human intestinal epithelium. Clin. Exp. Immunol. 141, 298–306 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Rehli, M. et al. PU.1 and interferon consensus sequence-binding protein regulate the myeloid expression of the human Toll-like receptor 4 gene. J. Biol. Chem. 275, 9773–9781 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Suzuki, M., Hisamatsu, T. & Podolsky, D. K. Gamma interferon augments the intracellular pathway for lipopolysaccharide (LPS) recognition in human intestinal epithelial cells through coordinated up-regulation of LPS uptake and expression of the intracellular Toll-like receptor 4–MD-2 complex. Infect. Immun. 71, 3503–3511 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mueller, T., Terada, T., Rosenberg, I. M., Shibolet, O. & Podolsky, D. K. Th2 cytokines down-regulate TLR expression and function in human intestinal epithelial cells. J. Immunol. 176, 5805–5814 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Dalpke, A. & Heeg, K. Signal integration following Toll-like receptor triggering. Crit. Rev. Immunol. 22, 217–250 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Lotz, M. et al. Cytokine-mediated control of lipopolysaccharide-induced activation of small intestinal epithelial cells. Immunology 122, 306–315 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lundin, A. et al. Gut flora, Toll-like receptors and nuclear receptors: a tripartite communication that tunes innate immunity in large intestine. Cell. Microbiol. 10, 1093–1103 (2008). This study shows that in the absence of commensal flora, mice have lower IEC expression of TLRs and are more susceptible to pathogenic infection.

    Article  CAS  PubMed  Google Scholar 

  20. Ewaschuk, J. B. et al. Surface expression of Toll-like receptor 9 is upregulated on intestinal epithelial cells in response to pathogenic bacterial DNA. Infect. Immun. 75, 2572–2579 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Moran, G. W., Leslie, F. C., Levison, S. E. & McLaughlin, J. T. Review: enteroendocrine cells: neglected players in gastrointestinal disorders? Therap. Adv. Gastroenterol. 1, 51–60 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Bogunovic, M. et al. Enteroendocrine cells express functional Toll-like receptors. Am. J. Physiol. Gastrointest. Liver Physiol. 292, G1770–G1783 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Palazzo, M. et al. Activation of enteroendocrine cells via TLRs induces hormone, chemokine, and defensin secretion. J. Immunol. 178, 4296–4303 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Chabot, S., Wagner, J. S., Farrant, S. & Neutra, M. R. TLRs regulate the gatekeeping functions of the intestinal follicle-associated epithelium. J. Immunol. 176, 4275–4283 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Fusunyan, R. D., Nanthakumar, N. N., Baldeon, M. E. & Walker, W. A. Evidence for an innate immune response in the immature human intestine: Toll-like receptors on fetal enterocytes. Pediatr. Res. 49, 589–593 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Gewirtz, A. T., Navas, T. A., Lyons, S., Godowski, P. J. & Madara, J. L. Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression. J. Immunol. 167, 1882–1885 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Rhee, S. H. et al. Pathophysiological role of Toll-like receptor 5 engagement by bacterial flagellin in colonic inflammation. Proc. Natl Acad. Sci. USA 102, 13610–13615 (2005). This study shows that TLR5 is expressed on the basolateral surface in human colon IECs and is therefore only activated when the epithelial barrier has been damaged, which limits responses to commensal organisms.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lee, J. et al. Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells. Nature Cell Biol. 8, 1327–1336 (2006). This study shows that the intracellular localization of TLRs in IECs differs from that in haematopoietic cells and that basolateral and apical recognition of PAMPs by TLR9 triggers distinct signalling programmes.

    Article  CAS  PubMed  Google Scholar 

  29. Bambou, J.C. et al. In vitro and ex vivo activation of the TLR5 signaling pathway in intestinal epithelial cells by a commensal Escherichia coli strain. J. Biol. Chem. 279, 42984–42992 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Vijay-Kumar, M. et al. Deletion of TLR5 results in spontaneous colitis in mice. J. Clin. Invest. 117, 3909–3921 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Uematsu, S. et al. Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5. Nature Immunol. 9, 769–776 (2008).

    Article  CAS  Google Scholar 

  32. Lenoir, C. et al. MD-2 controls bacterial lipopolysaccharide hyporesponsiveness in human intestinal epithelial cells. Life Sci. 82, 519–528 (2008).

    Article  CAS  PubMed  Google Scholar 

  33. Cario, E. et al. Commensal-associated molecular patterns induce selective Toll-like receptor-trafficking from apical membrane to cytoplasmic compartments in polarized intestinal epithelium. Am. J. Pathol. 160, 165–173 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Latz, E. et al. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nature Immunol. 5, 190–198 (2004).

