Abstract
Background
The intestinal barrier is a delicate structure composed of a single layer of epithelial cells, the mucus, commensal bacteria, immune cells, and antibodies. Furthermore, a wealth of antimicrobial peptides (AMPs) can be found in the mucus and defend the mucosa. Different lines of investigations now point to a prominent pathophysiological role of defensins, an important family of AMPs, in the pathogenesis of inflammatory bowel disease and, particularly, in small intestinal Crohn’s disease.
Purpose
In this review, we introduce the different antimicrobial peptides of the intestinal mucosa and describe their function, their expression pattern along the gastrointestinal tract, and their spatial relationship to the mucus layer. We then focus on the alterations found in inflammatory bowel disease. Small intestinal Crohn’s disease (CD) is closely linked to defects in Paneth cells (specialized secretory epithelial cells at the bottom crypts) which secrete α-defensin human defensin (HD)-5 in huge quantities in healthy individuals. Decreased expression of these antimicrobial peptides is found in ileal CD, and single nucleotide polymorphisms with the highest linkage to CD affect genes involved in Paneth cell biology and defensin secretion. Additionally, antimicrobial peptides have a role in ulcerative colitis, where the depleted mucus layer cannot fulfill its crucial function of binding defensins and other AMPs to their proper site of action.
Conclusion
Inflammatory bowel disease arises when the mucosal barrier is compromised in its defense against challenges from the intestinal microbiota. In ileal CD, a strong association can be found between diminished expression or defective function of defensins and the advent of intestinal inflammation.
Similar content being viewed by others
References
Guindi M, Riddell RH (2004) Indeterminate colitis. J Clin Pathol 57(12):1233–1244
Tollin M, Bergman P, Svenberg T, Jornvall H, Gudmundsson GH, Agerberth B (2003) Antimicrobial peptides in the first line defence of human colon mucosa. Peptides 24(4):523–530
Wehkamp J, Fellermann K, Herrlinger KR et al (2002) Human beta-defensin 2 but not beta-defensin 1 is expressed preferentially in colonic mucosa of inflammatory bowel disease. Eur J Gastroenterol Hepatol 14(7):745–752
Wehkamp J, Chu H, Shen B et al (2006) Paneth cell antimicrobial peptides: topographical distribution and quantification in human gastrointestinal tissues. FEBS Lett 580(22):5344–5350
Sallenave JM (2002) Antimicrobial activity of antiproteinases. Biochem Soc Trans 30(2):111–115
Zasloff M (2002) Antimicrobial peptides of multicellular organisms. Nature 415(6870):389–395
Ganz T (2003) Defensins: antimicrobial peptides of innate immunity. Nat Rev Immunol 3(9):710–720
Shen B, Porter EM, Reynoso E et al (2005) Human defensin 5 expression in intestinal metaplasia of the upper gastrointestinal tract. J Clin Pathol 58(7):687–694
Ghosh D, Porter EM, Wilk DJ, Poles MA, Ganz T, Bevins CL (2000) Proteolytic cleavage of human intestinal defensin 5 (HD5) precursor by intestinal proteases. Gastroenterology 118(4):A839
Ghosh D, Porter E, Shen B et al (2002) Paneth cell trypsin is the processing enzyme for human defensin-5. Nat Immunol 3(6):583–590
Chu H, Pazgier M, Jung G et al (2012) Human alpha-defensin 6 promotes mucosal innate immunity through self-assembled peptide nanonets. Science 337(6093):477–481
Zhao C, Wang I, Lehrer RI (1996) Widespread expression of beta-defensin hBD-1 in human secretory glands and epithelial cells. FEBS Lett 396(2–3):319–322
Pazgier M, Prahl A, Hoover DM, Lubkowski J (2007) Studies of the biological properties of human beta-defensin 1. J Biol Chem 282(3):1819–1829
Papo N, Shai Y (2003) Can we predict biological activity of antimicrobial peptides from their interactions with model phospholipid membranes? Peptides 24(11):1693–1703
