Skip to main content
SpringerLink
Log in

The Immune System in IBD: Antimicrobial Peptides

  • Chapter
  • First Online:
Crohn's Disease and Ulcerative Colitis

Abstract

Antimicrobial peptides are one of the most ancient forms of host defense in nature. Epithelial cells throughout the body express a collection of antimicrobial peptides that have overlapping and complementary activities. In the mammalian intestine, clear and compelling evidence supports that antimicrobial peptides play two fundamental roles: protection from enteric pathogens and shaping the composition of the colonizing microbiota. These functions likely hold relevance to host–microbe interactions that underlie inflammatory bowel disease (IBD) pathogenesis, since prevailing theories on the pathogenesis of IBD invoke a role for detrimental effects of intestinal microbes in the initiation and/or propagation of mucosal inflammation. Specialized epithelial cells of the small intestine named Paneth cells produce and secrete vast quantities of various antimicrobial peptides. The most abundant are the α(alpha)-defensin peptides, human defensin (HD)-5 and HD6, which in turn represent the most abundant antimicrobial peptides found anywhere in human gastrointestinal tract. Other abundant antimicrobials, which are larger in size, but with fundamentally similar physiological roles, are lysozyme, secretory phospholipase A2, and the C-type lectin RegIIIα(alpha). Evidence supports that reduced Paneth cell α(alpha)-defensin expression may be a key factor in the pathogenesis of ileal Crohn’s disease, a major subgroup of IBD. Furthermore, several susceptibility genes for Crohn’s disease appear to manifest their disease-associated activity, in part, through compromise of Paneth cell antimicrobial peptide production. For example, the microbial sensor NOD2, the autophagy-related proteins ATG16L1 and IRGM, the endoplasmic reticulum stress responder XBP1, the calcium dependent potassium channel KCa3.1, the WNT ligand co-receptor LRP6, and the transcription factor TCF7L2 (formerly TCF4) all influence Paneth cell biology and function. While not proven, mounting evidence supports that Paneth cell dysfunction, might substantially contribute to ileal Crohn’s disease pathogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Podolsky DK. Inflammatory bowel disease. N Engl J Med. 2002;347:417–29.

    Article  CAS  PubMed  Google Scholar 

  2. Cho JH. The genetics and immunopathogenesis of inflammatory bowel disease. Nat Rev Immunol. 2008;8(6):458–66.

    Article  CAS  PubMed  Google Scholar 

  3. Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature. 2011;474(7351):307–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Baumgart DC, Sandborn WJ. Crohn’s disease. Lancet. 2012;380(9853):1590–605.

    Article  PubMed  Google Scholar 

  5. Sartor RB. Microbial influences in inflammatory bowel diseases. Gastroenterology. 2008;134(2):577–94.

    Article  CAS  PubMed  Google Scholar 

  6. Nell S, Suerbaum S, Josenhans C. The impact of the microbiota on the pathogenesis of IBD: lessons from mouse infection models. Nat Rev Microbiol. 2010;8(8):564–77.

    Article  CAS  PubMed  Google Scholar 

  7. Sokol H, Seksik P. The intestinal microbiota in inflammatory bowel diseases: time to connect with the host. Curr Opin Gastroenterol. 2010;26(4):327–31.

    Article  PubMed  Google Scholar 

  8. Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease. Annu Rev Immunol. 2010;28:573–621.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491(7422):119–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Packey CD, Sartor RB. Commensal bacteria, traditional and opportunistic pathogens, dysbiosis and bacterial killing in inflammatory bowel diseases. Curr Opin Infect Dis. 2009;22(3):292–301.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Manichanh C, Borruel N, Casellas F, Guarner F. The gut microbiota in IBD. Nat Rev Gastroenterol Hepatol. 2012;9(10):599–608.

    Article  CAS  PubMed  Google Scholar 

  12. Bevins CL, Salzman NH. The potter’s wheel: the host’s role in sculpting its microbiota. Cell Mol Life Sci. 2011;68(22): 3675–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zasloff M. Antimicrobial peptides of multicellular organisms. Nature. 2002;415:389–95.

    Article  CAS  PubMed  Google Scholar 

  14. Reyes A, Haynes M, Hanson N, et al. Viruses in the faecal microbiota of monozygotic twins and their mothers. Nature. 2010;466(7304):334–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R. Diversity, stability and resilience of the human gut microbiota. Nature. 2012;489(7415):220–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Consortium THMP. Structure, function and diversity of the healthy human microbiome. Nature. 2012;486(7402):207–14.

    Article  CAS  Google Scholar 

  17. O'Hara AM, Shanahan F. The gut flora as a forgotten organ. EMBO Rep. 2006;7(7):688–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Tremaroli V, Backhed F. Functional interactions between the gut microbiota and host metabolism. Nature. 2012;489(7415):242–9.