    Article  CAS  Google Scholar 

  35. Leifer, C. A. et al. TLR9 is localized in the endoplasmic reticulum prior to stimulation. J. Immunol. 173, 1179–1183 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Akhtar, M., Watson, J. L., Nazli, A. & McKay, D. M. Bacterial DNA evokes epithelial IL-8 production by a MAPK-dependent, NF-κB-independent pathway. FASEB J. 17, 1319–1321 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Rachmilewitz, D. et al. Immunostimulatory oligonucleotides inhibit colonic proinflammatory cytokine production in ulcerative colitis. Inflamm. Bowel Dis. 12, 339–345 (2006).

    Article  PubMed  Google Scholar 

  38. Park, B. S. et al. The structural basis of lipopolysaccharide recognition by the TLR4–MD-2 complex. Nature 458, 1191–1195 (2009).

    Article  CAS  PubMed  Google Scholar 

  39. Saitoh, S. & Miyake, K. Regulatory molecules required for nucleotide-sensing Toll-like receptors. Immunol. Rev. 227, 32–43 (2009).

    Article  CAS  PubMed  Google Scholar 

  40. Hornef, M. W., Frisan, T., Vandewalle, A., Normark, S. & Richter-Dahlfors, A. Toll-like receptor 4 resides in the Golgi apparatus and colocalizes with internalized lipopolysaccharide in intestinal epithelial cells. J. Exp. Med. 195, 559–570 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hornef, M. W., Normark, B. H., Vandewalle, A. & Normark, S. Intracellular recognition of lipopolysaccharide by Toll-like receptor 4 in intestinal epithelial cells. J. Exp. Med. 198, 1225–1235 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Burns, K. et al. Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor. Nature Cell Biol. 2, 346–351 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Zhang, G. & Ghosh, S. Negative regulation of Toll-like receptor-mediated signaling by Tollip. J. Biol. Chem. 277, 7059–7065 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. Melmed, G. et al. Human intestinal epithelial cells are broadly unresponsive to Toll-like receptor 2-dependent bacterial ligands: implications for host-microbial interactions in the gut. J. Immunol. 170, 1406–1415 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Steenholdt, C., Andresen, L., Pedersen, G., Hansen, A. & Brynskov, J. Expression and function of Toll-like receptor 8 and Tollip in colonic epithelial cells from patients with inflammatory bowel disease. Scand. J. Gastroenterol. 44, 195–204 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Wald, D. et al. SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling. Nature Immunol. 4, 920–927 (2003).

    Article  CAS  Google Scholar 

  47. Garlanda, C. et al. Intestinal inflammation in mice deficient in Tir8, an inhibitory member of the IL-1 receptor family. Proc. Natl Acad. Sci. USA 101, 3522–3526 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Xiao, H. et al. The Toll-interleukin-1 receptor member SIGIRR regulates colonic epithelial homeostasis, inflammation, and tumorigenesis. Immunity 26, 461–475 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Dubuquoy, L. et al. Impaired expression of peroxisome proliferator-activated receptor γ in ulcerative colitis. Gastroenterology 124, 1265–1276 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Shimazu, R. et al. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J. Exp. Med. 189, 1777–1782 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Cario, E. et al. Trypsin-sensitive modulation of intestinal epithelial MD-2 as mechanism of lipopolysaccharide tolerance. J. Immunol. 176, 4258–4266 (2006).

    Article  CAS  PubMed  Google Scholar 

  52. Scoville, D. H., Sato, T., He, X. C. & Li, L. Current view: intestinal stem cells and signaling. Gastroenterology 134, 849–864 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Abrams, G. D., Bauer, H. & Sprinz, H. Influence of the normal flora on mucosal morphology and cellular renewal in the ileum. A comparison of germ-free and conventional mice. Lab. Invest. 12, 355–364 (1963).

    CAS  PubMed  Google Scholar 

  54. 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). This study shows that decreased IEC proliferation in germ-free mice is due to defective TLR signalling by macrophages that secrete trophic factors that lead to stem cell proliferation.

    Article  CAS  PubMed  Google Scholar 

  55. Nowacki, W., Cederblad, B., Renard, C., La Bonnardiere, C. & Charley, B. Age-related increase of porcine natural interferon α producing cell frequency and of interferon yield per cell. Vet. Immunol. Immunopathol. 37, 113–122 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Fukata, M. et al. Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 288, G1055–G1065 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Maslowski, K. M. et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461, 1282–1286 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Okayasu, I. et al. A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology 98, 694–702 (1990).