Sass V, Schneider T, Wilmes M et al (2010) Human beta-defensin 3 inhibits cell wall biosynthesis in staphylococci. Infect Immun 78(6):2793–2800
Schroeder BO, Wu Z, Nuding S et al (2011) Reduction of disulphide bonds unmasks potent antimicrobial activity of human beta-defensin 1. Nature 469(7330):419–423
Lehrer RI, Lu W (2012) alpha-Defensins in human innate immunity. Immunol Rev 245(1):84–112
Yang D, Chertov O, Bykovskaia SN et al (1999) β-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science 286:525–528
Rohrl J, Yang D, Oppenheim JJ, Hehlgans T (2010) Human beta-defensin 2 and 3 and their mouse orthologs induce chemotaxis through interaction with CCR2. J Immunol 184(12):6688–6694
Niyonsaba F, Iwabuchi K, Matsuda H, Ogawa H, Nagaoka I (2002) Epithelial cell-derived human beta-defensin-2 acts as a chemotaxin for mast cells through a pertussis toxin-sensitive and phospholipase C-dependent pathway. Int Immunol 14(4):421–426
Niyonsaba F, Ogawa H, Nagaoka I (2004) Human beta-defensin-2 functions as a chemotactic agent for tumour necrosis factor-alpha-treated human neutrophils. Immunology 111(3):273–281
de Leeuw E, Rajabi M, Zou G, Pazgier M, Lu W (2009) Selective arginines are important for the antibacterial activity and host cell interaction of human alpha-defensin 5. FEBS Lett 583(15):2507–2512
Kotarsky K, Sitnik KM, Stenstad H et al (2010) A novel role for constitutively expressed epithelial-derived chemokines as antibacterial peptides in the intestinal mucosa. Mucosal Immunol 3(1):40–48
Peyrin-Biroulet L, Chamaillard M (2007) NOD2 and defensins: translating innate to adaptive immunity in Crohn’s disease. J Endotoxin Res 13(3):135–139
Zanetti M (2005) The role of cathelicidins in the innate host defenses of mammals. Curr Issues Mol Biol 7(2):179–196
Nevalainen TJ, Graham GG, Scott KF (2008) Antibacterial actions of secreted phospholipases A2. Review. Biochim Biophys Acta 1781(1–2):1–9
Cash HL, Whitham CV, Behrendt CL, Hooper LV (2006) Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313(5790):1126–1130
Medveczky P, Szmola R, Sahin-Toth M (2009) Proteolytic activation of human pancreatitis-associated protein is required for peptidoglycan binding and bacterial aggregation. Biochem J 420(2):335–343
Canny G, Cario E, Lennartsson A et al (2006) Functional and biochemical characterization of epithelial bactericidal/permeability-increasing protein. Am J Physiol Gastrointest Liver Physiol 290(3):G557–G567
Canny G, Levy O, Furuta GT et al (2002) Lipid mediator-induced expression of bactericidal/permeability-increasing protein (BPI) in human mucosal epithelia. Proc Natl Acad Sci U S A 99(6):3902–3907
Jager S, Stange EF, Wehkamp J (2010) Antimicrobial peptides in gastrointestinal inflammation. Int J Inflamm 2010:910283
Stange EF (2009) For bugs in bile: the times they are a-changin’. Gastroenterology 136(4):1164–1167
Johansson ME, Ambort D, Pelaseyed T et al (2011) Composition and functional role of the mucus layers in the intestine. Cell Mol Life Sci 68(22):3635–3641
Johansson ME, Larsson JM, Hansson GC (2011) The two mucus layers of colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host-microbial interactions. Proc Natl Acad Sci U S A 108(Suppl 1):4659–4665
Subramani DB, Johansson ME, Dahlen G, Hansson GC (2010) Lactobacillus and Bifidobacterium species do not secrete protease that cleaves the MUC2 mucin which organises the colon mucus. Benefic Microbes 1(4):343–350
Meyer-Hoffert U, Hornef MW, Henriques-Normark B et al (2008) Secreted enteric antimicrobial activity localises to the mucus surface layer. Gut 57(6):764–771
Vaishnava S, Yamamoto M, Severson KM et al (2011) The antibacterial lectin RegIIIgamma promotes the spatial segregation of microbiota and host in the intestine. Science 334(6053):255–258