    Article  CAS  PubMed  Google Scholar 

  19. Sekirov I, Finlay BB. The role of the intestinal microbiota in enteric infection. J Physiol. 2009;587(Pt 17):4159–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol. 2009;9(5):313–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hooper LV, Macpherson AJ. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat Rev Immunol. 2010;10(3):159–69.

    Article  CAS  PubMed  Google Scholar 

  22. Sommer F, Backhed F. The gut microbiota—masters of host development and physiology. Nat Rev Microbiol. 2013;11(4): 227–38.

    Article  CAS  PubMed  Google Scholar 

  23. Mowat AM, Agace WW. Regional specialization within the intestinal immune system. Nat Rev Immunol. 2014;14(10):667–85.

    Article  CAS  PubMed  Google Scholar 

  24. Mukherjee S, Hooper LV. Antimicrobial defense of the intestine. Immunity. 2015;42(1):28–39.

    Article  CAS  PubMed  Google Scholar 

  25. Wehkamp J, Fellermann K, Herrlinger K, Bevins CL, Stange EF. Defensins in gastrointestinal diseases. Nat Clin Pract (Gastroenterol Hepatol). 2005;2:406–15.

    Article  CAS  Google Scholar 

  26. Bevins CL, Salzman NH. Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis. Nat Rev Microbiol. 2011;9(5):356–68.

    Article  CAS  PubMed  Google Scholar 

  27. Kostic AD, Xavier RJ, Gevers D. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology. 2014;146(6):1489–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Chacon O, Bermudez LE, Barletta RG. Johne’s disease, inflammatory bowel disease, and Mycobacterium paratuberculosis. Annu Rev Microbiol. 2004;58:329–63.

    Article  CAS  PubMed  Google Scholar 

  29. Frank DN, St Amand AL, Feldman RA, Boedeker EC, Harpaz N, Pace NR. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci U S A. 2007;104(34):13780–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Winter SE, Baumler AJ. Dysbiosis in the inflamed intestine: chance favors the prepared microbe. Gut Microbes. 2014;5(1):71–3.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Darfeuille-Michaud A, Boudeau J, Bulois P, et al. High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn’s disease. Gastroenterology. 2004;127(2):412–21.

    Article  PubMed  Google Scholar 

  32. Swidsinski A, Weber J, Loening-Baucke V, Hale LP, Lochs H. Spatial organization and composition of the mucosal flora in patients with inflammatory bowel disease. J Clin Microbiol. 2005;43(7):3380–9.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Baumgart M, Dogan B, Rishniw M, et al. Culture independent analysis of ileal mucosa reveals a selective increase in invasive Escherichia coli of novel phylogeny relative to depletion of Clostridiales in Crohn’s disease involving the ileum. ISME J. 2007;1(5):403–18.

    Article  CAS  PubMed  Google Scholar 

  34. Sokol H, Pigneur B, Watterlot L, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A. 2008;105(43):16731–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kim SC, Tonkonogy SL, Albright CA, et al. Variable phenotypes of enterocolitis in interleukin 10-deficient mice monoassociated with two different commensal bacteria. Gastroenterology. 2005;128(4):891–906.

    Article  CAS  PubMed  Google Scholar 

  36. Elson CO, Cong Y, McCracken VJ, Dimmitt RA, Lorenz RG, Weaver CT. Experimental models of inflammatory bowel disease reveal innate, adaptive, and regulatory mechanisms of host dialogue with the microbiota. Immunol Rev. 2005;206:260–76.

    Article  PubMed  Google Scholar 

  37. Lupp C, Robertson ML, Wickham ME, et al. Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae. Cell Host Microbe. 2007;2(2):119–29.

    Article  CAS  PubMed  Google Scholar 

  38. Biswas A, Liu YJ, Hao L, et al. Induction and rescue of Nod2-dependent Th1-driven granulomatous inflammation of the ileum. Proc Natl Acad Sci U S A. 2010;107(33):14739–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Garrett WS, Gallini CA, Yatsunenko T, et al. Enterobacteriaceae act in concert with the gut microbiota to induce spontaneous and maternally transmitted colitis. Cell Host Microbe. 2010;8(3):292–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Schaubeck M, Clavel T, Calasan J, et al. Dysbiotic gut microbiota causes transmissible Crohn’s disease-like ileitis independent of failure in antimicrobial defence. Gut. 2016;65(2):225–37.

    Article  CAS  PubMed  Google Scholar 

  41. Hoffmann TW, Pham HP, Bridonneau C, et al. Microorganisms linked to inflammatory bowel disease-associated dysbiosis differentially impact host physiology in gnotobiotic mice. ISME J. 2016;10(2):460–77.

    Article  CAS  PubMed  Google Scholar 

  42. Dominguez-Bello MG, Costello EK, Contreras M, et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A. 2010;107(26):11971–5.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Funkhouser LJ, Bordenstein SR. Mom knows best: the universality of maternal microbial transmission. PLoS Biol. 2013;11(8):e1001631.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ley RE, Backhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI. Obesity alters gut microbial ecology. Proc Natl Acad Sci U S A. 2005;102:11070–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Turnbaugh PJ, Backhed F, Fulton L, Gordon JI. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe. 2008;3(4):213–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. David LA, Maurice CF, Carmody RN, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505(7484):559–63.