    Article  CAS  PubMed  Google Scholar 

  59. 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). This paper shows that TLR signalling is involved in repair of the intestinal barrier following injury. Animals deficient in MYD88, TLR4 or TLR2 had higher mortality than wild-type mice following DSS-induced colitis. Treatment of wild-type mice with antibiotics made them susceptible to colitis.

    Article  CAS  PubMed  Google Scholar 

  60. Araki, A. et al. MyD88-deficient mice develop severe intestinal inflammation in dextran sodium sulfate colitis. J. Gastroenterol. 40, 16–23 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Abreu, M. T., Fukata, M. & Arditi, M. TLR signaling in the gut in health and disease. J. Immunol. 174, 4453–4460 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Brown, S. L. et al. Myd88-dependent positioning of Ptgs2-expressing stromal cells maintains colonic epithelial proliferation during injury. J. Clin. Invest. 117, 258–269 (2007). This study indicates that following injury of the intestine, proliferation of IECs requires the repositioning of COX2-expressing mesenchymal stromal cells to the stem cell niche. Mesenchymal stromal cell repositioning and PGE 2 production required MYD88, suggesting that TLR signalling is involved in regulating proliferation through the stem cell niche.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ungaro, R. et al. A novel Toll-like receptor 4 antagonist antibody ameliorates inflammation but impairs mucosal healing in murine colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G1167–G1179 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Fort, M. M. et al. A synthetic TLR4 antagonist has anti-inflammatory effects in two murine models of inflammatory bowel disease. J. Immunol. 174, 6416–6423 (2005).

    Article  CAS  PubMed  Google Scholar 

  65. Zheng, L., Riehl, T. & Stenson, W. F. Regulation of colonic epithelial repair in mice by Toll-like receptors and hyaluronic acid. Gastroenterology 6, 2041–2051 (2009).

    Article  CAS  Google Scholar 

  66. Fukata, M. et al. Cox-2 is regulated by Toll-like receptor-4 (TLR4) signaling: role in proliferation and apoptosis in the intestine. Gastroenterology 131, 862–877 (2006). This study indicates that TLR4-deficient IECs fail to upregulate COX2 expression following injury. The absence of COX2 and PGE 2 results in decreased IEC proliferation, implicating an autocrine effect of TLR4 signalling in IECs in promoting proliferation in response to injury.

    Article  CAS  PubMed  Google Scholar 

  67. Fukata, M. et al. Innate immune signaling by Toll-like receptor-4 (TLR4) shapes the inflammatory microenvironment in colitis-associated tumors. Inflamm. Bowel Dis. 15, 997–1006 (2009).

    Article  PubMed  Google Scholar 

  68. Giraud, A. S. X. Trefoil peptide and EGF receptor/ligand transgenic mice. Am. J. Physiol. Gastrointest. Liver Physiol. 278, G501–G506 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. Fukata, M. et al. Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors. Gastroenterology 133, 1869–1881 (2007). In addition to reference 66, this study shows that TLR4-deficient mice are protected against colitis-associated neoplasia. This has implications for targeting TLR4 in dysplasia and cancer in patients with ulcerative colitis.

    Article  CAS  PubMed  Google Scholar 

  70. Vijay-Kumar, M. et al. Flagellin treatment protects against chemicals, bacteria, viruses, and radiation. J. Immunol. 180, 8280–8285 (2008).

    Article  CAS  PubMed  Google Scholar 

  71. Cario, E., Gerken, G. & Podolsky, D. K. Toll-like receptor 2 controls mucosal inflammation by regulating epithelial barrier function. Gastroenterology 132, 1359–1374 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Vijay-Kumar, M. et al. Activation of Toll-like receptor 3 protects against DSS-induced acute colitis. Inflamm. Bowel Dis. 13, 856–864 (2007).

    Article  PubMed  Google Scholar 

  73. Rachmilewitz, D. et al. Immunostimulatory DNA ameliorates experimental and spontaneous murine colitis. Gastroenterology 122, 1428–1441 (2002).

