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  • Review Article
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Epithelial Toll-like receptors and their role in gut homeostasis and disease

Nature Reviews Gastroenterology & Hepatology volume 17, pages 263–278 (2020)Cite this article

Subjects

Abstract

The human gastrointestinal tract is colonized by trillions of microorganisms that interact with the host to maintain structural and functional homeostasis. Acting as the interface between the site of the highest microbial burden in the human body and the richest immune compartment, a single layer of intestinal epithelial cells specializes in nutrient absorption, stratifies microorganisms to limit colonization of tissues and shapes the responses of the subepithelial immune cells. In this Review, we focus on the expression, regulation and functions of Toll-like receptors (TLRs) in the different intestinal epithelial lineages to analyse how epithelial recognition of bacteria participates in establishing homeostasis in the gut. In particular, we elaborate on the involvement of epithelial TLR signalling in controlling crypt dynamics, enhancing epithelial barrier integrity and promoting immune tolerance towards the gut microbiota. Furthermore, we comment on the regulatory mechanisms that fine-tune TLR-driven immune responses towards pathogens and revisit the role of TLRs in epithelial repair after injury. Finally, we discuss how dysregulation of epithelial TLRs can lead to the generation of dysbiosis, thereby increasing susceptibility to colitis and tumorigenesis.

Key points

  • The intestinal epithelium provides a physical and immune barrier between the host and the gut microbiota that is dynamically regulated through the production of metabolites and the signalling of pattern recognition receptors.

  • Toll-like receptors (TLRs) are microbial-induced proteins that are expressed in most epithelial cell lineages and have important antimicrobial functions. Tight regulation mechanisms prevent excessive responses towards commensal microorganisms.

  • Activation of TLRs controls crypt dynamics by altering proliferation and apoptosis in stem cells and transit amplifying cells. Differentiation into secretory lineages, particularly via the NOTCH pathway, occurs in a myeloid differentiation primary response protein 88 (MYD88) and TLR4-dependent manner.

  • TLR recognition of microbial motifs enhances the intestinal epithelial barrier function by inducing the tightening of intercellular junctions, the secretion of mucus and antimicrobial peptides, and the production of reactive oxygen species.

  • Microbial signalling through TLRs participates in intestinal epithelial repair after injury by inducing the production of trefoil factor 3, amphiregulin and prostaglandin E2, which enhance migration, epithelial cell survival and proliferation, and by promoting the restitution of the normal epithelial architecture.

  • Dysregulation of TLR signalling can lead to inefficient clearance of pathobionts and alterations in the normal microbial composition. Imbalances in microbial composition increase susceptibility to colitis and tumorigenesis.

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Fig. 1: Anatomy of the intestinal immune system.
Fig. 2: TLRs strengthen the intestinal epithelial barrier.
Fig. 3: TLRs participate in the generation of dysbiosis, epithelial restitution, and initiation and progression of tumorigenesis.
Fig. 4: TLR activation elicits anti-apoptotic and proliferative pathways in cancer stem cells.

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References

  1. Sender, R., Fuchs, S. & Milo, R. Revised estimates for the number of human and bacteria cells in the body. PLOS Biol. 14, e1002533 (2016). This paper readdresses the total numbers of host and microbial cells in the human body, updating the previous 1:10 ratio to an estimated 1:1 ratio.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Mowat, A. M. & Agace, W. W. Regional specialization within the intestinal immune system. Nat. Rev. Immunol. 14, 667–685 (2014). This review discusses the structural and cellular organization of the immune system along the different sections of the gastrointestinal tract, commenting on the functional implications.

    Article  CAS  PubMed  Google Scholar 

  3. Rooks, M. G. & Garrett, W. S. Gut microbiota, metabolites and host immunity. Nat. Rev. Immunol. 16, 341–352 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Medzhitov, R. & Janeway, C. Jr. Innate immune recognition: mechanisms and pathways. Immunol. Rev. 173, 89–97 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Boyapati, R. K., Rossi, A. G., Satsangi, J. & Ho, G. T. Gut mucosal DAMPs in IBD: from mechanisms to therapeutic implications. Mucosal Immunol. 9, 567–582 (2016).

    Article  CAS  PubMed  Google Scholar 

  6. Hernandez, C., Huebener, P. & Schwabe, R. F. Damage-associated molecular patterns in cancer: a double-edged sword. Oncogene 35, 5931–5941 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kawai, T. & Akira, S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34, 637–650 (2011).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  9. Motta, V., Soares, F., Sun, T. & Philpott, D. J. NOD-like receptors: versatile cytosolic sentinels. Physiol. Rev. 95, 149–178 (2015).

    Article  PubMed  Google Scholar 

  10. Brown, G. D., Willment, J. A. & Whitehead, L. C-type lectins in immunity and homeostasis. Nat. Rev. Immunol. 18, 374–389 (2018).

    Article  CAS  PubMed  Google Scholar 

  11. Kell, A. M. & Gale, M. Jr. RIG-I in RNA virus recognition. Virology 479–480, 110–121 (2015).

    Article  PubMed  CAS  Google Scholar 

  12. Lugrin, J. & Martinon, F. The AIM2 inflammasome: sensor of pathogens and cellular perturbations. Immunol. Rev. 281, 99–114 (2018).

    Article  CAS  PubMed  Google Scholar 

  13. Sun, L., Wu, J., Du, F., Chen, X. & Chen, Z. J. Cyclic GMP–AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339, 786–791 (2013).

    Article  CAS  PubMed  Google Scholar 

  14. Palanissami, G. & Paul, S. F. D. RAGE and its ligands: molecular interplay between glycation, inflammation, and hallmarks of cancer—a review. Horm. Cancer 9, 295–325 (2018).

    Article  CAS  PubMed  Google Scholar 

  15. Helander, H. F. & Fandriks, L. Surface area of the digestive tract—revisited. Scand. J. Gastroenterol. 49, 681–689 (2014). This paper combines a review of the available literature with morphometric determinations to provide a revised estimate of the actual surface of the human gastrointestinal tract.

    Article  PubMed  Google Scholar 

  16. Brelje, T. C. & Sorenson, R. L. Chapter 14 — gastrointestinal tract. Histology Guide http://www.histologyguide.org/slidebox/14-gastrointestinal-tract.html (2014).