    Article  CAS  PubMed  Google Scholar 

  47. Willing BP, Russell SL, Finlay BB. Shifting the balance: antibiotic effects on host-microbiota mutualism. Nat Rev Microbiol. 2011;9(4):233–43.

    Article  CAS  PubMed  Google Scholar 

  48. Spor A, Koren O, Ley R. Unravelling the effects of the environment and host genotype on the gut microbiome. Nat Rev Microbiol. 2011;9(4):279–90.

    Article  CAS  PubMed  Google Scholar 

  49. Jacobs JP, Braun J. Immune and genetic gardening of the intestinal microbiome. FEBS Lett. 2014;588(22):4102–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Rawls JF, Mahowald MA, Ley RE, Gordon JI. Reciprocal gut microbiota transplants from zebrafish and mice to germ-free recipients reveal host habitat selection. Cell. 2006;127(2):423–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ochman H, Worobey M, Kuo CH, et al. Evolutionary relationships of wild hominids recapitulated by gut microbial communities. PLoS Biol. 2010;8(11):e1000546.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Bosch TC. Cnidarian-microbe interactions and the origin of innate immunity in metazoans. Annu Rev Microbiol. 2013;67:499–518.

    Article  CAS  PubMed  Google Scholar 

  53. Charroux B, Royet J. Drosophila immune response From systemic antimicrobial peptide production in fat body cells to local defense in the intestinal tract. Fly. 2010;4(1):40–7.

    Article  CAS  PubMed  Google Scholar 

  54. Cerutti A, Rescigno M. The biology of intestinal immunoglobulin A responses. Immunity. 2008;28(6):740–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Suzuki K, Meek B, Doi Y, et al. Aberrant expansion of segmented filamentous bacteria in IgA-deficient gut. Proc Natl Acad Sci U S A. 2004;101:1981–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Peterson DA, McNulty NP, Guruge JL, Gordon JI. IgA response to symbiotic bacteria as a mediator of gut homeostasis. Cell Host Microbe. 2007;2(5):328–39.

    Article  CAS  PubMed  Google Scholar 

  57. Hapfelmeier S, Lawson MAE, Slack E, et al. Reversible microbial colonization of germ-free mice reveals the dynamics of IgA immune responses. Science. 2010;328(5986):1705–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Wei M, Shinkura R, Doi Y, Maruya M, Fagarasan S, Honjo T. Mice carrying a knock-in mutation of Aicda resulting in a defect in somatic hypermutation have impaired gut homeostasis and compromised mucosal defense. Nat Immunol. 2011;12(3):264-U102.

    Article  CAS  Google Scholar 

  59. Kawamoto S, Tran TH, Maruya M, et al. The inhibitory receptor PD-1 regulates IgA selection and bacterial composition in the gut. Science. 2012;336(6080):485–9.

    Article  CAS  PubMed  Google Scholar 

  60. Mirpuri J, Raetz M, Sturge CR, et al. Proteobacteria-specific IgA regulates maturation of the intestinal microbiota. Gut Microbes. 2014;5(1):28–39.

    Article  PubMed  Google Scholar 

  61. Kawamoto S, Maruya M, Kato LM, et al. Foxp3(+) T cells regulate immunoglobulin a selection and facilitate diversification of bacterial species responsible for immune homeostasis. Immunity. 2014;41(1):152–65.

    Article  CAS  PubMed  Google Scholar 

  62. Kau AL, Planer JD, Liu J, et al. Functional characterization of IgA-targeted bacterial taxa from undernourished Malawian children that produce diet-dependent enteropathy. Sci Transl Med. 2015;7(276):276ra224.

    Article  CAS  Google Scholar 

  63. Moon C, Baldridge MT, Wallace MA, Burnham CA, Virgin HW, Stappenbeck TS. Vertically transmitted faecal IgA levels determine extra-chromosomal phenotypic variation. Nature. 2015;521(7550):90–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Salzman NH, Hung K, Haribhai D, et al. Enteric defensins are essential regulators of intestinal microbial ecology. Nat Immunol. 2010;11(1):76–83.

    Article  CAS  PubMed  Google Scholar 

  65. Stecher B, Robbiani R, Walker AW, et al. Salmonella enterica serovar typhimurium exploits inflammation to compete with the intestinal microbiota. PLoS Biol. 2007;5(10):2177–89.