    Article  CAS  PubMed  Google Scholar 

  74. Rachmilewitz, D. et al. Toll-like receptor 9 signaling mediates the anti-inflammatory effects of probiotics in murine experimental colitis. Gastroenterology 126, 520–528 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Katakura, K. et al. Toll-like receptor 9-induced type I IFN protects mice from experimental colitis. J. Clin. Invest. 115, 695–702 (2005). This study shows that TLR9 signalling in the intestine results in the production of IFNα or IFNβ, not TNF as occurs in macrophages, and protects against colitis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Vijay-Kumar, M. et al. Flagellin suppresses epithelial apoptosis and limits disease during enteric infection. Am. J. Pathol. 169, 1686–1700 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Yu, Y. et al. TLR5-mediated phosphoinositide 3-kinase activation negatively regulates flagellin-induced proinflammatory gene expression. J. Immunol. 176, 6194–6201 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. Zeng, H. et al. Flagellin/TLR5 responses in epithelia reveal intertwined activation of inflammatory and apoptotic pathways. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G96–G108 (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Mohiuddin, M. et al. Preoperative chemoradiation in fixed distal rectal cancer: dose time factors for pathological complete response. Int. J. Radiat. Oncol. Biol. Phys. 46, 883–888 (2000).

    Article  CAS  PubMed  Google Scholar 

  80. Lee, C. M., Lee, R. J., Handrahan, D. L. & Sause, W. T. Comparison of late rectal toxicity from conventional versus three-dimensional conformal radiotherapy for prostate cancer: analysis of clinical and dosimetric factors. Urology 65, 114–119 (2005).

    Article  PubMed  Google Scholar 

  81. Manichanh, C. et al. The gut microbiota predispose to the pathophysiology of acute postradiotherapy diarrhea. Am. J. Gastroenterol. 103, 1754–1761 (2008).

    Article  CAS  PubMed  Google Scholar 

  82. Riehl, T., Cohn, S., Tessner, T., Schloemann, S. & Stenson, W. F. Lipopolysaccharide is radioprotective in the mouse intestine through a prostaglandin-mediated mechanism. Gastroenterology 118, 1106–1116 (2000).

    Article  CAS  PubMed  Google Scholar 

  83. Riehl, T. E., Newberry, R. D., Lorenz, R. G. & Stenson, W. F. TNFR1 mediates the radioprotective effects of lipopolysaccharide in the mouse intestine. Am. J. Physiol. Gastrointest. Liver Physiol. 286, G166–G173 (2004).

    Article  CAS  PubMed  Google Scholar 

  84. Burdelya, L. G. et al. An agonist of Toll-like receptor 5 has radioprotective activity in mouse and primate models. Science 320, 226–230 (2008). This study shows that administration of synthetic flagellin protects the intestine from radiation-induced apoptosis, identifying a potential clinical application for TLR ligands.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Sanders, C. J., Moore, D. A., Williams, I. R. & Gewirtz, A. T. Both radioresistant and hemopoietic cells promote innate and adaptive immune responses to flagellin. J. Immunol. 180, 7184–7192 (2008).

    Article  CAS  PubMed  Google Scholar 

  86. Persing, D. H. et al. Taking toll: lipid A mimetics as adjuvants and immunomodulators. Trends Microbiol. 10, S32–S37 (2002).

    Article  CAS  PubMed  Google Scholar 

  87. Soraisham, A. S., Amin, H. J., Al-Hindi, M. Y., Singhal, N. & Sauve, R. S. Does necrotising enterocolitis impact the neurodevelopmental and growth outcomes in preterm infants with birthweight < or =1250 g? J. Paediatr. Child Health 42, 499–504 (2006).

    Google Scholar 

  88. Guner, Y. S. et al. Necrotizing enterocolitis — bench to bedside: novel and emerging strategies. Semin. Pediatr. Surg. 17, 255–265 (2008).

    Article  PubMed  Google Scholar 

  89. Jilling, T. et al. The roles of bacteria and TLR4 in rat and murine models of necrotizing enterocolitis. J. Immunol. 177, 3273–3282 (2006).

    Article  CAS  PubMed  Google Scholar 

  90. Leaphart, C. L. et al. A critical role for TLR4 in the pathogenesis of necrotizing enterocolitis by modulating intestinal injury and repair. J. Immunol. 179, 4808–4820 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Lotz, M. et al. Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells. J. Exp. Med. 203, 973–984 (2006). This study shows that following colonization with maternal flora, neonatal mice have decreased IEC responsiveness to LPS, due in part to post-transcriptional downregulation of IRAK1. This observation may explain why premature infants develop NEC, in which TLR4 signalling seems to have a detrimental role.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Liu, Y. et al. Changes in intestinal Toll-like receptors and cytokines precede histological injury in a rat model of necrotizing enterocolitis. Am. J. Physiol. Gastrointest. Liver Physiol. 297, G442–G450 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Sodhi, C. P. et al. Toll-like receptor-4 inhibits enterocyte proliferation via impaired β-catenin signaling in necrotizing enterocolitis. Gastroenterology 138, 185–196 (2009).