  17. Schmidt, G. H., Winton, D. J. & Ponder, B. A. Development of the pattern of cell renewal in the crypt–villus unit of chimaeric mouse small intestine. Development 103, 785–790 (1988).

    CAS  PubMed  Google Scholar 

  18. Barker, N. Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration. Nat. Rev. Mol. Cell Biol. 15, 19–33 (2014). This review summarizes current knowledge on intestinal stem cells and how the intestinal epithelium organizes and self-renews.

    Article  CAS  PubMed  Google Scholar 

  19. Vermeulen, L. & Snippert, H. J. Stem cell dynamics in homeostasis and cancer of the intestine. Nat. Rev. Cancer 14, 468–480 (2014).

    Article  CAS  PubMed  Google Scholar 

  20. Altmann, G. G. Morphological observations on mucus-secreting nongoblet cells in the deep crypts of the rat ascending colon. Am. J. Anat. 167, 95–117 (1983).

    Article  CAS  PubMed  Google Scholar 

  21. Sasaki, N. et al. Reg4+ deep crypt secretory cells function as epithelial niche for Lgr5+ stem cells in colon. Proc. Natl Acad. Sci. USA 113, E5399–E5407 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Odenwald, M. A. & Turner, J. R. The intestinal epithelial barrier: a therapeutic target? Nat. Rev. Gastroenterol. Hepatol. 14, 9–21 (2017).

    Article  CAS  PubMed  Google Scholar 

  23. Zeissig, S. et al. Changes in expression and distribution of claudin 2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn’s disease. Gut 56, 61–72 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Chang, J. et al. Impaired intestinal permeability contributes to ongoing bowel symptoms in patients with inflammatory bowel disease and mucosal healing. Gastroenterology 153, 723–731.e1 (2017).

    Article  PubMed  Google Scholar 

  25. Kaetzel, C. S., Robinson, J. K., Chintalacharuvu, K. R., Vaerman, J. P. & Lamm, M. E. The polymeric immunoglobulin receptor (secretory component) mediates transport of immune complexes across epithelial cells: a local defense function for IgA. Proc. Natl Acad. Sci. USA 88, 8796–8800 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. McGuckin, M. A., Linden, S. K., Sutton, P. & Florin, T. H. Mucin dynamics and enteric pathogens. Nat. Rev. Microbiol. 9, 265–278 (2011).

    Article  CAS  PubMed  Google Scholar 

  27. Johansson, M. E. et al. Composition and functional role of the mucus layers in the intestine. Cell Mol. Life Sci. 68, 3635–3641 (2011).

    Article  CAS  PubMed  Google Scholar 

  28. McDole, J. R. et al. Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. Nature 483, 345–349 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Johansson, M. E. et al. Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis. Gut 63, 281–291 (2014).

    Article  CAS  PubMed  Google Scholar 

  30. Sato, T. et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 469, 415–418 (2011). This paper defines, for the first time, the main growth factors that maintain stemness in the crypts and shows that these factors are provided by Paneth cells, setting the basis for organoid culture.

    Article  CAS  PubMed  Google Scholar 

  31. Bevins, C. L. & Salzman, N. H. Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis. Nat. Rev. Microbiol. 9, 356–368 (2011).

    Article  CAS  PubMed  Google Scholar 

  32. Latorre, R., Sternini, C., De Giorgio, R. & Greenwood-Van Meerveld, B. Enteroendocrine cells: a review of their role in brain–gut communication. Neurogastroenterol. Motil. 28, 620–630 (2016).

    Article  CAS  PubMed  Google Scholar 

  33. Banerjee, A., McKinley, E. T., von Moltke, J., Coffey, R. J. & Lau, K. S. Interpreting heterogeneity in intestinal tuft cell structure and function. J. Clin. Invest. 128, 1711–1719 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Mabbott, N. A., Donaldson, D. S., Ohno, H., Williams, I. R. & Mahajan, A. Microfold (M) cells: important immunosurveillance posts in the intestinal epithelium. Mucosal Immunol. 6, 666–677 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Mowat, A. M. To respond or not to respond — a personal perspective of intestinal tolerance. Nat. Rev. Immunol. 18, 405–415 (2018).

    Article  CAS  PubMed  Google Scholar 

  36. Hayes, C. L. et al. Commensal microbiota induces colonic barrier structure and functions that contribute to homeostasis. Sci. Rep. 8, 14184 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Johansson, M. E. et al. Normalization of host intestinal mucus layers requires long-term microbial colonization. Cell Host Microbe 18, 582–592 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 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 

  39. Larsson, E. et al. Analysis of gut microbial regulation of host gene expression along the length of the gut and regulation of gut microbial ecology through MyD88. Gut 61, 1124–1131 (2012).

    Article  CAS  PubMed  Google Scholar 

  40. Park, J. H. et al. Promotion of intestinal epithelial cell turnover by commensal bacteria: role of short-chain fatty acids. PLOS ONE 11, e0156334 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Hormann, N. et al. Gut microbial colonization orchestrates TLR2 expression, signaling and epithelial proliferation in the small intestinal mucosa. PLOS ONE 9, e113080 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Pollard, M. & Sharon, N. Responses of the Peyer’s patches in germ-free mice to antigenic stimulation. Infect. Immun. 2, 96–100 (1970).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bandeira, A. et al. Localization of γ/δ T cells to the intestinal epithelium is independent of normal microbial colonization. J. Exp. Med. 172, 239–244 (1990).

    Article  CAS  PubMed  Google Scholar 

  44. 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 

  45. Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011).

    Article  CAS  PubMed  Google Scholar 

  46. Crabbe, P. A., Bazin, H., Eyssen, H. & Heremans, J. F. The normal microbial flora as a major stimulus for proliferation of plasma cells synthesizing IgA in the gut. The germ-free intestinal tract. Int. Arch. Allergy Appl. Immunol. 34, 362–375 (1968).