    Article  CAS  PubMed  Google Scholar 

  66. Winter SE, Thiennimitr P, Winter MG, et al. Gut inflammation provides a respiratory electron acceptor for Salmonella. Nature. 2010;467(7314):426–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Fischbach MA, Lin HN, Zhou L, et al. The pathogen-associated iroA gene cluster mediates bacterial evasion of lipocalin 2. Proc Natl Acad Sci U S A. 2006;103(44):16502–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Raffatellu M, George MD, Akiyama Y, et al. Lipocalin-2 resistance confers an advantage to Salmonella enterica serotype Typhimurium for growth and survival in the inflamed intestine. Cell Host Microbe. 2009;5(5):476–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Hornsby MJ, Huff JL, Kays RJ, Canfield DR, Bevins CL, Solnick JV. Helicobacter pylori induces an antimicrobial response in rhesus macaques in a cag pathogenicity island-dependent manner. Gastroenterology. 2008;134(4):1049–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Franzenburg S, Walter J, Kunzel S, et al. Distinct antimicrobial peptide expression determines host species-specific bacterial associations. Proc Natl Acad Sci U S A. 2013;110(39):E3730–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Ganz T. Defensins: antimicrobial peptides of innate immunity. Nat Rev Immunol. 2003;3(9):710–20.

    Article  CAS  PubMed  Google Scholar 

  72. Lehrer RI. Primate defensins. Nat Rev Microbiol. 2004;2:727–38.

    Article  CAS  PubMed  Google Scholar 

  73. Selsted ME, Ouellette AJ. Mammalian defensins in the antimicrobial immune response. Nat Immunol. 2005;6:551–7.

    Article  CAS  PubMed  Google Scholar 

  74. Lehrer RI, Lu W. Alpha-defensins in human innate immunity. Immunol Rev. 2012;245(1):84–112.

    Article  CAS  PubMed  Google Scholar 

  75. Bevins CL. Innate immune functions of alpha-defensins in the small intestine. Dig Dis. 2013;31(3–4):299–304.

    Article  PubMed  Google Scholar 

  76. Wilson CL, Ouellette AJ, Satchell DP, et al. Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense. Science. 1999;286(5437):113–7.

    Article  CAS  PubMed  Google Scholar 

  77. Salzman NH, Ghosh D, Huttner KM, Paterson Y, Bevins CL. Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin. Nature. 2003;422(6931):522–6.

    Article  CAS  PubMed  Google Scholar 

  78. Chu H, Pazgier M, Jung G, et al. Human alpha-defensin 6 promotes mucosal innate immunity through self-assembled peptide nanonets. Science. 2012;337(6093):477–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Lynn DJ, Lloyd AT, Fares MA, O'Farrelly C. Evidence of positively selected sites in mammalian alpha-defensins. Mol Biol Evol. 2004;21:819–27.

    Article  CAS  PubMed  Google Scholar 

  80. Ghosh D, Porter E, Shen B, et al. Paneth cell trypsin is the processing enzyme for human defensin-5. Nat Immunol. 2002;3(6):583–90.

    Article  CAS  PubMed  Google Scholar 

  81. Lehrer RI, Lichtenstein AK, Ganz T. Defensins: antimicrobial and cytotoxic peptides of mammalian cells. Annu Rev Immunol. 1993;11:105–28.

    Article  CAS  PubMed  Google Scholar 

  82. de Leeuw E, Li C, Zeng P, et al. Functional interaction of human neutrophil peptide-1 with the cell wall precursor lipid II. FEBS Lett. 2010;584(8):1543–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Sass V, Schneider T, Wilmes M, et al. Human beta-defensin 3 inhibits cell wall biosynthesis in Staphylococci. Infect Immun. 2010;78(6):2793–800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Schneider T, Kruse T, Wimmer R, et al. Plectasin, a fungal defensin, targets the bacterial cell wall precursor Lipid II. Science. 2010;328(5982):1168–72.

    Article  CAS  PubMed  Google Scholar 

  85. Ericksen B, Wu Z, Lu W, Lehrer RI. Antibacterial activity and specificity of the six human {alpha}-defensins. Antimicrob Agents Chemother. 2005;49(1):269–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Schroeder BO, Ehmann D, Precht JC, et al. Paneth cell alpha-defensin 6 (HD-6) is an antimicrobial peptide. Mucosal Immunol. 2015;8(3):661–71.

    Article  CAS  PubMed  Google Scholar 

  87. Chairatana P, Nolan EM. Molecular basis for self-assembly of a human host-defense peptide that entraps bacterial pathogens. J Am Chem Soc. 2014;136:13267–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Yang D, Chertov O, Bykovskaia SN, et al. Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science. 1999;286:525–8.

    Article  CAS  PubMed  Google Scholar 

  89. Yang D, Biragyn A, Kwak LW, Oppenheim JJ. Mammalian defensins in immunity: more than just microbicidal. Trends Immunol. 2002;23:291–6.

    Article  CAS  PubMed  Google Scholar 

  90. Lehrer RI, Jung G, Ruchala P, Andre S, Gabius HJ, Lu W. Multivalent binding of carbohydrates by the human {alpha}-defensin, HD5. J Immunol. 2009;183(1):480–90.