    Article  CAS  PubMed  Google Scholar 

  94. Gribar, S. C. et al. Reciprocal expression and signaling of TLR4 and TLR9 in the pathogenesis and treatment of necrotizing enterocolitis. J. Immunol. 182, 636–646 (2009).

    Article  CAS  PubMed  Google Scholar 

  95. Le Mandat Schultz, A. et al. Expression of TLR-2, TLR-4, NOD2 and pNF-κB in a neonatal rat model of necrotizing enterocolitis. PLoS ONE 2, e1102 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Lin, H. C. et al. Oral probiotics prevent necrotizing enterocolitis in very low birth weight preterm infants: a multicenter, randomized, controlled trial. Pediatrics 122, 693–700 (2008).

    Article  PubMed  Google Scholar 

  97. Hooper, L. V. et al. Molecular analysis of commensal host-microbial relationships in the intestine. Science 291, 881–884 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Cario, E., Gerken, G. & Podolsky, D. K. Toll-like receptor 2 enhances ZO-1-associated intestinal epithelial barrier integrity via protein kinase C. Gastroenterology 127, 224–238 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. Gibson, D. L. et al. Toll-like receptor 2 plays a critical role in maintaining mucosal integrity during Citrobacter rodentium-induced colitis. Cell. Microbiol. 10, 388–403 (2008).

    Article  CAS  PubMed  Google Scholar 

  100. Vora, P. et al. β-defensin-2 expression is regulated by TLR signaling in intestinal epithelial cells. J. Immunol. 173, 5398–5405 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Selsted, M. E. & Ouellette, A. J. Mammalian defensins in the antimicrobial immune response. Nature Immunol. 6, 551–557 (2005).

    Article  CAS  Google Scholar 

  102. 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 

  103. Cash, H. L., Whitham, C. V., Behrendt, C. L. & Hooper, L. V. Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313, 1126–1130 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Cash, H. L., Whitham, C. V. & Hooper, L. V. Refolding, purification, and characterization of human and murine RegIII proteins expressed in Escherichia coli. Protein Expr. Purif. 48, 151–159 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Ayabe, T. et al. Secretion of microbicidal α-defensins by intestinal Paneth cells in response to bacteria. Nature Immunol. 1, 113–118 (2000).

    Article  CAS  Google Scholar 

  106. Dessein, R. et al. Toll-like receptor 2 is critical for induction of Reg3β expression and intestinal clearance of Yersinia pseudotuberculosis. Gut 58, 771–776 (2009).

    Article  CAS  PubMed  Google Scholar 

  107. 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 

  108. 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 

  109. 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). Using MYD88-deficient mice, reference 108 shows that TLR signalling is required for the production of antimicrobial lectins, which limit infection and dissemination of Listeria monocytogenes . Reference 109 indicates that TLR signalling by Paneth cells themselves is required for the production of REG3γ and other antimicrobial peptides.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Brandl, K. et al. Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits. Nature 455, 804–807 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Macpherson, A. J., McCoy, K. D., Johansen, F. E. & Brandtzaeg, P. The immune geography of IgA induction and function. Mucosal Immunol. 1, 11–22 (2008).

    Article  CAS  PubMed  Google Scholar 

  112. 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). This study shows that activation of TLRs in IECs induces the expression of APRIL, which promotes local (lamina propria) class switching of IgA1 to IgA2.

    Article  CAS  PubMed  Google Scholar 

  113. Castigli, E. et al. TACI and BAFF-R. mediate isotype switching in B cells. J. Exp. Med. 201, 35–39 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Shang, L. et al. Toll-like receptor signaling in small intestinal epithelium promotes B-cell recruitment and IgA production in lamina propria. Gastroenterology 135, 529–538 (2008).

    Article  CAS  PubMed  Google Scholar 

  115. Chieppa, M., Rescigno, M., Huang, A. Y. & Germain, R. N. Dynamic imaging of dendritic cell extension into the small bowel lumen in response to epithelial cell TLR engagement. J. Exp. Med. 203, 2841–2852 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Nenci, A. et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446, 557–561 (2007).

    Article  CAS  PubMed  Google Scholar 

  117. Kim, J. Y., Kajino-Sakamoto, R., Omori, E., Jobin, C. & Ninomiya-Tsuji, J. Intestinal epithelial-derived TAK1 signaling is essential for cytoprotection against chemical-induced colitis. PLoS ONE 4, e4561 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Kajino-Sakamoto, R. et al. Enterocyte-derived TAK1 signaling prevents epithelium apoptosis and the development of ileitis and colitis. J. Immunol. 181, 1143–1152 (2008).