    Article  CAS  PubMed  Google Scholar 

  47. Thompson, G. R. & Trexler, P. C. Gastrointestinal structure and function in germ-free or gnotobiotic animals. Gut 12, 230–235 (1971).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Schwechheimer, C. & Kuehn, M. J. Outer-membrane vesicles from Gram-negative bacteria: biogenesis and functions. Nat. Rev. Microbiol. 13, 605–619 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Medzhitov, R., Preston-Hurlburt, P. & Janeway, C. A. Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388, 394–397 (1997). This paper characterizes, for the first time, a TLR (TLR4) in human cells and shows that activation of this receptor leads to the activation of innate immune responses.

    Article  CAS  PubMed  Google Scholar 

  50. Schaefer, L. Complexity of danger: the diverse nature of damage-associated molecular patterns. J. Biol. Chem. 289, 35237–35245 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Medzhitov, R. et al. MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol. Cell 2, 253–258 (1998).

    Article  CAS  PubMed  Google Scholar 

  52. Zhang, F. X. et al. Bacterial lipopolysaccharide activates nuclear factor-κB through interleukin-1 signaling mediators in cultured human dermal endothelial cells and mononuclear phagocytes. J. Biol. Chem. 274, 7611–7614 (1999).

    Article  CAS  PubMed  Google Scholar 

  53. Yamamoto, M. et al. Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-β promoter in the Toll-like receptor signaling. J. Immunol. 169, 6668–6672 (2002).

    Article  CAS  PubMed  Google Scholar 

  54. Yamamoto, M. et al. Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science 301, 640–643 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Kawai, T. & Akira, S. TLR signaling. Cell Death Differ. 13, 816–825 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Li, X., Jiang, S. & Tapping, R. I. Toll-like receptor signaling in cell proliferation and survival. Cytokine 49, 1–9 (2010).

    Article  CAS  PubMed  Google Scholar 

  57. Price, A. E. et al. A map of Toll-like receptor expression in the intestinal epithelium reveals distinct spatial, cell type-specific, and temporal patterns. Immunity 49, 560–575.e6 (2018). This paper uses reporter mice to demonstrate the regional and cellular expression of TLR2, TLR4, TLR5, TLR7 and TLR9 along the gut, shedding light on this controversial topic.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  59. Gururajan, M., Jacob, J. & Pulendran, B. Toll-like receptor expression and responsiveness of distinct murine splenic and mucosal B-cell subsets. PLOS ONE 2, e863 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Otte, J. M., Rosenberg, I. M. & Podolsky, D. K. Intestinal myofibroblasts in innate immune responses of the intestine. Gastroenterology 124, 1866–1878 (2003).

    Article  CAS  PubMed  Google Scholar 

  61. Burgueno, J. F. et al. TLR2 and TLR9 modulate enteric nervous system inflammatory responses to lipopolysaccharide. J. Neuroinflammation 13, 187 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. 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).

    Article  CAS  PubMed  Google Scholar 

  63. 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 

  64. Kamdar, K. et al. Innate recognition of the microbiota by TLR1 promotes epithelial homeostasis and prevents chronic inflammation. J. Immunol. 201, 230–242 (2018).

    Article  CAS  PubMed  Google Scholar 

  65. 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 

  66. Ortega-Cava, C. F. et al. Epithelial Toll-like receptor 5 is constitutively localized in the mouse cecum and exhibits distinctive down-regulation during experimental colitis. Clin. Vaccine Immunol. 13, 132–138 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Neal, M. D. et al. Toll-like receptor 4 is expressed on intestinal stem cells and regulates their proliferation and apoptosis via the p53 up-regulated modulator of apoptosis. J. Biol. Chem. 287, 37296–37308 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Cario, E. et al. Lipopolysaccharide activates distinct signaling pathways in intestinal epithelial cell lines expressing toll-like receptors. J. Immunol. 164, 966–972 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. 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 

  70. 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). This paper characterizes how IECs challenged with TLR ligands modulate their responses by inducing TOLLIP and reducing receptor expression in the cell surface.

    Article  CAS  PubMed  Google Scholar 

  71. 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 

  72. Lee, J. et al. Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells. Nat. Cell Biol. 8, 1327–1336 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. 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).

    Article  CAS  PubMed  Google Scholar 

  74. Knoop, K. A., McDonald, K. G., McCrate, S., McDole, J. R. & Newberry, R. D. Microbial sensing by goblet cells controls immune surveillance of luminal antigens in the colon. Mucosal Immunol. 8, 198–210 (2015).

    Article  CAS  PubMed  Google Scholar 

  75. Birchenough, G. M., Nystrom, E. E., Johansson, M. E. & Hansson, G. C. A sentinel goblet cell guards the colonic crypt by triggering Nlrp6-dependent Muc2 secretion. Science 352, 1535–1542 (2016). This paper identifies sentinel goblet cells, which recognize TLR ligands to induce the release of mucus in adjacent goblet cells, expelling the microorganisms from the crypt.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Rumio, C. et al. Induction of Paneth cell degranulation by orally administered Toll-like receptor ligands. J. Cell Physiol. 227, 1107–1113 (2012).

    Article  CAS  PubMed  Google Scholar 

  77. 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 

  78. 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 

  79. 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 

  80. Cashman, S. B. & Morgan, J. G. Transcriptional analysis of Toll-like receptors expression in M cells. Mol. Immunol. 47, 365–372 (2009).

    Article  CAS  PubMed  Google Scholar 

  81. Kaiko, G. E. et al. The colonic crypt protects stem cells from microbiota-derived metabolites. Cell 165, 1708–1720 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Park, J. H., Lee, J. M., Lee, E. J., Kim, D. J. & Hwang, W. B. Kynurenine promotes the goblet cell differentiation of HT-29 colon carcinoma cells by modulating Wnt, Notch and AhR signals. Oncol. Rep. 39, 1930–1938 (2018).

    CAS  PubMed  Google Scholar 

  83. Metidji, A. et al. The environmental sensor AHR protects from inflammatory damage by maintaining intestinal stem cell homeostasis and barrier integrity. Immunity 49, 353–362.e5 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 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 demonstrates that TLR signalling is essential for epithelial repair following injury.

    Article  CAS  PubMed  Google Scholar 

  85. Rose, W. A. II, Sakamoto, K. & Leifer, C. A. TLR9 is important for protection against intestinal damage and for intestinal repair. Sci. Rep. 2, 574 (2012).

