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Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis

Key Points

  • The intestinal microbiota is important for many physiological functions and contributes to host defence by providing resistance to colonization by pathogens and through effects on the mucosal immune system.

  • Paneth cells are specialized secretory epithelial cells that are located in the small intestinal crypts and produce a diverse group of antimicrobial, immune system-stimulating and trophic molecules.

  • Paneth cells have several essential roles for the maintenance of immune homeostasis, such as regulating the composition of the intestinal microbiota, defending against intestinal pathogens and supporting the function of crypt epithelial stem cells.

  • Antimicrobial α-defensins are essential effectors that are produced and secreted by Paneth cells. These effectors modulate acquired immunity in the host through their ability to regulate the composition of the intestinal microbiota.

  • There are numerous susceptibility genes associated with an increased risk of developing Crohn's disease, and many of these genes affect Paneth cell function, strongly suggesting a critical role for these cells in the pathogenesis of Crohn's disease.

Abstract

Building and maintaining a homeostatic relationship between a host and its colonizing microbiota entails ongoing complex interactions between the host and the microorganisms. The mucosal immune system, including epithelial cells, plays an essential part in negotiating this equilibrium. Paneth cells (specialized cells in the epithelium of the small intestine) are an important source of antimicrobial peptides in the intestine. These cells have become the focus of investigations that explore the mechanisms of host–microorganism homeostasis in the small intestine and its collapse in the processes of infection and chronic inflammation. In this Review, we provide an overview of the intestinal microbiota and describe the cell biology of Paneth cells, emphasizing the composition of their secretions and the roles of these cells in intestinal host defence and homeostasis. We also highlight the implications of Paneth cell dysfunction in susceptibility to chronic inflammatory bowel disease.

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Figure 1: Morphology and histology of Paneth cells (secretory cells of the small intestinal crypts).
Figure 2: Paneth cell α-defensins, the microbiota and mucosal inflammatory tone.
Figure 3: Paneth cell dysfunction may predispose to intestinal inflammation.

References

  1. Ley, R. E., Lozupone, C. A., Hamady, M., Knight, R. & Gordon, J. I. Worlds within worlds: evolution of the vertebrate gut microbiota. Nature Rev. Microbiol. 7, 776–788 (2008).

    Article  CAS  Google Scholar 

  2. Round, J. L. & Mazmanian, S. K. The gut microbiota shapes intestinal immune responses during health and disease. Nature Rev. Immunol. 9, 313–323 (2009).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Garrett, W. S., Gordon, J. I. & Glimcher, L. H. Homeostasis and inflammation in the intestine. Cell 140, 859–870 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sekirov, I., Russell, S. L., Antunes, L. C. & Finlay, B. B. Gut microbiota in health and disease. Physiol. Rev. 90, 859–904 (2010).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sekirov, I. & Finlay, B. B. The role of the intestinal microbiota in enteric infection. J. Physiol. 587, 4159–4167 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cerf-Bensussan, N. & Gaboriau-Routhiau, V. The immune system and the gut microbiota: friends or foes? Nature Rev. Immunol. 10, 735–744 (2010).

    Article  CAS  Google Scholar 

  10. Ley, R. E. et al. Obesity alters gut microbial ecology. Proc. Natl Acad. Sci. USA 102, 11070–11075 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rawls, J. F., Mahowald, M. A., Ley, R. E. & Gordon, J. I. Reciprocal gut microbiota transplants from zebrafish and mice to germ-free recipients reveal host habitat selection. Cell 127, 423–433 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Garrett, W. S. et al. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell 131, 33–45 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Saha, S. et al. Peptidoglycan recognition proteins protect mice from experimental colitis by promoting normal gut flora and preventing induction of interferon-γ. Cell Host Microbe 8, 147–162 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zasloff, M. Antimicrobial peptides of multicellular organisms. Nature 415, 389–395 (2002).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  16. Wehkamp, J., Fellermann, K., Herrlinger, K., Bevins, C. L. & Stange, E. F. Defensins in gastrointestinal diseases. Nature Clin. Pract. Gastroenterol. Hepatol. 2, 406–415 (2005).