    Article  CAS  PubMed  Google Scholar 

  119. Zaph, C. et al. Epithelial-cell-intrinsic IKK-β expression regulates intestinal immune homeostasis. Nature 446, 552–556 (2007).

    Article  CAS  PubMed  Google Scholar 

  120. Zaph, C. et al. Commensal-dependent expression of IL-25 regulates the IL-23–IL-17 axis in the intestine. J. Exp. Med. 205, 2191–2198 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Zeuthen, L. H., Fink, L. N. & Frokiaer, H. Epithelial cells prime the immune response to an array of gut-derived commensals towards a tolerogenic phenotype through distinct actions of thymic stromal lymphopoietin and transforming growth factor-β. Immunology 123, 197–208 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Troy, A. E. et al. IL-27 regulates homeostasis of the intestinal CD4+ effector T cell pool and limits intestinal inflammation in a murine model of colitis. J. Immunol. 183, 2037–2044 (2009).

    Article  CAS  PubMed  Google Scholar 

  123. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Butler, M. et al. Modulation of dendritic cell phenotype and function in an in vitro model of the intestinal epithelium. Eur. J. Immunol. 36, 864–874 (2006).

    Article  CAS  PubMed  Google Scholar 

  125. Dignass, A., Lynch-Devaney, K., Kindon, H., Thim, L. & Podolsky, D. K. Trefoil peptides promote epithelial migration through a transforming growth factor β-independent pathway. J. Clin. Invest. 94, 376–383 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Mashimo, H., Wu, D. C., Podolsky, D. K. & Fishman, M. C. Impaired defense of intestinal mucosa in mice lacking intestinal trefoil factor. Science 274, 262–265 (1996).

    Article  CAS  PubMed  Google Scholar 

  127. Podolsky, D. K., Gerken, G., Eyking, A. & Cario, E. Colitis-associated variant of TLR2 causes impaired mucosal repair because of TFF3 deficiency. Gastroenterology 137, 209–220 (2009). This paper indicates that the production of TFF3 depends on TLR2 signalling and protects against colitis.

    Article  CAS  PubMed  Google Scholar 

  128. Segditsas, S. & Tomlinson, I. Colorectal cancer and genetic alterations in the Wnt pathway. Oncogene 25, 7531–7537 (2006).

    Article  CAS  PubMed  Google Scholar 

  129. Su, L. K. et al. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 256, 668–670 (1992).

    Article  CAS  PubMed  Google Scholar 

  130. Powell, S. M. et al. APC mutations occur early during colorectal tumorigenesis. Nature 359, 235–237 (1992).

    Article  CAS  PubMed  Google Scholar 

  131. Dove, W. F. et al. Intestinal neoplasia in the ApcMin mouse: independence from the microbial and natural killer (beige locus) status. Cancer Res. 57, 812–814 (1997).

    CAS  PubMed  Google Scholar 

  132. Rakoff-Nahoum, S. & Medzhitov, R. Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88. Science 317, 124–127 (2007). Using a mouse model of APC-dependent colorectal cancer, this study suggests that TLR signalling is necessary for growth of intestinal tumours.

    Article  CAS  PubMed  Google Scholar 

  133. Phelps, R. A. et al. A two-step model for colon adenoma initiation and progression caused by APC loss. Cell 137, 623–634 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Rutter, M. et al. Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology 126, 451–459 (2004).

    Article  PubMed  Google Scholar 

  135. Clevers, H. At the crossroads of inflammation and cancer. Cell 118, 671–674 (2004).

    Article  CAS  PubMed  Google Scholar 

  136. Yang, G. Y., Taboada, S. & Liao, J. Inflammatory bowel disease: a model of chronic inflammation-induced cancer. Methods Mol. Biol. 511, 193–233 (2009).

    Article  CAS  PubMed  Google Scholar 

  137. Garlanda, C. et al. Increased susceptibility to colitis-associated cancer of mice lacking TIR8, an inhibitory member of the interleukin-1 receptor family. Cancer Res. 67, 6017–6021 (2007).

    Article  CAS  PubMed  Google Scholar 

  138. Rhee, S. H., Im, E. & Pothoulakis, C. Toll-like receptor 5 engagement modulates tumor development and growth in a mouse xenograft model of human colon cancer. Gastroenterology 135, 518–528 (2008).

    Article  CAS  PubMed  Google Scholar 

  139. Huang, B. et al. Toll-like receptors on tumor cells facilitate evasion of immune surveillance. Cancer Res. 65, 5009–5014 (2005).