    Article  PubMed  CAS  Google Scholar 

  86. Naito, T. et al. Lipopolysaccharide from crypt-specific core microbiota modulates the colonic epithelial proliferation-to-differentiation balance. mBio 8, e01680-177 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Santaolalla, R. et al. TLR4 activates the β-catenin pathway to cause intestinal neoplasia. PLOS ONE 8, e63298 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Sodhi, C. P. et al. Intestinal epithelial Toll-like receptor 4 regulates goblet cell development and is required for necrotizing enterocolitis in mice. Gastroenterology 143, 708–718.e5 (2012).

    Article  CAS  PubMed  Google Scholar 

  89. Sato, T. & Clevers, H. Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications. Science 340, 1190–1194 (2013).

    Article  CAS  PubMed  Google Scholar 

  90. Date, S. & Sato, T. Mini-gut organoids: reconstitution of the stem cell niche. Annu. Rev. Cell Dev. Biol. 31, 269–289 (2015).

    Article  CAS  PubMed  Google Scholar 

  91. Yang, Q., Bermingham, N. A., Finegold, M. J. & Zoghbi, H. Y. Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science 294, 2155–2158 (2001).

    Article  CAS  PubMed  Google Scholar 

  92. Fre, S. et al. Notch signals control the fate of immature progenitor cells in the intestine. Nature 435, 964–968 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. Troll, J. V. et al. Microbiota promote secretory cell determination in the intestinal epithelium by modulating host Notch signaling. Development 145, dev155317 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Dheer, R. et al. Intestinal epithelial Toll-like receptor 4 signaling affects epithelial function and colonic microbiota and promotes a risk for transmissible colitis. Infect. Immun. 84, 798–810 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Gong, J. et al. Epithelial-specific blockade of MyD88-dependent pathway causes spontaneous small intestinal inflammation. Clin. Immunol. 136, 245–256 (2010).

    Article  CAS  PubMed  Google Scholar 

  96. Poling, H. M. et al. Mechanically induced development and maturation of human intestinal organoids in vivo. Nat. Biomed. Eng. 2, 429–442 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Sharkey, K. A., Beck, P. L. & McKay, D. M. Neuroimmunophysiology of the gut: advances and emerging concepts focusing on the epithelium. Nat. Rev. Gastroenterol. Hepatol. 15, 765–784 (2018).

    Article  CAS  PubMed  Google Scholar 

  98. Gibson, D. L. et al. MyD88 signalling plays a critical role in host defence by controlling pathogen burden and promoting epithelial cell homeostasis during Citrobacter rodentium-induced colitis. Cell Microbiol. 10, 618–631 (2008).

    Article  CAS  PubMed  Google Scholar 

  99. 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 

  100. 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 

  101. Karczewski, J. et al. Regulation of human epithelial tight junction proteins by Lactobacillus plantarum in vivo and protective effects on the epithelial barrier. Am. J. Physiol. Gastrointest. Liver Physiol. 298, G851–G859 (2010).

    Article  CAS  PubMed  Google Scholar 

  102. Frantz, A. L. et al. Targeted deletion of MyD88 in intestinal epithelial cells results in compromised antibacterial immunity associated with downregulation of polymeric immunoglobulin receptor, mucin-2, and antibacterial peptides. Mucosal Immunol. 5, 501–512 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Guo, S., Al-Sadi, R., Said, H. M. & Ma, T. Y. Lipopolysaccharide causes an increase in intestinal tight junction permeability in vitro and in vivo by inducing enterocyte membrane expression and localization of TLR-4 and CD14. Am. J. Pathol. 182, 375–387 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Nighot, M. et al. Lipopolysaccharide-induced increase in intestinal epithelial tight permeability is mediated by Toll-like receptor 4/myeloid differentiation primary response 88 (MyD88) activation of myosin light chain kinase expression. Am. J. Pathol. 187, 2698–2710 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. 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 

  107. Carvalho, F. A. et al. Transient inability to manage proteobacteria promotes chronic gut inflammation in TLR5-deficient mice. Cell Host Microbe 12, 139–152 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Chassaing, B., Ley, R. E. & Gewirtz, A. T. Intestinal epithelial cell Toll-like receptor 5 regulates the intestinal microbiota to prevent low-grade inflammation and metabolic syndrome in mice. Gastroenterology 147, 1363–1377.e17 (2014). This paper demonstrates that epithelial dysregulation of TLR5 impairs pathobiont clearing and induces a microbial-dependent susceptibility to developing colitis and metabolic syndrome.

    Article  CAS  PubMed  Google Scholar 

  109. Menendez, A. et al. Bacterial stimulation of the TLR–MyD88 pathway modulates the homeostatic expression of ileal Paneth cell α-defensins. J. Innate Immun. 5, 39–49 (2013).

    Article  CAS  PubMed  Google Scholar 

  110. Rojas, R. & Apodaca, G. Immunoglobulin transport across polarized epithelial cells. Nat. Rev. Mol. Cell Biol. 3, 944–955 (2002).

    Article  CAS  PubMed  Google Scholar 

  111. Bruno, M. E., Frantz, A. L., Rogier, E. W., Johansen, F. E. & Kaetzel, C. S. Regulation of the polymeric immunoglobulin receptor by the classical and alternative NF-κB pathways in intestinal epithelial cells. Mucosal Immunol. 4, 468–478 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Moon, C., VanDussen, K. L., Miyoshi, H. & Stappenbeck, T. S. Development of a primary mouse intestinal epithelial cell monolayer culture system to evaluate factors that modulate IgA transcytosis. Mucosal Immunol. 7, 818–828 (2014).

    Article  CAS  PubMed  Google Scholar 

  113. Alvarez, L. A. et al. NADPH oxidase-derived H2O2 subverts pathogen signaling by oxidative phosphotyrosine conversion to PB-DOPA. Proc. Natl Acad. Sci. USA 113, 10406–10411 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Hayes, P. et al. Defects in NADPH oxidase genes NOX1 and DUOX2 in very early onset inflammatory bowel disease. Cell Mol. Gastroenterol. Hepatol. 1, 489–502 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Botteaux, A., Hoste, C., Dumont, J. E., Van Sande, J. & Allaoui, A. Potential role of Noxes in the protection of mucosae: H2O2 as a bacterial repellent. Microbes Infect. 11, 537–544 (2009).