    Article  CAS  Google Scholar 

  17. Duerkop, B. A., Vaishnava, S. & Hooper, L. V. Immune responses to the microbiota at the intestinal mucosal surface. Immunity 31, 368–376 (2009).

    Article  CAS  PubMed  Google Scholar 

  18. Porter, E. M., Bevins, C. L., Ghosh, D. & Ganz, T. The multifaceted Paneth cell. Cell. Mol. Life Sci. 59, 156–170 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Ouellette, A. J. Paneth cells and innate mucosal immunity. Curr. Opin. Gastroenterol. 26, 547–553 (2010).

    PubMed  Google Scholar 

  20. Wilson, C. L. et al. Regulation of intestinal α-defensin activation by the metalloproteinase matrilysin in innate host defense. Science 286, 113–117 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. Salzman, N. H., Ghosh, D., Huttner, K. M., Paterson, Y. & Bevins, C. L. Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin. Nature 422, 522–526 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. 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 

  23. Salzman, N. et al. Enteric defensins are essential regulators of intestinal microbial ecology. Nature Immunol. 11, 76–82 (2010).

    CAS  Google Scholar 

  24. Sato, T. et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 469, 415–418 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Costello, E. K. et al. Bacterial community variation in human body habitats across space and time. Science 326, 1694–1697 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Palmer, C., Bik, E. M., DiGiulio, D. B., Relman, D. A. & Brown, P. O. Development of the human infant intestinal microbiota. PLoS Biol. 5, e177 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ley, R. E. et al. Evolution of mammals and their gut microbes. Science 320, 1647–1651 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Eckburg, P. B. et al. Diversity of the human intestinal microbial flora. Science 308, 1635–1638 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Backhed, F., Ley, R. E., Sonnenburg, J. L., Peterson, D. A. & Gordon, J. I. Host-bacterial mutualism in the human intestine. Science 307, 1915–1920 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Ley, R. E., Turnbaugh, P. J., Klein, S. & Gordon, J. I. Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022–1023 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Wostmann, B. S. The germfree animal in nutritional studies. Annu. Rev. Nutr. 1, 257–279 (1981).

    Article  CAS  PubMed  Google Scholar 

  35. Gustafsson, B. E. The physiological importance of the colonic microflora. Scand. J. Gastroenterol. Suppl. 77, 117–131 (1982).

    CAS  PubMed  Google Scholar 

  36. Hooper, L. V. & Gordon, J. I. Commensal Host-Bacterial Relationships in the Gut. Science 292, 1115–1158 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Hooper, L. V., Midtvedt, T. & Gordon, J. I. How host-microbial interactions shape the nutrient environment of the mammalian intestine. Annu. Rev. Nutr. 22, 283–307 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Falk, P. G., Hooper, L. V., Midtvedt, T. & Gordon, J. I. Creating and maintaining the gastrointestinal ecosystem: what we know and need to know from gnotobiology. Microbiol. Mol. Biol. Rev. 62, 1157–1170 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Bouskra, D. et al. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 456, 507–510 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  41. Hapfelmeier, S. et al. Reversible microbial colonization of germ-free mice reveals the dynamics of IgA immune responses. Science 328, 1705–1709 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  43. Ayabe, T. et al. Activation of Paneth cell α-defensins in mouse small intestine. J. Biol. Chem. 277, 5219–5228 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. 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 

  45. 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 

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

    Article  CAS  PubMed  Google Scholar 

  47. Talham, G. L., Jiang, H. Q., Bos, N. A. & Cebra, J. J. Segmented filamentous bacteria are potent stimuli of a physiologically normal state of the murine gut mucosal immune system. Infect. Immun. 67, 1992–2000 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Umesaki, Y., Setoyama, H., Matsumoto, S., Imaoka, A. & Itoh, K. Differential roles of segmented filamentous bacteria and clostridia in development of the intestinal immune system. Infect. Immun. 67, 3504–3511 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Heczko, U., Abe, A. & Finlay, B. B. Segmented filamentous bacteria prevent colonization of enteropathogenic Escherichia coli 0103 in rabbits. J. Infect. Dis. 181, 1027–1033 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. 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 