    Article  CAS  PubMed  Google Scholar 

  140. Sun, Q., Liu, Q., Zheng, Y. & Cao, X. Rapamycin suppresses TLR4-triggered IL-6 and PGE2 production of colon cancer cells by inhibiting TLR4 expression and NF-κB activation. Mol. Immunol. 45, 2929–2936 (2008).

    Article  CAS  PubMed  Google Scholar 

  141. Tanabe, H. et al. Mouse Paneth cell secretory responses to cell surface glycolipids of virulent and attenuated pathogenic bacteria. Infect. Immun. 73, 2312–2320 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Ortega-Cava, C. F. et al. Strategic compartmentalization of Toll-like receptor 4 in the mouse gut. J. Immunol. 170, 3977–3985 (2003).

    Article  CAS  PubMed  Google Scholar 

  143. Gomariz, R. P. et al. Time-course expression of Toll-like receptors 2 and 4 in inflammatory bowel disease and homeostatic effect of VIP. J. Leukoc. Biol. 78, 491–502 (2005).

    Article  CAS  PubMed  Google Scholar 

  144. Ruiz, P. A., Shkoda, A., Kim, S. C., Sartor, R. B. & Haller, D. IL-10 gene-deficient mice lack TGF-β/Smad signaling and fail to inhibit proinflammatory gene expression in intestinal epithelial cells after the colonization with colitogenic Enterococcus faecalis. J. Immunol. 174, 2990–2999 (2005).

    Article  CAS  PubMed  Google Scholar 

  145. Singh, J. C. et al. Toll-like receptor-mediated responses of primary intestinal epithelial cells during the development of colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 288, G514–G524 (2005).

    Article  CAS  PubMed  Google Scholar 

  146. Gopal, R., Birdsell, D. & Monroy, F. Regulation of Toll-like receptors in intestinal epithelial cells by stress and Toxoplasma gondii infection. Parasite Immunol. 30, 563–576 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Furrie, E., Macfarlane, S., Thomson, G. & Macfarlane, G. T. Toll-like receptors-2, -3 and -4 expression patterns on human colon and their regulation by mucosal-associated bacteria. Immunology 115, 565–574 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Naik, S., Kelly, E. J., Meijer, L., Pettersson, S. & Sanderson, I. R. Absence of Toll-like receptor 4 explains endotoxin hyporesponsiveness in human intestinal epithelium. J. Pediatr. Gastroenterol. Nutr. 32, 449–453 (2001).

    Article  CAS  PubMed  Google Scholar 

  149. Zhou, R. B., Wei, H. M., Sun, R. & Tian, Z. G. Recognition of double-stranded RNA by TLR3 induces severe small intestinal injury in mice. J. Immunol. 178, 4548–4556 (2007).

    Article  CAS  PubMed  Google Scholar 

  150. Ohkawara, T. et al. Regulation of Toll-like receptor 4 expression in mouse colon by macrophage migration inhibitory factor. Histochem. Cell Biol. 125, 575–582 (2006).

    Article  CAS  PubMed  Google Scholar 

  151. Reigstad, C., Lundén, G., Felin, J. & Bäckhed, F. Regulation of serum amyloid A3 (SAA3) in mouse colonic epithelium and adipose tissue by the intestinal microbiota. PLoS ONE 4, e5842 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Neal, M. D. et al. Enterocyte TLR4 mediates phagocytosis and translocation of bacteria across the intestinal barrier. J. Immunol. 176, 3070–3079 (2006).

    Article  CAS  PubMed  Google Scholar 

  153. Tyrer, P., Foxwell, A. R., Cripps, A. W., Apicella, M. A. & Kyd, J. M. Microbial pattern recognition receptors mediate M-cell uptake of a Gram-negative bacterium. Infect. Immun. 74, 625–631 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Bashir, M. E., Louie, S., Shi, H. N. & Nagler-Anderson, C. Toll-like receptor 4 signaling by intestinal microbes influences susceptibility to food allergy. J. Immunol. 172, 6978–6987 (2004).

    Article  CAS  PubMed  Google Scholar 

  155. Abreu, M. T. et al. TLR signaling at the intestinal epithelial interface. J. Endotoxin Res. 9, 322–330 (2003).

    Article  CAS  PubMed  Google Scholar 

  156. Miyamoto, Y., Iimura, M., Kaper, J., B., Torres, A., G. & Kagnoff, M., F. Role of Shiga toxin versus H7 flagellin in enterohaemorrhagic Escherichia coli signalling of human colon epithelium in vivo. Cell. Microbiol. 8, 869–879 (2006).