    Article  CAS  PubMed  Google Scholar 

  116. Corcionivoschi, N. et al. Mucosal reactive oxygen species decrease virulence by disrupting Campylobacter jejuni phosphotyrosine signaling. Cell Host Microbe 12, 47–59 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Grasberger, H., El-Zaatari, M., Dang, D. T. & Merchant, J. L. Dual oxidases control release of hydrogen peroxide by the gastric epithelium to prevent Helicobacter felis infection and inflammation in mice. Gastroenterology 145, 1045–1054 (2013).

    Article  CAS  PubMed  Google Scholar 

  118. Levine, A. P. et al. Genetic complexity of Crohn’s disease in two large Ashkenazi Jewish families. Gastroenterology 151, 698–709 (2016).

    Article  PubMed  Google Scholar 

  119. Parlato, M. et al. First identification of biallelic inherited DUOX2 inactivating mutations as a cause of very early onset inflammatory bowel disease. Gastroenterology 153, 609–611.e3 (2017).

    Article  PubMed  Google Scholar 

  120. Burgueño, J. F. et al. Intestinal epithelial cells respond to chronic inflammation and dysbiosis by synthesizing H2O2. Front. Physiol. 10, 1484 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Bocker, U. et al. Responsiveness of intestinal epithelial cell lines to lipopolysaccharide is correlated with Toll-like receptor 4 but not Toll-like receptor 2 or CD14 expression. Int. J. Colorectal Dis. 18, 25–32 (2003).

    Article  PubMed  Google Scholar 

  122. Khan, M. A. et al. The single IgG IL-1-related receptor controls TLR responses in differentiated human intestinal epithelial cells. J. Immunol. 184, 2305–2313 (2010).

    Article  CAS  PubMed  Google Scholar 

  123. Bielaszewska, M. et al. Enterohemorrhagic Escherichia coli O157 outer membrane vesicles induce interleukin 8 production in human intestinal epithelial cells by signaling via Toll-like receptors TLR4 and TLR5 and activation of the nuclear factor NF-κB. Int. J. Med. Microbiol. 308, 882–889 (2018).

    Article  CAS  PubMed  Google Scholar 

  124. Hyun, J. et al. Human intestinal epithelial cells express interleukin-10 through Toll-like receptor 4-mediated epithelial–macrophage crosstalk. J. Innate Immun. 7, 87–101 (2015).

    Article  CAS  PubMed  Google Scholar 

  125. Kanmani, P. & Kim, H. Functional capabilities of probiotic strains on attenuation of intestinal epithelial cell inflammatory response induced by TLR4 stimuli. Biofactors 45, 223–235 (2019).

    Article  CAS  PubMed  Google Scholar 

  126. Eun, C. S. et al. Attenuation of colonic inflammation by PPARγ in intestinal epithelial cells: effect on Toll-like receptor pathway. Dig. Dis. Sci. 51, 693–697 (2006).

    Article  CAS  PubMed  Google Scholar 

  127. Chabot, S. M., Shawi, M., Eaves-Pyles, T. & Neutra, M. R. Effects of flagellin on the functions of follicle-associated epithelium. J. Infect. Dis. 198, 907–910 (2008).

    Article  PubMed  Google Scholar 

  128. Rimoldi, M. et al. Intestinal immune homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells. Nat. Immunol. 6, 507–514 (2005). This paper uses co-culture models to demonstrate that microbial challenge of IECs induces the production of TSLP and promotes tolerogenic phenotypes in DCs.

    Article  CAS  PubMed  Google Scholar 

  129. Rimoldi, M. et al. Monocyte-derived dendritic cells activated by bacteria or by bacteria-stimulated epithelial cells are functionally different. Blood 106, 2818–2826 (2005).

    Article  CAS  PubMed  Google Scholar 

  130. Friedrich, C. et al. MyD88 signaling in dendritic cells and the intestinal epithelium controls immunity against intestinal infection with C. rodentium. PLOS Pathog. 13, e1006357 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Atarashi, K. et al. Th17 cell induction by adhesion of microbes to intestinal epithelial cells. Cell 163, 367–380 (2015). This paper shows that adherent microorganisms induce the production of serum amyloid A and ROS by IECs, promoting the polarization of naive T cells into T H17 cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Grasberger, H. et al. Increased expression of DUOX2 is an epithelial response to mucosal dysbiosis required for immune homeostasis in mouse intestine. Gastroenterology 149, 1849–1859 (2015).

    Article  CAS  PubMed  Google Scholar 

  133. 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 paper reports the production of APRIL in IECs upon TLR challenge, which induced B cells to produce and release IgA2.

    Article  CAS  PubMed  Google Scholar 

  134. Liew, F. Y., Xu, D., Brint, E. K. & O’Neill, L. A. Negative regulation of Toll-like receptor-mediated immune responses. Nat. Rev. Immunol. 5, 446–458 (2005).

    Article  CAS  PubMed  Google Scholar 

  135. Leifer, C. A. & Medvedev, A. E. Molecular mechanisms of regulation of Toll-like receptor signaling. J. Leukoc. Biol. 100, 927–941 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. 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 

  137. 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 

  138. 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 

  139. Candia, E. et al. Increased production of soluble TLR2 by lamina propria mononuclear cells from ulcerative colitis patients. Immunobiology 217, 634–642 (2012).

    Article  CAS  PubMed  Google Scholar 

  140. Henrick, B. M. et al. Milk matters: soluble Toll-like receptor 2 (sTLR2) in breast milk significantly inhibits HIV-1 infection and inflammation. PLOS ONE 7, e40138 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Bentala, H. et al. Removal of phosphate from lipid A as a strategy to detoxify lipopolysaccharide. Shock 18, 561–566 (2002).