  51. Barthel, M. et al. Pretreatment of mice with streptomycin provides a Salmonella enterica serovar Typhimurium colitis model that allows analysis of both pathogen and host. Infect. Immun. 71, 2839–2858 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Garner, C. D. et al. Perturbation of the small intestine microbial ecology by streptomycin alters pathology in a Salmonella enterica serovar Typhimurium murine model of infection. Infect. Immun. 77, 2691–2702 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wells, C. L., Jechorek, R. P. & Erlandsen, S. L. Evidence for the translocation of Enterococcus faecalis across the mouse intestinal tract. J. Infect. Dis. 162, 82–90 (1990).

    Article  CAS  PubMed  Google Scholar 

  54. Merrell, D. S. & Camilli, A. The cadA gene of Vibrio cholera is induce during infection and plays a role in acid tolerance. Mol. Microbiol. 34, 836–849 (1999).

    Article  CAS  PubMed  Google Scholar 

  55. Sekirov, I. et al. Antibiotic-induced perturbations of the intestinal microbiota alter host susceptibility to enteric infection. Infect. Immun. 76, 4726–4736 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Croswell, A., Amir, E., Teggatz, P., Barman, M. & Salzman, N. H. Prolonged impact of antibiotics on intestinal microbial ecology and susceptibility to enteric Salmonella infection. Infect. Immun. 77, 2741–2753 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Stecher, B. et al. Like will to like: abundances of closely related species can predict susceptibility to intestinal colonization by pathogenic and commensal bacteria. PLoS Pathog. 6, e1000711 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 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 

  59. Turnbaugh, P. J., Backhed, F., Fulton, L. & Gordon, J. I. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe 3, 213–223 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Dominguez-Bello, M. G. et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc. Natl Acad. Sci. USA 107, 11971–11975 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Ochman, H. et al. Evolutionary relationships of wild hominids recapitulated by gut microbial communities. PLoS Biol. 8, e1000546 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Dethlefsen, L., Huse, S., Sogin, M. L. & Relman, D. A. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol. 6, e280 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Peterson, D. A., McNulty, N. P., Guruge, J. L. & Gordon, J. I. IgA response to symbiotic bacteria as a mediator of gut homeostasis. Cell Host Microbe 2, 328–339 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  66. Mukherjee, S., Vaishnava, S. & Hooper, L. V. Multi-layered regulation of intestinal antimicrobial defense. Cell. Mol. Life Sci. 65, 3019–3027 (2008).

    Article  CAS  PubMed  Google Scholar 

  67. Petnicki-Ocwieja, T. et al. Nod2 is required for the regulation of commensal microbiota in the intestine. Proc.Natl Acad. Sci. USA 106, 15813–15818 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Satoh, Y., Habara, Y., Ono, K. & Kanno, T. Carbamylcholine- and catecholamine-induced intracellular calcium dynamics of epithelial cells in mouse ileal crypts. Gastroenterology 108, 1345–1356 (1995).

    Article  CAS  PubMed  Google Scholar 

  69. 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 

  70. Ayabe, T. et al. Modulation of mouse Paneth cell α-defensin secretion by mIKCa1, a Ca2+-activated, intermediate conductance potassium channel. J. Biol. Chem. 277, 3793–3800 (2002).

    Article  CAS  PubMed  Google Scholar 

  71. van der Flier, L. G. & Clevers, H. Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu. Rev. Physiol. 71, 241–260 (2009).

    Article  CAS  PubMed  Google Scholar 

  72. Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).

    Article  CAS  PubMed  Google Scholar 

  73. Snippert, H. J. et al. Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143, 134–144 (2010).

    Article  CAS  PubMed  Google Scholar 

  74. Lopez-Garcia, C., Klein, A. M., Simons, B. D. & Winton, D. J. Intestinal stem cell replacement follows a pattern of neutral drift. Science 330, 822–825 (2010).