    Article  CAS  PubMed  Google Scholar 

  157. Rumio, C. et al. Degranulation of paneth cells via Toll-like receptor 9. Am. J. Pathol. 165, 373–381 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

I thank L. Hayes for her assistance in the preparation of this review.

Author information

Authors and Affiliations

  1. Division of Gastroenterology, University of Miami Miller School of Medicine, P.O. Box 016960 (D-49), Miami, 33101, Florida, USA

    Maria T. Abreu

Authors
  1. Maria T. Abreu
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The author declares no competing financial interests.

Supplementary information

Supplementary information S1 (Table)

Expression of Toll-like receptors in cell lines (PDF 143 kb)

Related links

Related links

FURTHER INFORMATION

Maria T. Abreu's homepage

National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) Program

Glossary

Lamina propria

The layer of mucosal tissue directly under the mucosal epithelial cell surface of the gastrointestinal tract, in which mucosal effector immune cells reside.

Goblet cells

Mucus-producing cells found in the epithelial cell lining of the intestine and lungs.

Enteroendocrine cells

Specialized endocrine cells of the gastrointestinal tract that differentiate from pluripotent stem cells. They are characterized by their ability to produce hormones such as serotonin, somatostatin, motilin, cholecystokinin, vasoactive intestinal peptide and enteroglucagon.

Paneth cells

Specialized cells that are generally only found at the base of small intestinal crypts, although they can also be seen in the human colon in chronic inflammatory conditions. Paneth cells produce antimicrobial peptides or lectins, including REG3 proteins and defensins.

Tight junction

A belt-like region of adhesion between adjacent epithelial or endothelial cells that regulates paracellular flux. Tight junction proteins include the integral membrane proteins occludin and claudin, in association with cytoplasmic zonula occludens proteins.

Laser capture microdissection

A method used to isolate specific subpopulations of cells under direct microscopy of the tissue. A laser is used to separate the desired cells from the tissue on a microscope slide and the cells of interest are then captured for subsequent analysis.

Crypts

Tubular invaginations of the intestinal epithelium. At the base of the crypts, there are Paneth cells, which produce bactericidal defensins, and stem cells, which continuously divide and are the source of all intestinal epithelial cells.

CpG-containing oligodeoxynucleotides

Synthetic DNA sequences that include a cytosine–guanosine sequence and certain flanking nucleotides, which have been found to induce innate immune responses through interaction with TLR9.

Crohn's disease

A form of chronic inflammatory bowel disease that can affect the entire gastrointestinal tract but is most common in the colon and terminal ileum. It is characterized by transmural inflammation, strictures and granuloma formation, and is thought to result from an abnormal T cell-mediated immune response to commensal bacteria. Symptoms include abdominal pain, rectal bleeding, diarrhoea and weight loss.

Villi

Projections into the lumen that have an outer layer that mainly consists of mature, absorptive enterocytes and mucus-secreting goblet cells.

Follicle-associated epithelium

(FAE). The epithelium that overlies mucosal lymphoid tissues, such as the Peyer's patches and the isolated lymphoid follicles in the intestine. Lymphoid tissues induce the differentiation of normal intestinal epithelium into FAE, which is specialized in antigen capture and transport.

WNT proteins

Glycoproteins related to the Drosophila melanogaster protein Wingless, a ligand that regulates the temporal and spatial development of the embryo. WNT-mediated signalling has been shown to regulate cell fate determination, proliferation, adhesion, migration and polarity during development. WNT and its downstream signalling molecules also have been implicated in tumorigenesis and have causative roles in human colon cancers.

Cross-tolerance

A state of unresponsiveness in which cells exposed to a TLR ligand show tolerance to subsequent challenge with the same stimulus and also to subsequent challenges with other stimuli that signal through one or more different TLRs.

Septic shock

A systemic response to severe bacterial infections or Gram-negative bacterial endotoxins (such as LPS) that leads to a hyperactive and dysregulated network of inflammatory cytokines, affecting vascular permeability, cardiac function and metabolic balance, which leads to tissue necrosis, multiple-organ failure and death.

Necrotizing enterocolitis

(NEC). A gastrointestinal disease predominantly affecting premature low-birth-weight infants. NEC involves infection and inflammation that causes destruction of the intestine. Although the pathophysiology of NEC is not completely defined, increasing evidence indicates that immaturity of intestinal innate immune function of the premature gut, characterized by over-exuberant IL-8 responses of intestinal epithelial cells to LPS, is a key factor.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Abreu, M. Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nat Rev Immunol 10, 131–144 (2010). https://doi.org/10.1038/nri2707

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2707

This article is cited by

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