    Article  CAS  PubMed  Google Scholar 

  91. Lencer WI, Cheung G, Strohmeier GR, et al. Induction of epithelial chloride secretion by channel-forming cryptins 2 and 3. Proc Natl Acad Sci U S A. 1997;94:8585–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Yue G, Merlin D, Selsted ME, Lencer WI, Madara JL, Eaton DC. Cryptdin 3 forms anion selective channels in cytoplasmic membranes of human embryonic kidney cells. Am J Physiol Gastrointest Liver Physiol. 2002;282:G757–65.

    Article  CAS  PubMed  Google Scholar 

  93. Ganz T, Gabayan V, Liao HI, et al. Increased inflammation in lysozyme M-deficient mice in response to Micrococcus luteus and its peptidoglycan. Blood. 2003;101:2388–92.

    Article  CAS  PubMed  Google Scholar 

  94. Lambeau G, Gelb MH. Biochemistry and physiology of mammalian secreted phospholipases A(2). Annu Rev Biochem. 2008;77:495–520.

    Article  CAS  PubMed  Google Scholar 

  95. Murakami M, Taketomi Y, Girard C, Yamamoto K, Lambeau G. Emerging roles of secreted phospholipase A(2) enzymes: lessons from transgenic and knockout mice. Biochimie. 2010;92(6):561–82.

    Article  CAS  PubMed  Google Scholar 

  96. Qu XD, Lloyd KC, Walsh JH, Lehrer RI. Secretion of type II phospholipase A2 and cryptdin by rat small intestinal Paneth cells. Infect Immun. 1996;64:5161–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Nevalainen TJ, Graham GG, Scott KF. Antibacterial actions of secreted phospholipases A(2). Review. Biochim Biophys Acta. 2008;1781(1–2):1–9.

    Article  CAS  PubMed  Google Scholar 

  98. Harwig SSL, Tan L, Qu X-D, Cho Y, Eisenhauer PB, Lehrer RI. Bactericidal properties of murine intestinal phospholipase A2. J Clin Invest. 1995;95:603–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. MacPhee M, Chepenik KP, Liddell RA, Nelson KK, Siracusa LD, Buchberg AM. The secretory phospholipase A2 gene is a candidate for the Mom1 locus, a major modifier of ApcMin-induced intestinal neoplasia. Cell. 1995;81:957–66.

    Article  CAS  PubMed  Google Scholar 

  100. Cormier RT, Hong KH, Halberg RB, et al. Secretory phospholipase Pla2g2a confers resistance to intestinal tumorigenesis. Nat Genet. 1997;17(1):88–91.

    Article  CAS  PubMed  Google Scholar 

  101. Fijneman RJA, Cormier RT. The roles of sPLA2-IIA (Pla2g2a) in cancer of the small and large intestine. Front Biosci. 2008;13:4144–74.

    Article  CAS  PubMed  Google Scholar 

  102. Cash HL, Whitham CV, Behrendt CL, Hooper LV. Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science. 2006;313:1126–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Mukherjee S, Partch CL, Lehotzky RE, et al. Regulation of C-type lectin antimicrobial activity by a flexible N-terminal prosegment. J Biol Chem. 2009;284(8):4881–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Brandl K, Plitas G, Schnabl B, DeMatteo RP, Pamer EG. MyD88-mediated signals induce the bactericidal lectin RegIII gamma and protect mice against intestinal Listeria monocytogenes infection. J Exp Med. 2007;204(8):1891–900.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Mukherjee S, Zheng H, Derebe MG, et al. Antibacterial membrane attack by a pore-forming intestinal C-type lectin. Nature. 2014;505(7481):103–7.

    Article  PubMed  CAS  Google Scholar 

  106. Christa L, Carnot F, Simon MT, et al. HIP/PAP is an adhesive protein expressed in hepatocarcinoma, normal Paneth, and pancreatic cells. Am J Physiol. 1996;271(6 Pt 1):993–1002.

    Google Scholar 

  107. Wehkamp J, Salzman NH, Porter E, et al. Reduced Paneth cell alpha-defensins in ileal Crohn’s disease. Proc Natl Acad Sci U S A. 2005;102(50):18129–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Komiya T, Tanigawa Y, Hirohashi S. Cloning of the novel gene intelectin, which is expressed in intestinal paneth cells in mice. Biochem Biophys Res Commun. 1998;251:759–62.

    Article  CAS  PubMed  Google Scholar 

  109. Wesener DA, Wangkanont K, McBride R, et al. Recognition of microbial glycans by human intelectin-1. Nat Struct Mol Biol. 2015;22(8):603–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Barrett JC, Hansoul S, Nicolae DL, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet. 2008;40(8):955–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Ganz T. Iron in innate immunity: starve the invaders. Curr Opin Immunol. 2009;21(1):63–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Flo TH, Smith KD, Sato S, et al. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature. 2004;432:917–21.