    Article  PubMed  Google Scholar 

  142. Campbell, E. L. et al. Resolvin E1-induced intestinal alkaline phosphatase promotes resolution of inflammation through LPS detoxification. Proc. Natl Acad. Sci. USA 107, 14298–14303 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Vereecke, L. et al. Enterocyte-specific A20 deficiency sensitizes to tumor necrosis factor-induced toxicity and experimental colitis. J. Exp. Med. 207, 1513–1523 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Vereecke, L. et al. A20 controls intestinal homeostasis through cell-specific activities. Nat. Commun. 5, 5103 (2014).

    Article  CAS  PubMed  Google Scholar 

  145. Byndloss, M. X. et al. Microbiota-activated PPAR-γ signaling inhibits dysbiotic Enterobacteriaceae expansion. Science 357, 570–575 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Sham, H. P. et al. SIGIRR, a negative regulator of TLR/IL-1R signalling promotes microbiota dependent resistance to colonization by enteric bacterial pathogens. PLOS Pathog. 9, e1003539 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Maillard, M. H. et al. Toll-interacting protein modulates colitis susceptibility in mice. Inflamm. Bowel Dis. 20, 660–670 (2014).

    Article  PubMed  Google Scholar 

  148. Xiao, H. et al. The Toll-interleukin-1 receptor member SIGIRR regulates colonic epithelial homeostasis, inflammation, and tumorigenesis. Immunity 26, 461–475 (2007). This paper highlights the importance of epithelial SIGIRR in regulating proliferation and apoptosis of IECs during homeostasis and injury.

    Article  CAS  PubMed  Google Scholar 

  149. Biswas, A. et al. Negative regulation of Toll-like receptor signaling plays an essential role in homeostasis of the intestine. Eur. J. Immunol. 41, 182–194 (2011).

    Article  CAS  PubMed  Google Scholar 

  150. Matta, R. et al. Knockout of Mkp-1 exacerbates colitis in IL-10-deficient mice. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G1322–G1335 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Baumgart, D. C. & Carding, S. R. Inflammatory bowel disease: cause and immunobiology. Lancet 369, 1627–1640 (2007).

    Article  CAS  PubMed  Google Scholar 

  152. Gitter, A. H., Wullstein, F., Fromm, M. & Schulzke, J. D. Epithelial barrier defects in ulcerative colitis: characterization and quantification by electrophysiological imaging. Gastroenterology 121, 1320–1328 (2001).

    Article  CAS  PubMed  Google Scholar 

  153. Duboc, H. et al. Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases. Gut 62, 531–539 (2013).

    Article  CAS  PubMed  Google Scholar 

  154. Machiels, K. et al. A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut 63, 1275–1283 (2014).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  156. Ogura, Y. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411, 603–606 (2001).

    Article  CAS  PubMed  Google Scholar 

  157. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  160. Chu, H. et al. Gene–microbiota interactions contribute to the pathogenesis of inflammatory bowel disease. Science 352, 1116–1120 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Torok, H. P. et al. Epistasis between Toll-like receptor-9 polymorphisms and variants in NOD2 and IL23R modulates susceptibility to Crohn’s disease. Am. J. Gastroenterol. 104, 1723–1733 (2009).

    Article  PubMed  CAS  Google Scholar 

  162. Franchimont, D. et al. Deficient host–bacteria interactions in inflammatory bowel disease? The Toll-like receptor (TLR)-4 Asp299gly polymorphism is associated with Crohn’s disease and ulcerative colitis. Gut 53, 987–992 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Pierik, M. et al. Toll-like receptor-1, -2, and -6 polymorphisms influence disease extension in inflammatory bowel diseases. Inflamm. Bowel Dis. 12, 1–8 (2006).

    Article  PubMed  Google Scholar 

  164. 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 

  165. Fukata, M. et al. Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors. Gastroenterology 133, 1869–1881 (2007). This paper shows that TLR4, which is increased in ulcerative colitis and dysplastic samples, participates in tumour progression by inducing the expression of PGE 2 and EGFR ligands.

    Article  CAS  PubMed  Google Scholar 

  166. Seksik, P. et al. Alterations of the dominant faecal bacterial groups in patients with Crohn’s disease of the colon. Gut 52, 237–242 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Manichanh, C. et al. Reduced diversity of faecal microbiota in Crohn’s disease revealed by a metagenomic approach. Gut 55, 205–211 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Kang, S. et al. Dysbiosis of fecal microbiota in Crohn’s disease patients as revealed by a custom phylogenetic microarray. Inflamm. Bowel Dis. 16, 2034–2042 (2010).

    Article  PubMed  Google Scholar 

  169. Matsuoka, K. & Kanai, T. The gut microbiota and inflammatory bowel disease. Semin. Immunopathol. 37, 47–55 (2015).

    Article  CAS  PubMed  Google Scholar 

  170. Fritsch, J. & Abreu, M. T. The microbiota and the immune response: what is the chicken and what is the egg? Gastrointest. Endosc. Clin. N. Am. 29, 381–393 (2019).

    Article  PubMed  Google Scholar 

  171. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Nagao-Kitamoto, H. et al. Functional characterization of inflammatory bowel disease-associated gut dysbiosis in gnotobiotic mice. Cell Mol. Gastroenterol. Hepatol. 2, 468–481 (2016). This paper reports that humanization of germ-free Il10-knockout mice with the microbiota of patients with IBD caused more severe colitis than humanization with the microbiota of healthy subjects.

    Article  PubMed  PubMed Central  Google Scholar 

  174. Rakoff-Nahoum, S., Hao, L. & Medzhitov, R. Role of Toll-like receptors in spontaneous commensal-dependent colitis. Immunity 25, 319–329 (2006). This paper demonstrates that TLR signalling is necessary for the development of spontaneous colitis in Il10-knockout mice.