    Article  CAS  PubMed  Google Scholar 

  75. Barker, N. et al. Lgr5+ve stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell 6, 25–36 (2010).

    Article  CAS  PubMed  Google Scholar 

  76. de Santa Barbara, P., van den Brink, G. R. & Roberts, D. J. Development and differentiation of the intestinal epithelium. Cell. Mol. Life Sci. 60, 1322–1332 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. 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 

  78. Ganz, T. Defensins: antimicrobial peptides of innate immunity. Nature Rev. Immunol. 3, 710–720 (2003).

    Article  CAS  Google Scholar 

  79. Lehrer, R. I. Primate defensins. Nature Rev. Microbiol. 2, 727–738 (2004).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  81. de Leeuw, E. et al. Functional interaction of human neutrophil peptide-1 with the cell wall precursor lipid II. FEBS Lett. 584, 1543–1548 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Sass, V. et al. Human β-defensin 3 inhibits cell wall biosynthesis in staphylococci. Infect. Immun. 78, 2793–2800 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Schneider, T. et al. Plectasin, a fungal defensin, targets the bacterial cell wall precursor Lipid II. Science 328, 1168–1172 (2010).

    Article  CAS  PubMed  Google Scholar 

  84. Lehrer, R. I., Lichtenstein, A. K. & Ganz, T. Defensins: antimicrobial and cytotoxic peptides of mammalian cells. Annu. Rev. Immunol. 11, 105–128 (1993).

    Article  CAS  PubMed  Google Scholar 

  85. Yang, D. et al. β-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science 286, 525–528 (1999).

    Article  CAS  PubMed  Google Scholar 

  86. Yang, D., Biragyn, A., Kwak, L. W. & Oppenheim, J. J. Mammalian defensins in immunity: more than just microbicidal. Trends Immunol. 23, 291–296 (2002).

    Article  CAS  PubMed  Google Scholar 

  87. Lencer, W. I. et al. Induction of epithelial chloride secretion by channel-forming cryptdins 2 and 3. Proc. Natl Acad. Sci. USA 94, 8585–8589 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Yue, G. et al. Cryptdin 3 forms anion selective channels in cytoplasmic membranes of human embryonic kidney cells. Am. J. Physiol. Gastrointest. Liver Physiol. 282, G757–G765 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Lehrer, R. I. et al. Multivalent binding of carbohydrates by the human α-defensin, HD5. J. Immunol. 183, 480–490 (2009).

    Article  CAS  PubMed  Google Scholar 

  90. Huttner, K. M., Selsted, M. E. & Ouellette, A. J. Structure and diversity of the murine cryptdin gene family. Genomics 19, 448–453 (1994).

    Article  CAS  PubMed  Google Scholar 

  91. Hornef, M. W., Putsep, K., Karlsson, J., Refai, E. & Andersson, M. Increased diversity of intestinal antimicrobial peptides by covalent dimer formation. Nature Immunol. 5, 836–843 (2004).

    Article  CAS  Google Scholar 

  92. Shanahan, M. T., Tanabe, H. & Ouellette, A. J. Strain-specific polymorphisms in Paneth cell-defensins of C57BL/6 mice and evidence of vestigial myeloid-defensin pseudogenes. Infect. Immun. 79, 459–473 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Lynn, D. J., Lloyd, A. T., Fares, M. A. & O'Farrelly, C. Evidence of positively selected sites in mammalian α-defensins. Mol. Biol. Evol. 21, 819–827 (2004).

    Article  CAS  PubMed  Google Scholar 

  94. Ouellette, A. J., Pravtcheva, D., Ruddle, F. H. & James, M. Localization of the cryptdin locus on mouse chromosome 8. Genomics 5, 233–239 (1989).