    Article  CAS  PubMed  Google Scholar 

  113. Sunil VR, Patel KJ, Nilsen-Hamilton M, Heck DE, Laskin JD, Laskin DL. Acute endotoxemia is associated with upregulation of lipocalin 24p3/Lcn2 in lung and liver. Exp Mol Pathol. 2007;83(2):177–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Huttner KM, Ouellette AJ. A family of defensin-like genes codes for diverse cysteine-rich peptides in mouse Paneth cells. Genomics. 1994;24:99–109.

    Article  CAS  PubMed  Google Scholar 

  115. Hornef MF, Pütsep K, Karlsson J, Refai E, Andersson M. Increased variability of intestinal antimicrobial peptides by covalent dimer formation. Nat Immunol. 2004;5:836–43.

    Article  CAS  PubMed  Google Scholar 

  116. Shanahan MT, Vidrich A, Shirafuji Y, et al. Elevated expression of Paneth cell CRS4C in ileitis-prone SAMP1/YitFc mice: regional distribution, subcellular localization, and mechanism of action. J Biol Chem. 2010;285(10):7493–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Hooper LV, Stappenbeck TS, Hong CV, Gordon JI. Angiogenins: a new class of microbicidal proteins involved in innate immunity. Nat Immunol. 2003;4:269–73.

    Article  CAS  PubMed  Google Scholar 

  118. Harder J, Schroder J-M. RNase 7, a novel innate immune defense antimicrobial protein of healthy human skin. J Biol Chem. 2002;277(48):46779–84.

    Article  CAS  PubMed  Google Scholar 

  119. Czaran TL, Hoekstra RF, Pagie L. Chemical warfare between microbes promotes biodiversity. Proc Natl Acad Sci U S A. 2002;99(2):786–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Duquesne S, Destoumieux-Garzon D, Peduzzi J, Rebuffat S. Microcins, gene-encoded antibacterial peptides from enterobacteria. Nat Prod Rep. 2007;24(4):708–34.

    Article  CAS  PubMed  Google Scholar 

  121. Gillor O, Etzion A, Riley MA. The dual role of bacteriocins as anti- and probiotics. Appl Microbiol Biotechnol. 2008;81(4):591–606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Dobson A, Cotter PD, Ross RP, Hill C. Bacteriocin production: a probiotic trait? Appl Environ Microbiol. 2012;78(1):1–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Nishie M, Nagao J, Sonomoto K. Antibacterial peptides “bacteriocins”: an overview of their diverse characteristics and applications. Biocontrol Sci. 2012;17(1):1–16.

    Article  CAS  PubMed  Google Scholar 

  124. Porter EM, Bevins CL, Ghosh D, Ganz T. The multifaceted Paneth cell. Cell Mol Life Sci. 2002;59(1):156–70.

    Article  CAS  PubMed  Google Scholar 

  125. Ouellette AJ. Paneth cells and innate mucosal immunity. Curr Opin Gastroenterol. 2010;26(6):547–53.

    Article  PubMed  Google Scholar 

  126. Clevers HC, Bevins CL. Paneth cells: maestros of the small intestinal crypts. Annu Rev Physiol. 2013;75:289–311.

    Article  CAS  PubMed  Google Scholar 

  127. Watson CL, Mahe MM, Munera J, et al. An in vivo model of human small intestine using pluripotent stem cells. Nat Med. 2014;20(11):1310–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Wilson SS, Tocchi A, Holly MK, Parks WC, Smith JG. A small intestinal organoid model of non-invasive enteric pathogen-epithelial cell interactions. Mucosal Immunol. 2015;8(2):352–61.

    Article  CAS  PubMed  Google Scholar 

  129. Vaishnava S, Behrendt CL, Ismail AS, Eckmann L, Hooper LV. Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc Natl Acad Sci U S A. 2008;105(52):20858–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Zhang Q, Pan Y, Yan R, et al. Commensal bacteria direct selective cargo sorting to promote symbiosis. Nat Immunol. 2015;16:918–26.

    Article  CAS  PubMed  Google Scholar 

  131. Mastroianni JR, Ouellette AJ. Alpha-defensins in enteric innate immunity: functional Paneth cell alpha-defensins in mouse colonic lumen. J Biol Chem. 2009;284(41):27848–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Nieuwenhuis EE, Matsumoto T, Lindenbergh D, et al. Cd1d-dependent regulation of bacterial colonization in the intestine of mice. J Clin Invest. 2009;119(5):1241–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Kobayashi KS, Chamaillard M, Ogura Y, et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science. 2005;307(5710):731–4.

    Article  CAS  PubMed  Google Scholar 

  134. George MD, Wehkamp J, Kays RJ, et al. In vivo gene expression profiling of human intestinal epithelial cells: analysis by laser microdissection of formalin fixed tissues. BMC Genomics. 2008;9:209.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Wolfs TG, Derikx JP, Hodin CM, et al. Localization of the lipopolysaccharide recognition complex in the human healthy and inflamed premature and adult gut. Inflamm Bowel Dis. 2010;16(1):68–75.