Satsangi J, Silverberg MS, Vermeire S, Colombel JF (2006) The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut 55(6):749–753
Inoue N, Tamura K, Kinouchi Y et al (2002) Lack of common NOD2 variants in Japanese patients with Crohn's disease. Gastroenterology 123(1):86–91
Hoffmann JC, Preiss JC, Autschbach F et al (2008) Clinical practice guideline on diagnosis and treatment of Crohn’s disease. Z Gastroenterol 46(9):1094–1146
Franke A, McGovern DP, Barrett JC et al (2010) Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet 42(12):1118–1125
Anderson CA, Boucher G, Lees CW et al (2011) Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet 43(3):246–252
Sandow MJ, Whitehead R (1979) The Paneth cell. Gut 20(5):420–431
Wehkamp J, Salzman NH, Porter E et al (2005) Reduced Paneth cell alpha-defensins in ileal Crohn’s disease. Proc Natl Acad Sci U S A 102(50):18129–18134
Vaishnava S, Behrendt CL, Ismail AS, Eckmann L, Hooper LV (2008) Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc Natl Acad Sci U S A 105(52):20858–20863
Petnicki-Ocwieja T, Hrncir T, Liu YJ et al (2009) Nod2 is required for the regulation of commensal microbiota in the intestine. Proc Natl Acad Sci U S A 106(37):15813–15818
Salzman NH, Hung K, Haribhai D et al (2010) Enteric defensins are essential regulators of intestinal microbial ecology. Nat Immunol 11(1):76–83
Cuthbert AP, Fisher SA, Mirza MM et al (2002) The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease. Gastroenterology 122(4):867–874
Barrett JC, Hansoul S, Nicolae DL et al (2008) Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet 40(8):955–962
Lala S, Ogura Y, Osborne C et al (2003) Crohn’s disease and the NOD2 gene: a role for paneth cells. Gastroenterology 125(1):47–57
Wilson CL, Ouellette AJ, Satchell DP et al (1999) Regulation of intestinal α-defensin activation by the metalloproteinase matrilysin in innate host defense. Science 286:113–117
Simms LA, Doecke JD, Walsh MD, Huang N, Fowler EV, Radford-Smith GL (2008) Reduced alpha-defensin expression is associated with inflammation and not NOD2 mutation status in ileal Crohn’s disease. Gut 57(7):903–910
Elphick D, Liddell S, Mahida YR (2008) Impaired luminal processing of human defensin-5 in Crohn’s disease: persistence in a complex with chymotrypsinogen and trypsin. Am J Pathol 172(3):702–713
Rumio C, Besusso D, Palazzo M et al (2004) Degranulation of paneth cells via toll-like receptor 9. Am J Pathol 165(2):373–381
Hampe J, Cuthbert A, Croucher PJ et al (2001) Association between insertion mutation in NOD2 gene and Crohn’s di German and British populations. Lancet 357(9272):1925–1928, 2001; 357:1925–1928
Cadwell K, Liu JY, Brown SL et al (2008) A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 456(7219):259–263
Thachil E, Hugot JP, Arbeille B et al (2012) Abnormal activation of autophagy-induced crinophagy in paneth cells from patients with Crohn’s disease. Gastroenterology 142(5):1097–1099
Kaser A, Lee AH, Franke A et al (2008) XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 134(5):743–756
van Es JH, Jay P, Gregorieff A et al (2005) Wnt signalling induces maturation of Paneth cells in intestinal crypts. Nat Cell Biol 7(4):381–386
Wehkamp J, Wang G, Kubler I et al (2007) The Paneth cell alpha-defensin deficiency of ileal Crohn’s disease is linked to Wnt/Tcf-4. J Immunol 179(5):3109–3118
Koslowski MJ, Kubler I, Chamaillard M et al (2009) Genetic variants of Wnt transcription factor TCF-4 (TCF7L2) putative promoter region are associated with small intestinal Crohn’s disease. PLoS One 4(2):e4496
Koslowski MJ, Teltschik Z, Beisner J et al (2012) Association of a functional variant in the Wnt co-receptor LRP6 with early onset ileal Crohn’s disease. PLoS Genet 8(2):e1002523