    Article  CAS  PubMed  Google Scholar 

  95. Ouellette, A. J. Paneth cell α-defensin synthesis and function. Curr. Top. Microbiol. Immunol. 306, 1–25 (2006).

    CAS  PubMed  Google Scholar 

  96. Shirafuji, Y. et al. Structural determinants of procryptdin recognition and cleavage by matrix metalloproteinase-7. J. Biol. Chem. 278, 7910–7919 (2003).

    Article  CAS  PubMed  Google Scholar 

  97. Ghosh, D. et al. Paneth cell trypsin is the processing enzyme for human defensin-5. Nature Immunol. 3, 583–590 (2002).

    Article  CAS  Google Scholar 

  98. Porter, E. et al. Isolation of human intestinal defensins from ileal neobladder urine. FEBS Lett. 434, 272–276 (1998).

    Article  CAS  PubMed  Google Scholar 

  99. Ganz, T. et al. Increased inflammation in lysozyme M-deficient mice in response to Micrococcus luteus and its peptidoglycan. Blood 101, 2388–2392 (2003).

    Article  CAS  PubMed  Google Scholar 

  100. Qu, X.-D., Lloyd, K. C., Walsh, J. H. & Lehrer, R. I. Secretion of type II phospholipase A2 and cryptdin by rat small intestinal Paneth cells. Infect. Immun. 64, 5161–5165 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Lambeau, G. & Gelb, M. H. Biochemistry and physiology of mammalian secreted phospholipases A2 . Annu. Rev. Biochem. 77, 495–520 (2008).

    Article  CAS  PubMed  Google Scholar 

  102. Murakami, M., Taketomi, Y., Girard, C., Yamamoto, K. & Lambeau, G. Emerging roles of secreted phospholipase A2 enzymes: lessons from transgenic and knockout mice. Biochimie 92, 561–582 (2010).

    Article  CAS  PubMed  Google Scholar 

  103. Nevalainen, T. J., Graham, G. G. & Scott, K. F. Antibacterial actions of secreted phospholipases A2. Review. Biochim. Biophys. Acta 1781, 1–9 (2008).

    Article  CAS  PubMed  Google Scholar 

  104. Harwig, S. S. L. et al. Bactericidal properties of murine intestinal phospholipase A2 . J. Clin. Invest. 95, 603–610 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Kennedy, B. P. et al. A natural disruption of the secretory group II phospholipase A2 gene in inbred mouse strains. J. Biol. Chem. 270, 22378–22385 (1995).

    Article  CAS  PubMed  Google Scholar 

  106. MacPhee, M. et al. The secretory phospholipase A2 gene is a candidate for the Mom1 locus, a major modifier of ApcMin-induced intestinal neoplasia. Cell 81, 957–966 (1995).

    Article  CAS  PubMed  Google Scholar 

  107. Cormier, R. T. et al. Secretory phospholipase Pla2g2a confers resistance to intestinal tumorigenesis. Nature Genet. 17, 88–91 (1997).

    Article  CAS  PubMed  Google Scholar 

  108. Lasserre, C., Colnot, C., Brechot, C. & Poirier, F. HIP/PAP gene, encoding a C-type lectin overexpressed in primary liver cancer, is expressed in nervous system as well as in intestine and pancreas of the postimplantation mouse embryo. Am. J. Pathol. 154, 1601–1610 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Iovanna, J. L. & Dagorn, J. C. The multifunctional family of secreted proteins containing a C-type lectin-like domain linked to a short N-terminal peptide. Biochim. Biophys. Acta 1723, 8–18 (2005).

    Article  CAS  PubMed  Google Scholar 

  110. Medveczky, P., Szmola, R. & Sahin-Toth, M. Proteolytic activation of human pancreatitis-associated protein is required for peptidoglycan binding and bacterial aggregation. Biochem. J. 420, 335–343 (2009).

    Article  CAS  PubMed  Google Scholar 

  111. Mukherjee, S. et al. Regulation of C-type lectin antimicrobial activity by a flexible N-terminal prosegment. J. Biol. Chem. 284, 4881–4888 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Lehotzky, R. E. et al. Molecular basis for peptidoglycan recognition by a bactericidal lectin. Proc. Natl Acad. Sci. USA 107, 7722–7727 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Christa, L. et al. HIP/PAP is an adhesive protein expressed in hepatocarcinoma, normal Paneth, and pancreatic cells. Am. J. Physiol. 271, G993–G1002 (1996).

    CAS  PubMed  Google Scholar 

  114. 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 

  115. Harder, J. & Schroder, J. M. RNase 7, a novel innate immune defense antimicrobial protein of healthy human skin. J. Biol. Chem. 277, 46779–46784 (2002).

    Article  CAS  PubMed  Google Scholar 

  116. Crabtree, B., Holloway, D. E., Baker, M. D., Acharya, K. R. & Subramanian, V. Biological and structural features of murine angiogenin-4, an angiogenic protein. Biochemistry 46, 2431–2443 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Riley, M. A. Molecular mechanisms of bacteriocin evolution. Annu. Rev. Genet. 32, 255–278 (1998).

    Article  CAS  PubMed  Google Scholar 

  119. Baba, T. & Schneewind, O. Instruments of microbial warfare: bacteriocin synthesis, toxicity and immunity. Trends Microbiol. 6, 66–71 (1998).

    Article  CAS  PubMed  Google Scholar 

  120. Czaran, T. L., Hoekstra, R. F. & Pagie, L. Chemical warfare between microbes promotes biodiversity. Proc. Natl Acad. Sci. USA 99, 786–790 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Duquesne, S., Destoumieux-Garzon, D., Peduzzi, J. & Rebuffat, S. Microcins, gene-encoded antibacterial peptides from enterobacteria. Nat. Prod. Rep. 24, 708–734 (2007).

    Article  CAS  PubMed  Google Scholar 

  122. Gillor, O., Etzion, A. & Riley, M. A. The dual role of bacteriocins as anti- and probiotics. Appl. Microbiol. Biotechnol. 81, 591–606 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Richards, S. M., Strandberg, K. L. & Gunn, J. S. Salmonella-regulated lipopolysaccharide modifications. Subcell. Biochem. 53, 101–122 (2010).

    Article  CAS  PubMed  Google Scholar 

  124. Kraus, D. & Peschel, A. Molecular mechanisms of bacterial resistance to antimicrobial peptides. Curr. Top. Microbiol. Immunol. 306, 231–250 (2006).

    CAS  PubMed  Google Scholar 

  125. Stecher, B. et al. Salmonella enterica serovar Typhimurium exploits inflammation to compete with the intestinal microbiota. PLoS Biol. 5, e244 (2007).

    Article  CAS  PubMed Central  Google Scholar 

  126. Barman, M. et al. Enteric salmonellosis disrupts the microbial ecology of the murine gastrointestinal tract. Infect. Immun. 76, 907–915 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. 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 

  129. Ubeda, C. et al. Vancomycin-resistant Enterococcus domination of intestinal microbiota is enabled by antibiotic treatment in mice and precedes bloodstream invasion in humans. J. Clin. Invest. 120, 4332–4341 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. 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 

  131. Biswas, A. et al. Induction and rescue of Nod2-dependent Th1-driven granulomatous inflammation of the ileum. Proc. Natl Acad. Sci. USA 107, 14739–14744 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Nieuwenhuis, E. E. et al. Cd1d-dependent regulation of bacterial colonization in the intestine of mice. J. Clin. Invest. 119, 1241–1250 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  134. Abraham, C. & Cho, J. H. Inflammatory bowel disease. N. Engl. J. Med. 361, 2066–2078 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Wehkamp, J. & Stange, E. F. Paneth's disease. J. Crohn's Colitis 4, 523–531 (2010).

    Article  Google Scholar 

  136. 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 

  137. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Hampe, J. et al. Association of NOD2 (CARD15) genotype with clinical course of Crohn's disease: a cohort study. Lancet 359, 1661–1665 (2002).