    Article  PubMed  Google Scholar 

  136. Untersmayr E, Bises G, Starkl P, et al. The high affinity IgE receptor Fc epsilonRI is expressed by human intestinal epithelial cells. PLoS One. 2010;5(2):e9023.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Sato T, van Es JH, Snippert HJ, et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature. 2011;469(7330):415–8.

    Article  CAS  PubMed  Google Scholar 

  138. Shanahan MT, Carroll IM, Gulati AS. Critical design aspects involved in the study of Paneth cells and the intestinal microbiota. Gut Microbes. 2014;5(2):208–14.

    Article  PubMed  Google Scholar 

  139. Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med. 2009;361(21):2066–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Wehkamp J, Stange EF. Paneth’s disease. J Crohns Colitis. 2010;4(5):523–31.

    Article  PubMed  Google Scholar 

  141. Thachil E, Hugot JP, Arbeille B, et al. Abnormal activation of autophagy-induced crinophagy in Paneth cells from patients with Crohn’s disease. Gastroenterology. 2012;142(5):1097–9. e1094.

    Article  PubMed  Google Scholar 

  142. Liu TC, Gao F, McGovern DP, Stappenbeck TS. Spatial and temporal stability of paneth cell phenotypes in Crohn’s disease: implications for prognostic cellular biomarker development. Inflamm Bowel Dis. 2014;20(4):646–51.

    Article  PubMed  PubMed Central  Google Scholar 

  143. VanDussen KL, Liu TC, Li D, et al. Genetic variants synthesize to produce paneth cell phenotypes that define subtypes of Crohn’s disease. Gastroenterology. 2014;146(1):200–9.

    Article  CAS  PubMed  Google Scholar 

  144. Adolph TE, Tomczak MF, Niederreiter L, et al. Paneth cells as a site of origin for intestinal inflammation. Nature. 2013;503(7475):272–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Simms LA, Doecke JD, Roberts RL, et al. KCNN4 gene variant is associated with ileal Crohn’s Disease in the Australian and New Zealand population. Am J Gastroenterol. 2010;105(10):2209–17.

    Article  CAS  PubMed  Google Scholar 

  146. Hugot JP, Chamaillard M, Zouali H, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature. 2001;411:599–603.

    Article  CAS  PubMed  Google Scholar 

  147. Ogura Y, Bonen DK, Inohara N, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature. 2001;411:603–6.

    Article  CAS  PubMed  Google Scholar 

  148. Rioux JD, Xavier RJ, Taylor KD, et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet. 2007;39(5):596–604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Kaser A, Lee AH, Franke A, et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell. 2008;134(5):743–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Brest P, Lapaquette P, Souidi M, et al. A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn’s disease. Nat Genet. 2011;43(3):242–5.

    Article  CAS  PubMed  Google Scholar 

  151. Koslowski MJ, Kubler I, Chamaillard M, et al. Genetic variants of Wnt transcription factor TCF-4 (TCF7L2) putative promoter region are associated with small intestinal Crohn’s disease. PLoS One. 2009;4(2):e4496.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Koslowski MJ, Teltschik Z, Beisner J, et al. Association of a functional variant in the Wnt co-receptor LRP6 with early onset ileal Crohn’s disease. PLoS Genet. 2012;8(2):e1002523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Wehkamp J, Harder J, Weichenthal M, et al. NOD2 (CARD15) mutations in Crohn’s disease are associated with diminished mucosal alpha-defensin expression. Gut. 2004;53(11):1658–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Russell RK, Drummond HE, Nimmo EE, et al. Genotype-phenotype analysis in childhood-onset Crohn’s disease: NOD2/CARDI 5 variants consistently predict phenotypic characteristics of severe disease. Inflamm Bowel Dis. 2005;11(11):955–64.

    Article  PubMed  Google Scholar 

  155. Seiderer J, Schnitzler F, Brand S, 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. 2006;41(12): 1421–32.

    Article  CAS  PubMed  Google Scholar 

  156. Wehkamp J, Wang G, Kubler I, et al. The Paneth cell {alpha}-defensin deficiency of ileal Crohn’s disease is linked to Wnt/Tcf-4. J Immunol. 2007;179(5):3109–18.

    Article  CAS  PubMed  Google Scholar 

  157. van Es JH, Jay P, Gregorieff A, et al. Wnt signalling induces maturation of Paneth cells in intestinal crypts. Nat Cell Biol. 2005;7(4):381–6.

    Article  PubMed  CAS  Google Scholar 

  158. Simms LA, Doecke JD, Walsh MD, Huang N, Fowler EV, Radford-Smith GL. Reduced alpha-defensin expression is associated with inflammation and not NOD2 mutation status in ileal Crohn’s disease. Gut. 2008;57:903–10.

    Article  CAS  PubMed  Google Scholar 

  159. Bevins CL, Stange EF, Wehkamp J. Decreased Paneth cell defensin expression in ileal Crohn’s disease is independent of inflammation, but linked to the NOD2 1007fs genotype. Gut. 2009;58(6):882–3. discussion 883–4.