    Article  CAS  PubMed  Google Scholar 

  175. Winter, S. E., Lopez, C. A. & Baumler, A. J. The dynamics of gut-associated microbial communities during inflammation. EMBO Rep. 14, 319–327 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Spiga, L. & Winter, S. E. Using enteric pathogens to probe the gut microbiota. Trends Microbiol. 27, 243–253 (2019). This review discusses how gut microbial communities adapt to the host environment and how pathogens alter the host–microbial crosstalk to outcompete the gut resident microbiota.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Winter, S. E. et al. Host-derived nitrate boosts growth of E. coli in the inflamed gut. Science 339, 708–711 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Hughes, E. R. et al. Microbial respiration and formate oxidation as metabolic signatures of inflammation-associated dysbiosis. Cell Host Microbe 21, 208–219 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Zhu, W. et al. Precision editing of the gut microbiota ameliorates colitis. Nature 553, 208–211 (2018). This paper targets the microbial metabolic pathways that confer a fitness advantage to facultative anaerobes during inflammation to reduce the severity of chemically induced colitis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Chassaing, B., Koren, O., Carvalho, F. A., Ley, R. E. & Gewirtz, A. T. AIEC pathobiont instigates chronic colitis in susceptible hosts by altering microbiota composition. Gut 63, 1069–1080 (2014).

    Article  CAS  PubMed  Google Scholar 

  182. Kamdar, K. et al. Genetic and metabolic signals during acute enteric bacterial infection alter the microbiota and drive progression to chronic inflammatory disease. Cell Host Microbe 19, 21–31 (2016). This paper shows that TLR1-deficient mice have impaired clearing of pathobionts, which in turn leads to the development of dysbiotic microbiota that increases susceptibility to colitis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Lu, P. et al. Intestinal epithelial Toll-like receptor 4 prevents metabolic syndrome by regulating interactions between microbes and intestinal epithelial cells in mice. Mucosal Immunol. 11, 727–740 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Letran, S. E. et al. TLR5-deficient mice lack basal inflammatory and metabolic defects but exhibit impaired CD4 T cell responses to a flagellated pathogen. J. Immunol. 186, 5406–5412 (2011).

    Article  CAS  PubMed  Google Scholar 

  187. Miyoshi, J. et al. Minimizing confounders and increasing data quality in murine models for studies of the gut microbiome. PeerJ 6, e5166 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  188. Hernandez-Chirlaque, C. et al. Germ-free and antibiotic-treated mice are highly susceptible to epithelial injury in DSS colitis. J. Crohns Colitis 10, 1324–1335 (2016).

    Article  PubMed  Google Scholar 

  189. Cario, E. Therapeutic impact of Toll-like receptors on inflammatory bowel diseases: a multiple-edged sword. Inflamm. Bowel Dis. 14, 411–421 (2008).

    Article  PubMed  Google Scholar 

  190. 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 

  191. Katakura, K. et al. Toll-like receptor 9-induced type I IFN protects mice from experimental colitis. J. Clin. Invest. 115, 695–702 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Manieri, N. A., Drylewicz, M. R., Miyoshi, H. & Stappenbeck, T. S. Igf2bp1 is required for full induction of Ptgs2 mRNA in colonic mesenchymal stem cells in mice. Gastroenterology 143, 110–121.e10 (2012).

    Article  CAS  PubMed  Google Scholar 

  194. Jain, U. et al. Temporal regulation of the bacterial metabolite deoxycholate during colonic repair is critical for crypt regeneration. Cell Host Microbe 24, 353–363.e5 (2018). This paper discusses the role that the bacterial metabolite deoxycholic acid plays in regulating the transition through the different phases of epithelial repair.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. 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).

    Article  CAS  PubMed  Google Scholar 

  196. Miyoshi, H. et al. Prostaglandin E2 promotes intestinal repair through an adaptive cellular response of the epithelium. EMBO J. 36, 5–24 (2017).

    Article  CAS  PubMed  Google Scholar 

  197. Podolsky, D. K. Mechanisms of regulatory peptide action in the gastrointestinal tract: trefoil peptides. J. Gastroenterol. 35, 69–74 (2000).

    Article  CAS  PubMed  Google Scholar 

  198. 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 

  199. Hsu, D. et al. Toll-like receptor 4 differentially regulates epidermal growth factor-related growth factors in response to intestinal mucosal injury. Lab. Invest. 90, 1295–1305 (2010).

    Article  CAS  PubMed  Google Scholar 

  200. Miyoshi, H., Ajima, R., Luo, C. T., Yamaguchi, T. P. & Stappenbeck, T. S. Wnt5a potentiates TGF-β signaling to promote colonic crypt regeneration after tissue injury. Science 338, 108–113 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Boucard-Jourdin, M. et al. β8 integrin expression and activation of TGF-β by intestinal dendritic cells are determined by both tissue microenvironment and cell lineage. J. Immunol. 197, 1968–1978 (2016).

    Article  CAS  PubMed  Google Scholar 

  203. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Zhan, Y. et al. Gut microbiota protects against gastrointestinal tumorigenesis caused by epithelial injury. Cancer Res. 73, 7199–7210 (2013).

    Article  CAS  PubMed  Google Scholar 

  205. American Cancer Society. Key statistics for colorectal cancer. American Cancer Society https://www.cancer.org/cancer/colon-rectal-cancer/about/key-statistics.html (2019).

  206. Ullman, T. A. & Itzkowitz, S. H. Intestinal inflammation and cancer. Gastroenterology 140, 1807–1816 (2011).

    Article  CAS  PubMed  Google Scholar 

  207. Rakoff-Nahoum, S. & Medzhitov, R. Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88. Science 317, 124–127 (2007). This paper establishes that TLR activation causes tumour progression by upregulating genes associated with the tissue repair response.

    Article  CAS  PubMed  Google Scholar 

  208. Li, Y. et al. Gut microbiota accelerate tumor growth via c-jun and STAT3 phosphorylation in APCMin/+ mice. Carcinogenesis 33, 1231–1238 (2012).

    Article  CAS  PubMed  Google Scholar 

  209. Grivennikov, S. I. et al. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 491, 254–258 (2012). This paper shows that activation of MYD88 in myeloid cells induces the production of IL-23, which is identified as a major promoter of tumour progression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Coleman, O. I. et al. Activated ATF6 induces intestinal dysbiosis and innate immune response to promote colorectal tumorigenesis. Gastroenterology 155, 1539–1552.e12 (2018). This paper demonstrates that activation of ATF6 led to dysbiosis that caused tumour initiation and progression in a TLR-dependent manner.

    Article  CAS  PubMed  Google Scholar 

  211. Ekbom, A., Helmick, C., Zack, M. & Adami, H. O. Ulcerative colitis and colorectal cancer. A population-based study. N. Engl. J. Med. 323, 1228–1233 (1990).