    Article  CAS  PubMed  Google Scholar 

  141. Lesage, S. et al. CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease. Am. J. Hum. Genet. 70, 845–857 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Russell, R. K. et al. Genotype-pheotype analysis in childhood-onset Crohn's disease: NOD2/CARD15 variants consistently predict phenotypic characteristics of severe disease. Inflamm. Bowel Dis. 11, 955–964 (2005).

    Article  PubMed  Google Scholar 

  143. Seiderer, J. et al. Homozygosity for the CARD15 frameshift mutation 1007fs is predictive of early onset of Crohn's disease with ileal stenosis, entero-enteral fistulas, and frequent need for surgical intervention with high risk of re-stenosis. Scand. J. Gastroenterol. 41, 1421–1432 (2006).

    Article  CAS  PubMed  Google Scholar 

  144. van Es, J. H. et al. Wnt signaling induces maturation of Paneth cells in intestinal crypts. Nature Cell Biol. 7, 381–386 (2005).

    Article  CAS  PubMed  Google Scholar 

  145. Wehkamp, J. et al. The Paneth cell α-defensin deficiency of ileal Crohn's disease is linked to Wnt/Tcf-4. J. Immunol. 179, 3109–3118 (2007).

    Article  CAS  PubMed  Google Scholar 

  146. Koslowski, M. J. et al. Genetic variants of Wnt transcription factor TCF-4 (TCF7L2) putative promoter region are associated with small intestinal Crohn's disease. PLoS ONE 4, e4496 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Rioux, J. D. et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nature Genet. 39, 596–604 (2007).

    Article  CAS  PubMed  Google Scholar 

  148. Levine, B. & Kroemer, G. Autophagy in the pathogenesis of disease. Cell 132, 27–42 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Cadwell, K. et al. A key role for autophagy and the autophagy gene Atg16L1 in mouse and human intestinal Paneth cells. Nature 456, 259–263 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Simms, L. A. et al. KCNN4 gene variant is associated with ileal Crohn's Disease in the Australian and New Zealand population. Am. J. Gastroenterol. 105, 2209–2217 (2010).

    Article  CAS  PubMed  Google Scholar 

  152. Di, L. et al. Inhibition of the K+ channel KCa3.1 ameliorates T cell–mediated colitis. Proc. Natl Acad. Sci. USA 107, 1541–1546 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Klassen, H. et al. Intestinal, segmented, filamentous bacteria in a wide range of vertebrate species. Lab. Anim. 27, 141–150 (1993).

    Article  Google Scholar 

  155. Yamauchi, K. E. & Snel, J. Transmission electron microscopic demonstration of phagocytosis and intracellual processing of segmented filamentous bacteria by intestinal epithelial cells of the chick ileum. Infect. Immun. 68, 6496–6504 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Stepankova, R. et al. Segmented filamentous bacteria in a defined bacterial cocktail induce intestinal inflammation in SCID mice reconstituted with CD45RBhigh CD4+ T cells. Inflamm. Bowel Dis. 13, 1202–1211 (2007).

    Article  PubMed  Google Scholar 

  157. Wu, H. J. et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32, 815–827 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Lee, Y. K., Menezes, J. S., Umesaki, Y. & Mazmanian, S. K. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 28 Jul 2010 (doi:10.1073/pnas.1000082107).

  159. Paneth, J. Ueber die secernirenden Zellen des Dünndarm-Epithels. Arc. Mikrosk. Anat. 31, 113–191 (1887).

    Article  Google Scholar 

  160. Jones, D. E. & Bevins, C. L. Paneth cells of the human small intestine express an antimicrobial peptide gene. J. Biol. Chem. 267, 23216–23225 (1992).

    CAS  PubMed  Google Scholar 

  161. Mallow, E. B. et al. Human enteric defensins: gene structure and developmental expression. J. Biol. Chem. 271, 4038–4045 (1996).