Ayabe T, Wulff H, Darmoul D, Cahalan MD, Chandy KG, Ouellette AJ (2002) Modulation of mouse Paneth cell alpha-defensin secretion by mIKCa1, a Ca2+−activated, intermediate conductance potassium channel. J Biol Chem 277(5):3793–3800
Simms LA, Doecke JD, Roberts RL et al (2010) KCNN4 gene variant is associated with ileal Crohn’s disease in the Australian and New Zealand population. Am J Gastroenterol 105(10):2209–2217
Gunther C, Martini E, Wittkopf N et al (2011) Caspase-8 regulates TNF-alpha-induced epithelial necroptosis and terminal ileitis. Nature 477(7364):335–339
Wehkamp J, Stange EF (2010) Paneth’s disease. J Crohns Colitis 4(5):523–531
Hollox EJ, Barber JC, Brookes AJ, Armour JA (2008) Defensins and the dynamic genome: what we can learn from structural variation at human chromosome band 8p23.1. Genome Res 18(11):1686–1697
Kocsis AK, Lakatos PL, Somogyvari F et al (2008) Association of beta-defensin 1 single nucleotide polymorphisms with Crohn’s disease. Scand J Gastroenterol 43(3):299–307
Peyrin-Biroulet L, Beisner J, Wang G et al (2010) Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon. Proc Natl Acad Sci U S A 107(19):8772–8777
Wehkamp J, Harder J, Weichenthal M et al (2003) Inducible and constitutive beta-defensins are differentially expressed in Crohn’s disease and ulcerative colitis. Inflamm Bowel Dis 9(4):215–223
Maurice MM, Nakamura H, Gringhuis S et al (1999) Expression of the thioredoxin-thioredoxin reductase system in the inflamed joints of patients with rheumatoid arthritis. Arthritis Rheum 42(11):2430–2439
Zilbauer M, Dorrell N, Boughan PK et al (2005) Intestinal innate immunity to Campylobacter jejuni results in induction of bactericidal human beta-defensins 2 and 3. Infect Immun 73(11):7281–7289
Mondel M, Schroeder BO, Zimmermann K et al (2008) Probiotic E. coli treatment mediates antimicrobial human beta-defensin synthesis and fecal excretion in humans. Mucosal Immunol 2(2):166–172
Wehkamp J, Harder J, Wehkamp K et al (2004) NF-kappaB- and AP-1-mediated induction of human beta defensin-2 in intestinal epithelial cells by Escherichia coli Nissle 1917: a novel effect of a probiotic bacterium. Infect Immun 72(10):5750–5758
Gaffen SL (2009) Structure and signalling in the IL-17 receptor family. Nat Rev Immunol 9(8):556–567
Aldhous MC, Noble CL, Satsangi J (2009) Dysregulation of human beta-defensin-2 protein in inflammatory bowel disease. PLoS One 4(7):e6285
Nuding S, Fellermann K, Wehkamp J, Stange EF (2007) Reduced mucosal antimicrobial activity in Crohn’s disease of the colon. Gut 56(9):1240–1247
Fellermann K, Stange DE, Schaeffeler E et al (2006) A chromosome 8 gene-cluster polymorphism with low human beta-defensin 2 gene copy number predisposes to Crohn disease of the colon. Am J Hum Genet 79(3):439–448
Bentley RW, Pearson J, Gearry RB et al (2009) Association of higher DEFB4 genomic copy number with Crohn’s disease. Am J Gastroenterol 105(2):354–359
Hollox EJ, Armour JA, Barber JC (2003) Extensive normal copy number variation of a beta-defensin antimicrobial-gene cluster. Am J Hum Genet 73(3):591–600
Voss E, Wehkamp J, Wehkamp K, Stange EF, Schroder JM, Harder J (2006) NOD2/CARD15 mediates induction of the antimicrobial peptide human beta-defensin-2. J Biol Chem 281(4):2005–2011
Mastroianni JR, Ouellette AJ (2009) Alpha-defensins in enteric innate immunity: functional Paneth cell alpha-defensins in mouse colonic lumen. J Biol Chem 284(41):27848–27856
Cunliffe RN, Rose FRAJ, Keyte J, Abberley L, Chan WC, Mahida YR (2001) Human defensin 5 is stored in precursor form in normal Paneth cells and is expressed by some viloous epithelial cells and by metaplastic Paneth cells in the colon in inflammatory bowel disease. Gut 48:176–185
Langhorst J, Junge A, Rueffer A et al (2009) Elevated human beta-defensin-2 levels indicate an activation of the innate immune system in patients with irritable bowel syndrome. Am J Gastroenterol 104(2):404–410