    Article  CAS  PubMed  Google Scholar 

  212. Jess, T., Rungoe, C. & Peyrin-Biroulet, L. Risk of colorectal cancer in patients with ulcerative colitis: a meta-analysis of population-based cohort studies. Clin. Gastroenterol. Hepatol. 10, 639–645 (2012).

    Article  PubMed  Google Scholar 

  213. Bernstein, C. N., Blanchard, J. F., Kliewer, E. & Wajda, A. Cancer risk in patients with inflammatory bowel disease: a population-based study. Cancer 91, 854–862 (2001).

    Article  CAS  PubMed  Google Scholar 

  214. Sussman, D. A. et al. In silico and ex vivo approaches identify a role for Toll-like receptor 4 in colorectal cancer. J. Exp. Clin. Cancer Res. 33, 45 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  215. Fukata, M. et al. Constitutive activation of epithelial TLR4 augments inflammatory responses to mucosal injury and drives colitis-associated tumorigenesis. Inflamm. Bowel Dis. 17, 1464–1473 (2011).

    Article  PubMed  Google Scholar 

  216. Yuan, X. et al. Activation of TLR4 signaling promotes gastric cancer progression by inducing mitochondrial ROS production. Cell Death Dis. 4, e794 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Kesselring, R. et al. IRAK-M expression in tumor cells supports colorectal cancer progression through reduction of antimicrobial defense and stabilization of STAT3. Cancer Cell 29, 684–696 (2016).

    Article  CAS  PubMed  Google Scholar 

  218. 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 

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

    Article  CAS  PubMed  Google Scholar 

  220. Qin, J., Qian, Y., Yao, J., Grace, C. & Li, X. SIGIRR inhibits interleukin-1 receptor- and Toll-like receptor 4-mediated signaling through different mechanisms. J. Biol. Chem. 280, 25233–25241 (2005).

    Article  CAS  PubMed  Google Scholar 

  221. Kobayashi, K. et al. IRAK-M is a negative regulator of Toll-like receptor signaling. Cell 110, 191–202 (2002).

    Article  CAS  PubMed  Google Scholar 

  222. Berglund, M. et al. IL-1 receptor-associated kinase M downregulates DSS-induced colitis. Inflamm. Bowel Dis. 16, 1778–1786 (2010).

    Article  PubMed  Google Scholar 

  223. 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 

  224. Pimentel-Nunes, P. et al. Decreased Toll-interacting protein and peroxisome proliferator-activated receptor γ are associated with increased expression of Toll-like receptors in colon carcinogenesis. J. Clin. Pathol. 65, 302–308 (2012).

    Article  CAS  PubMed  Google Scholar 

  225. Fernandes, P. et al. Differential expression of key regulators of Toll-like receptors in ulcerative colitis and Crohn’s disease: a role for Tollip and peroxisome proliferator-activated receptor γ? Clin. Exp. Immunol. 183, 358–368 (2016).

    Article  CAS  PubMed  Google Scholar 

  226. Boone, D. L. et al. The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat. Immunol. 5, 1052–1060 (2004).

    Article  CAS  PubMed  Google Scholar 

  227. Wang, J., Ford, H. R. & Grishin, A. V. NF-κB-mediated expression of MAPK phosphatase-1 is an early step in desensitization to TLR ligands in enterocytes. Mucosal Immunol. 3, 523–534 (2010).

    Article  CAS  PubMed  Google Scholar 

  228. Appel, S. et al. PPAR-γ agonists inhibit Toll-like receptor-mediated activation of dendritic cells via the MAP kinase and NF-κB pathways. Blood 106, 3888–3894 (2005).

    Article  CAS  PubMed  Google Scholar 

  229. Adachi, M. et al. Peroxisome proliferator activated receptor γ in colonic epithelial cells protects against experimental inflammatory bowel disease. Gut 55, 1104–1113 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

M.T.A. is supported by grants from the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (R01DK099076, R01DK104844 and T32DK11678), Crohn’s and Colitis Foundation Award IBD-0389R, the Florida Academic Cancer Center Alliance (FACCA) Award, the Pfizer ASPIRE Award and the Takeda Pharmaceuticals Investigator Initiated Research (IIR) Award. Additional funding provided by The Micky & Madeleine Arison Family Foundation Crohn’s & Colitis Discovery Laboratory and Martin Kalser Chair. The authors acknowledge J. Fritsch and J. Pignac-Kobinger for preparing the initial figures for submission.

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  1. Division of Gastroenterology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA

    Juan F. Burgueño & Maria T. Abreu

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  1. Juan F. Burgueño
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M.T.A. made a substantial contribution to discussion of content and reviewed/edited the manuscript before submission. J.F.B. researched data for the article, made a substantial contribution to discussion of content, wrote the manuscript and reviewed/edited the manuscript before submission.

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Correspondence to Maria T. Abreu.

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Competing interests

M.T.A. is supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK099076, R01DK104844 and T32DK11678), Crohn’s and Colitis Foundation Award IBD-0389R, the Florida Academic Cancer Center Alliance (FACCA) Award, the Pfizer ASPIRE Award and the Takeda Pharmaceuticals Investigator Initiated Research (IIR) Award. Additional funding provided by The Micky & Madeleine Arison Family Foundation Crohn’s & Colitis Discovery Laboratory and Martin Kalser Chair. The funders had no role in the article’s conception, interpretation of data, or preparation of the manuscript. M.T.A. has served as a consultant for Boehringer Ingelheim Pharmaceuticals, Gilead, Janssen, Abbvie, Eli Lilly and Landos Biopharma; and serves as a trainer or lecturer for Imedex, Focus Medical Communications and Cornerstones Health, Inc. This does not alter the authors’ adherence to the journal’s policies on sharing data and materials. J.F.B. declares no competing interests.

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Nature Reviews Gastroenterology & Hepatology thanks E. Brint and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Burgueño, J.F., Abreu, M.T. Epithelial Toll-like receptors and their role in gut homeostasis and disease. Nat Rev Gastroenterol Hepatol 17, 263–278 (2020). https://doi.org/10.1038/s41575-019-0261-4

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