    Article  CAS  PubMed  Google Scholar 

  162. Bry, L. et al. Paneth cell differentiation in the developing intestine of normal and transgenic mice. Proc. Natl Acad. Sci. USA 91, 10335–10339 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Reilly, D. S., Tomassini, N., Bevins, C. L. & Zasloff, M. A Paneth cell analogue in Xenopus small intestine expresses antimicrobial peptide genes: conservation of an intestinal host-defense system. J. Histochem. Cytochem. 42, 697–704 (1994).

    Article  CAS  PubMed  Google Scholar 

  164. Cunliffe, R. N. et al. Human defensin 5 is stored in precursor form in normal Paneth cells and is expressed by some villous epithelial cells and by metaplastic Paneth cells in the colon in inflammatory bowel disease. Gut 48, 176–185 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Shen, B. et al. Human defensin 5 expression in intestinal metaplasia of the upper gastrointestinal tract. J. Clin. Pathol. 58, 687–694 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Blache, P. et al. SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 genes. J. Cell Biol. 166, 37–47 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Batlle, E. et al. β-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/EphrinB. Cell 111, 251–263 (2002).

    Article  CAS  PubMed  Google Scholar 

  168. Bastide, P. et al. Sox9 regulates cell proliferation and is required for Paneth cell differentiation in the intestinal epithelium. J. Cell Biol. 178, 635–648 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Mori-Akiyama, Y. et al. SOX9 is required for the differentiation of paneth cells in the intestinal epithelium. Gastroenterology 133, 539–546 (2007).

    Article  CAS  PubMed  Google Scholar 

  170. 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 

  171. Shroyer, N. F., Wallis, D., Venken, K. J., Bellen, H. J. & Zoghbi, H. Y. Gfi1 functions downstream of Math1 to control intestinal secretory cell subtype allocation and differentiation. Genes Dev. 19, 2412–2417 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Andreu, P. et al. Crypt-restricted proliferation and commitment to the Paneth cell lineage following Apc loss in the mouse intestine. Development 132, 1443–1451 (2005).

    Article  CAS  PubMed  Google Scholar 

  173. Porter, E., Liu, L., Oren, A., Anton, P. & Ganz, T. Localization of human intestinal defensin 5 in Paneth cell granules. Infect. Immun. 65, 2389–2395 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Salzman, N. H., Underwood, M. A. & Bevins, C. L. Paneth cells, defensins, and the commensal microbiota: a hypothesis on intimate interplay at the intestinal mucosa. Semin. Immunol. 19, 70–83 (2007).

    Article  CAS  PubMed  Google Scholar 

  175. Zheng, W. et al. Evaluation of AGR2 and AGR3 as candidate genes for inflammatory bowel disease. Genes Immun. 7, 11–18 (2006).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors acknowledge the valuable discussions and fruitful collaborations with many investigators in the field that have helped shape the opinions expressed in this Review, including M. A. Zasloff, T. Ganz, A. J. Ouellette, E. M. Porter, L. V. Hooper, B. Shen, A. J. Baumler, J. Wehkamp and E. F. Stange. We apologize for the fact that, because of scope and space restrictions, many interesting investigations could not be included. The authors' work was supported in part by the US National Institutes of Health (grants AI57757, AI32738 and AI50843).

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Glossary

Peyer's patches

Peyer's patches are lymphoid follicles that underlie the small intestinal epithelium, being contained within the intestinal mucosa and submucosa, and that appear as elevated nodules along the surface of the intestinal wall.

Isolated lymphoid follicles

Small aggregates that are formed predominantly of B lymphocytes and are contained within the large and small intestinal mucosae.

Colonocytes

Colonic epithelial cells.

Zymogen

An inactive enzyme precursor (or pro-enzyme).

Pro-inflammatory responses

Host immune responses that cause inflammation, with the release of chemokines and cytokines that result in the attraction and activation of host inflammatory cells.

Hypomorphic

Of a gene mutation: causing reduced gene expression.

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Bevins, C., Salzman, N. Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis. Nat Rev Microbiol 9, 356–368 (2011). https://doi.org/10.1038/nrmicro2546

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