    CAS  PubMed  Google Scholar 

  160. Ogura Y, Lala S, Xin W, et al. Expression of NOD2 in Paneth cells: a possible link to Crohn’s ileitis. Gut. 2003;52: 1591–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Shanahan MT, Carroll IM, Grossniklaus E, et al. Mouse Paneth cell antimicrobial function is independent of Nod2. Gut. 2014;63(6):903–10.

    Article  CAS  PubMed  Google Scholar 

  162. Petnicki-Ocwieja T, Hrncir T, Liu YJ, et al. Nod2 is required for the regulation of commensal microbiota in the intestine. Proc Natl Acad Sci U S A. 2009;106(37):15813–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008;132(1):27–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Ravikumar B, Sarkar S, Davies JE, et al. Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev. 2010;90(4):1383–435.

    Article  CAS  PubMed  Google Scholar 

  165. Cadwell K, Liu JY, Brown SL, et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature. 2008;456(7219):259–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Conway KL, Kuballa P, Song JH, et al. Atg16l1 is required for autophagy in intestinal epithelial cells and protection of mice from Salmonella infection. Gastroenterology. 2013;145(6):1347–57.

    Article  CAS  PubMed  Google Scholar 

  167. Lassen KG, Kuballa P, Conway KL, et al. Atg16L1 T300A variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense. Proc Natl Acad Sci U S A. 2014;111(21):7741–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Deuring JJ, Fuhler GM, Konstantinov SR, et al. Genomic ATG16L1 risk allele-restricted Paneth cell ER stress in quiescent Crohn’s disease. Gut. 2014;63(7):1081–91.

    Article  CAS  PubMed  Google Scholar 

  169. Frank DN, Robertson CE, Hamm CM, et al. Disease phenotype and genotype are associated with shifts in intestinal-associated microbiota in inflammatory bowel diseases. Inflamm Bowel Dis. 2010;17(1):179–84.

    Article  PubMed  Google Scholar 

  170. Cadwell K, Patel KK, Maloney NS, et al. Virus-plus-susceptibility gene interaction determines Crohn’s disease gene Atg16L1 phenotypes in intestine. Cell. 2010;141(7):1135–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Kangro HO, Chong SKF, Hardiman A, Heath RB, Walkersmith JA. A prospective-study of viral and mycoplasma-infections in chronic inflammatory bowel-disease. Gastroenterology. 1990; 98(3):549–53.

    Article  CAS  PubMed  Google Scholar 

  172. Parkes M, Barrett JC, Prescott NJ, et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn’s disease susceptibility. Nat Genet. 2007;39(7):830–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. McCarroll SA, Huett A, Kuballa P, et al. Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn’s disease. Nat Genet. 2008;40(9):1107–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Liu B, Gulati AS, Cantillana V, et al. Irgm1-deficient mice exhibit Paneth cell abnormalities and increased susceptibility to acute intestinal inflammation. Am J Physiol Gastrointest Liver Physiol. 2013;305(8):G573–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Gregoire IP, Richetta C, Meyniel-Schicklin L, et al. IRGM is a common target of RNA viruses that subvert the autophagy network. PLoS Pathog. 2011;7(12):e1002422.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Hosomi S, Kaser A, Blumberg RS. Role of endoplasmic reticulum stress and autophagy as interlinking pathways in the pathogenesis of inflammatory bowel disease. Curr Opin Gastroenterol. 2015;31(1):81–8.

    Article  PubMed  PubMed Central  Google Scholar 

  177. Ayabe T, Wulff H, Darmoul D, Cahalan MD, Chandy KG, Ouellette AJ. Modulation of mouse Paneth cell alpha-defensin secretion by mIKCa1, a Ca2+-activated, intermediate conductance potassium channel. J Biol Chem. 2002;277:3793–800.

    Article  CAS  PubMed  Google Scholar 

  178. He X, Semenov M, Tamai K, Zeng X. LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way. Development. 2004;131(8):1663–77.

    Article  CAS  PubMed  Google Scholar 

  179. Salzman NH, Bevins CL. Dysbiosis—a consequence of Paneth cell dysfunction. Semin Immunol. 2013;25(5):334–41.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology, University of California Davis School of Medicine, Davis, CA, 95616, USA

    Charles L. Bevins M.D., Ph.D.

Authors
  1. Charles L. Bevins M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Charles L. Bevins M.D., Ph.D. .

Editor information

Editors and Affiliations

  1. Inflammatory Bowel Disease Center, Department of Gastroenterology and Hepatology, Charité Medical School—Humboldt-University of Berlin, Berlin, Germany

    Daniel C. Baumgart

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Bevins, C.L. (2017). The Immune System in IBD: Antimicrobial Peptides. In: Baumgart, D. (eds) Crohn's Disease and Ulcerative Colitis. Springer, Cham. https://doi.org/10.1007/978-3-319-33703-6_5

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-33703-6_5

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-33701-2

  • Online ISBN: 978-3-319-33703-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation