To prevent bacterial overgrowth, colonization of the epithelium and subsequent translocation, the gastrointestinal tract maintains an effective mucosal barrier. Besides mucus the most important components of this protective system are epithelial antimicrobial peptides such as defensins, the cathelicidin LL-37, lysozyme, phospholipase A, and proteins with additional antimicrobial properties such as ubiquicidin, ribosomal proteins or histones. Commensal species may tolerate intestinal antimicrobial peptides, for example Bacteroides ssp. or Parabacteroides ssp. as major species in the human colon were highly resistant to the constitutive defensin HBD-1 and only susceptible to the inducible defensin HBD-3. Reduction of disulfide bonds is an important mechanism activating HBD-1. As several studies show, alterations in the expression of antimicrobial peptides directly influence the composition of the intestinal flora. Correspondingly, an increased production of defensins or inhibition of the processing of mouse defensins to their active form led to a quantitative shift of luminal and mucosal bacterial species. On the other hand, microorganisms also modulate the synthesis of host defensins by induction or inhibition of specific peptides. Lactobacilli, the probiotic strain Escherichia coli Nissle and Salmonella enteritica stimulate HBD-2 expression, whereas Shigella flexneri downregulates the synthesis of HBD-1, HBD-3 and LL-37. Thus, the proper balance between the luminal flora and the mucosa is a permanently dynamic, sensitive and host-specific relationship.

Keywords:
Host, Flora, Intestinal barrier, Antimicrobial peptides
1.
Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA: Diversity of the human intestinal microbial flora. Science 2005;308:1635-1638.
2.
Sears CL: A dynamic partnership: celebrating our gut flora. Anaerobe 2005;11:247-251.
3.
Zoetendal EG, Akkermans AD, Akkermans-van Vliet WM, de Visser JA, de Vos WM: The host genotype affects the bacterial community in the human gastrointestinal tract. Microbial Ecol Health Dis 2001;13:129-134.
4.
Tomczak MF, Erdman SE, Poutahidis T, Rogers AB, Holcombe H, Plank B, Fox JG, Horwitz BH: NF-κB is required within the innate immune system to inhibit microflora-induced colitis and expression of IL-12 p 40. J Immunol 2003;171:1484-1492.
5.
Hashimoto T, Perlot T, Rehman A, Trichereau J, Ishiguro H, Paolino M, Sigl V, Hanada T, Hanada R, Lipinski S, Wild B, Camargo SM, Singer D, Richter A, Kuba K, Fukamizu A, Schreiber S, Clevers H, Verrey F, Rosenstiel P, Penninger JM: ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature 2012;487:477-481.
6.
Elinav E, Strowig T, Kau AL, Henao-Mejia J, Thaiss CA, Booth CJ, Peaper DR, Bertin J, Eisenbarth SC, Gordon JI, Flavell RA: NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis Cell 2011;145:745-757.
7.
Palomino-Morales RJ, Oliver J, Gómez-García M, López-Nevot MA, Rodrigo L, Nieto A, Alizadeh BZ, Martín J: Association of ATG16L1 and IRGM genes polymorphisms with inflammatory bowel disease: a meta-analysis approach. Genes Immun 2009;10:356-364.
8.
Mai V, McCrary QM, Sinha R, Glei M: Associations between dietary habits and body mass index with gut microbiota composition and fecal water genotoxicity: an observational study in African American and Caucasian American volunteers. Nutr J. 2009;8:49.
9.
Rehman A, Sina C, Gavrilova O, Häsler R, Ott S, Baines JF, Schreiber S, Rosenstiel: Nod2 is essential for temporal development of intestinal microbial communities. Gut 2011;60:1354-1362.
10.
Petnicki-Ocwieja T, Hrncir T, Liu YJ, Biswas A, Hudcovic T, Tlaskalova-Hogenova H, Kobayashi KS: Nod2 is required for the regulation of commensal microbiota in the intestine. Proc Natl Acad Sci USA 2009;106:15813-15818.
11.
Couturier-Maillard A, Secher T, Rehman A, Normand S, De Arcangelis A, Haesler R, Huot L, Grandjean T, Bressenot A, Delanoye-Crespin A, Gaillot O, Schreiber S, Lemoine Y, Ryffel B, Hot D, Nùñez G, Chen G, Rosenstiel P, Chamaillard M: NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer. J Clin Invest 2013;123:700-711.
12.
Robertson SJ, Zhou JY, Geddes K, Rubino SJ, Cho JH, Girardin SE, Philpott DJ: Nod1 and Nod2 signaling does not alter the composition of the intestinal bacterial communities at homeostasis. Gut Microbes 2013;4:222-231.
13.
Hudault S, Guignot J, Servin AL: Escherichia coli strains colonising the gastrointestinal tract protect germ-free mice against Salmonella typhimurium infection. Gut 2001;49:47-55.
14.
Cario E: Bacterial interactions with cells of the intestinal mucosa: Toll-like receptors and NOD2. Gut 2005;54:1182-1193.
15.
Sanz Y, De Palma G: Gut microbiota and probiotics in modulation of epithelium and gut-associated lymphoid tissue function. Int Rev Immunol 2009;28:397-413.
16.
Otte JM, Kiehne K, Herzig KH: Antimicrobial peptides in innate immunity of the human intestine. J Gastroenterol 2003;38:717-726.
17.
Johansson ME, Phillipson M, Petersson J, Velcich A, Holm L, Hansson GC: The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc Natl Acad Sci USA 2008;105:15064-15069.
18.
Wehkamp J, Stange EF, Fellermann K: Defensin-immunology in inflammatory bowel disease. Gastroenterol Clin Biol 2009;33(suppl 3):S137-S144.
19.
Tollin M, Bergman P, Svenberg T, Jörnvall H, Gudmundsson GH, Agerberth B: Antimicrobial peptides in the first line defence of human colon mucosa. Peptides 2003;24:523-530.
20.
Howell SJ, Wilk D, Yadav SP, Bevins CL: Antimicrobial polypeptides of the human colonic epithelium. Peptides 2003;24:1763-1770.
21.
Bevins CL: Antimicrobial peptides as effector molecules of mammalian host defense; in Herwald H (ed): Host Response Mechanisms in Infectious Diseases. Contrib Microbiol. Basel, Karger, 2003, vol 10, pp 106-148.
22.
Zasloff M: Antimicrobial peptides of multicellular organisms. Nature 2002;415:389-395.
23.
Brogden KA: Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat Rev Microbiol 2005;3:238-250.
24.
Hale JD, Hancock RE: Alternative mechanisms of action of cationic antimicrobial peptides on bacteria. Expert Rev Anti Infect Ther 2007;5:951-959.
25.
Nuding S, Zabel LT, Enders C, Porter E, Fellermann K, Wehkamp J, Mueller HA, Stange EF: Antibacterial activity of human defensins on anaerobic intestinal bacterial species: a major role of HBD-3. Microbes Infect 2009;11:384-393.
26.
Schroeder BO, Wu Z, Nuding S, Groscurth S, Marcinowski M, Beisner J, Buchner J, Schaller M, Stange EF, Wehkamp J: Reduction of disulphide bonds unmasks potent antimicrobial activity of human β-defensin 1. Nature 2011;469:419-423.
27.
Wehkamp J, Salzman NH, Porter E, Nuding S, Weichenthal M, Petras RE, Shen B, Schaeffeler E, Schwab M, Linzmeier R, Feathers RW, Chu H, Lima H Jr, Fellermann K, Ganz T, Stange EF, Bevins CL: Reduced Paneth cell α-defensins in ileal Crohn's disease. Proc Natl Acad Sci USA 2005;102:18129-18134.
28.
Salzman NH: Paneth cell defensins and the regulation of the microbiome: détente at mucosal surfaces. Gut Microbes 2010;1:401-406.
29.
Islam D, Bandholtz L, Nilsson J, Wigzell H, Christensson B, Agerberth B, Gudmundsson G: Downregulation of bactericidal peptides in enteric infections: a novel immune escape mechanism with bacterial DNA as a potential regulator. Nat Med 2001;7:180-185.
30.
Sperandio B, Regnault B, Guo J, Zhang Z, Stanley SL Jr, Sansonetti PJ, Pédron T: Virulent Shigella flexneri subverts the host innate immune response through manipulation of antimicrobial peptide gene expression. J Exp Med 2008;205:1121-1132.
31.
Salzman NH, Chou MM, de Jong H, Liu L, Porter EM, Paterson Y: Enteric Salmonella infection inhibits Paneth cell antimicrobial peptide expression. Infect Immun 2003;71:1109-1115.
32.
Chakraborty K, Ghosh S, Koley H, Mukhopadhyay AK, Ramamurthy T, Saha DR, Mukhopadhyay D, Roychowdhury S, Hamabata T, Takeda Y, Das S: Bacterial exotoxins downregulate cathelicidin (hCAP-18/LL-37) and human β-defensin 1 (HBD-1) expression in the intestinal epithelial cells. Cell Microbiol 2008;10:2520-2537.
33.
Schlee M, Wehkamp J, Altenhoefer A, Oelschlaeger TA, Stange EF, Fellermann K: Induction of human β-defensin 2 by the probiotic Escherichia coli Nissle 1917 is mediated through flagellin. Infect Immun. 2007;75:2399-2407.
34.
Ehehalt R, Wagenblast J, Erben G, Lehmann WD, Hinz U, Merle U, Stremmel W: Phosphatidylcholine and lysophosphatidylcholine in intestinal mucus of ulcerative colitis patients. A quantitative approach by nanoElectrospray-tandem mass spectrometry. Scand J Gastroenterol 2004;39:737-742.
35.
Hayashi T, Ishida T, Motoya S, Itoh F, Takahashi T, Hinoda Y, Imai K: Mucins and immune reactions to mucins in ulcerative colitis. Digestion 2001;63(suppl 1):28-31.
36.
Strugala V, Allen A, Dettmar PW, Pearson JP: Colonic mucin: methods of measuring mucus thickness. Proc Nutr Soc 2003;62:237-243.
37.
Atuma C, Strugala V, Allen A, Holm L: The adherent gastrointestinal mucus gel layer: thickness and physical state in vivo. Am J Physiol Gastrointest Liver Physiol 2001;280:G922-G929.
38.
McGuckin MA, Eri R, Simms LA, Florin TH, Radford-Smith G: Intestinal barrier dysfunction in inflammatory bowel diseases. Inflamm Bowel Dis 2009;15:100-113.
39.
Kim YS, Ho SB: Intestinal goblet cells and mucins in health and disease: recent insights and progress. Curr Gastroenterol Rep 2010;12:319-330.
40.
Moran AP, Gupta A, Joshi L: Sweet-talk: role of host glycosylation in bacterial pathogenesis of the gastrointestinal tract Gut 2011;60:1412-1425.
41.
Shirazi T, Longman RJ, Corfield AP, Probert CS: Mucins and inflammatory bowel disease. Postgrad Med J 2000;76:473-478.
42.
Phillipson M, Johansson ME, Henriksnäs J, Petersson J, Gendler SJ, Sandler S, Persson AE, Hansson GC, Holm L: The gastric mucus layers: constituents and regulation of accumulation. Am J Physiol Gastrointest Liver Physiol 2008;295:G806-G812.
43.
Tytgat KM, Büller HA, Opdam FJ, Kim YS, Einerhand AW, Dekker J: Biosynthesis of human colonic mucin: Muc2 is the prominent secretory mucin. Gastroenterology 1994;107:1352-1363.
44.
Hansson GC, Johansson ME: The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Gut Microbes 2010;1:51-54.
45.
Van der Sluis M, De Koning BA, De Bruijn AC, Velcich A, Meijerink JP, Van Goudoever JB, Büller HA, Dekker J, Van Seuningen I, Renes IB, Einerhand AW: Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 2006;131:117-129.
46.
Meyer-Hoffert U, Hornef MW, Henriques-Normark B, Axelsson LG, Midtvedt T, Pütsep K, Andersson M: Secreted enteric antimicrobial activity localises to the mucus surface layer. Gut 2008;57:764-771.
47.
Antoni L, Nuding S, Weller D, Gersemann M, Ott G, Wehkamp J, Stange EF: Human colonic mucus is a reservoir for antimicrobial peptides. J Crohns Colitis 2013 DOI: 10.1016/j.crohns.2013.05.006.
48.
McGuckin M, Lindén SK, Sutton P, Florin TH: Mucin dynamics and enteric pathogens. Nat Rev Microbiol 2011;9:265-278.
49.
Lidell ME, Moncada DM, Chadee K, Hansson GC: Entamoeba histolytica cysteine proteases cleave the MUC2 mucin in its C-terminal domain and dissolve the protective colonic mucus gel. Proc Natl Acad Sci USA 2006;103:9298-9303.
50.
Silva AJ, Pham K, Benitez JA: Haemagglutinin/protease expression and mucin gel penetration in El Tor biotype Vibrio cholerae. Microbiology 2003;149:1883-1891.
51.
Mack DR, Michail S, Wei S, McDougall L, Hollingsworth MA: Probiotics inhibit enteropathogenic E. coli adherence in vitro by inducing intestinal mucin gene expression. Am J Physiol 1999;276:G941-G950.
52.
Caballero-Franco C, Keller K, De Simone C, Chadee K: The VSL#3 probiotic formula induces mucin gene expression and secretion in colonic epithelial cells. Am J Physiol Gastrointest Liver Physiol 2007;292:G315-G322.
53.
Darfeuille-Michaud A, Neut C, Barnich N, Lederman E, Di Martino P, Desreumaux P, Gambiez L, Joly B, Cortot A, Colombel JF: Presence of adherent Escherichia coli strains in ileal mucosa of patients with Crohn's disease. Gastroenterology 1998;115:1405-1413.
54.
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;43:3380-3389.
55.
Ryan P, Aarons S, Bennett MW, Lee G, O'Sullivan GC, O'Connell J, Shanahan F: Mycobacterium paratuberculosis detected by nested PCR in intestinal granulomas isolated by LCM in cases of Crohn's disease. Methods Mol Biol 2002;193:205-211.
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