Hiemstra PS (2002) Novel roles of protease inhibitors in infection and inflammation. Biochem Soc Trans 30(2):116–120
Schmid M, Fellermann K, Fritz P, Wiedow O, Stange EF, Wehkamp J (2007) Attenuated induction of epithelial and leukocyte serine antiproteases elafin and secretory leukocyte protease inhibitor in Crohn’s disease. J Leukoc Biol. doi:10.1189/jlb.0906581
Schauber J, Rieger D, Weiler F et al (2006) Heterogeneous expression of human cathelicidin hCAP18/LL-37 in inflammatory bowel diseases. Eur J Gastroenterol Hepatol 18(6):615–621
Iimura M, Gallo RL, Hase K, Miyamoto Y, Eckmann L, Kagnoff MF (2005) Cathelicidin mediates innate intestinal defense against colonization with epithelial adherent bacterial pathogens. J Immunol 174(8):4901–4907
Dignass A, Preiss JC, Aust DE et al (2011) Updated German guideline on diagnosis and treatment of ulcerative colitis, 2011. Z Gastroenterol 49(9):1276–1341
Kiehne K, Brunke G, Meyer D, Harder J, Herzig KH (2005) Oesophageal defensin expression during Candida infection and reflux disease. Scand J Gastroenterol 40(5):501–507
Scarpa M, Grillo A, Scarpa M et al (2012) Innate immune environment in ileal pouch mucosa: alpha5 defensin up-regulation as predictor of chronic/relapsing pouchitis. J Gastrointest Surg 16(1):188–201
Sartor RB (2005) Does Mycobacterium avium subspecies paratuberculosis cause Crohn’s disease? Gut 54(7):896–898
Khan KJ, Ullman TA, Ford AC et al (2011) Antibiotic therapy in inflammatory bowel disease: a systematic review and meta-analysis. Am J Gastroenterol 106(4):661–673
Danese S (2012) New therapies for inflammatory bowel disease: from the bench to the bedside. Gut 61(6):918–932
Summers RW, Elliott DE, Urban JF Jr, Thompson R, Weinstock JV (2005) Trichuris suis therapy in Crohn’s disease. Gut 54(1):87–90
Summers RW, Elliott DE, Urban JF Jr, Thompson RA, Weinstock JV (2005) Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial. Gastroenterology 128(4):825–832
Yazdanbakhsh M, Kremsner PG, van Ree R (2002) Allergy, parasites, and the hygiene hypothesis. Science 296(5567):490–494
Doetze A, Satoguina J, Burchard G et al (2000) Antigen-specific cellular hyporesponsiveness in a chronic human helminth infection is mediated by T(h)3/T(r)1-type cytokines IL-10 and transforming growth factor-beta but not by a T(h)1 to T(h)2 shift. Int Immunol 12(5):623–630
Hunter MM, Wang A, McKay DM (2007) Helminth infection enhances disease in a murine TH2 model of colitis. Gastroenterology 132(4):1320–1330
Bager P, Arnved J, Ronborg S et al (2010) Trichuris suis ova therapy for allergic rhinitis: a randomized, double-blind, placebo-controlled clinical trial. J Allergy Clin Immunol 125(1):123–130
Weber G, Heilborn JD, Chamorro Jimenez CI, Hammarsjo A, Torma H, Stahle M (2005) Vitamin D induces the antimicrobial protein hCAP18 in human skin. J Investig Dermatol 124(5):1080–1082
Wang TT, Dabbas B, Laperriere D et al (2010) Direct and indirect induction by 1,25-dihydroxyvitamin D3 of the NOD2/CARD15-defensin beta2 innate immune pathway defective in Crohn disease. J Biol Chem 285(4):2227–2231
Steinmann J, Halldorsson S, Agerberth B, Gudmundsson GH (2009) Phenylbutyrate induces antimicrobial peptide expression. Antimicrob Agents Chemother 53(12):5127–5133
Schlee M, Harder J, Koten B, Stange EF, Wehkamp J, Fellermann K (2008) Probiotic lactobacilli and VSL#3 induce enterocyte beta-defensin 2. Clin Exp Immunol 151(3):528–535
Conflicts of interest
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Jäger, S., Stange, E.F. & Wehkamp, J. Inflammatory bowel disease: an impaired barrier disease. Langenbecks Arch Surg 398, 1–12 (2013). https://doi.org/10.1007/s00423-012-1030-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00423-012-1030-9