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Intestinal barrier dysfunction: implications for chronic inflammatory conditions of the bowel

  • Warren M. Miner-Williams (a1) (a2) and Paul J. Moughan (a1)

Abstract

The intestinal epithelium of adult humans acts as a differentially permeable barrier that separates the potentially harmful contents of the lumen from the underlying tissues. Any dysfunction of this boundary layer that disturbs the homeostatic equilibrium between the internal and external environments may initiate and sustain a biochemical cascade that results in inflammation of the intestine. Key to such dysfunction are genetic, microbial and other environmental factors that, singularly or in combination, result in chronic inflammation that is symptomatic of inflammatory bowel disease (IBD). The aim of the present review is to assess the scientific evidence to support the hypothesis that defective transepithelial transport mechanisms and the heightened absorption of intact antigenic proinflammatory oligopeptides are important contributing factors in the pathogenesis of IBD.

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Corresponding author

* Corresponding author: Professor P. J. Moughan, email p.j.moughan@massey.ac.nz

References

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1. Davies, JM & Abreu, MT (2015) The innate immune system and inflammatory bowel disease. Scand J Gastroenterol 50, 2433.
2. Khan, MW, Kale, AA, Bere, P, et al. (2012) Microbes, intestinal inflammation and probiotics. Expert Rev Gastroenterol Hepatol 6, 8194.
3. Wehkamp, J, Schwind, B, Herrlinger, KR, et al. (2002) Innate immunity and colonic inflammation: enhanced expression of epithelial α-defensins. Dig Dis Sci 47, 13491355.
4. Wehkamp, J, Schmid, M, Fellermann, K, et al. (2005) Defensin deficiency, intestinal microbes, and the clinical phenotypes of Crohn’s disease. J Leuk Biol 77, 460465.
5. Cadwell, K, Patel, KK, Maloney, NS, et al. (2010) Virus-plus-susceptibility gene interaction determines Crohn’s disease gene Atg16L1 phenotypes in intestine. Cell 141, 11351145.
6. Gersemann, M, Wehkamp, J & Stange, EF (2012) Innate immune dysfunction in inflammatory bowel disease. J Intern Med 271, 421428.
7. Gruber, L, Lichti, P, Rath, E, et al. (2012) Nutrigenomics and nutrigenetics in inflammatory bowel diseases. J Clin Gastroenterol 46, 735747.
8. Xavier, RJ & Podolsky, DK (2007) Unravelling the pathogenesis of inflammatory bowel disease. Nature 448, 427434.
9. Ingersoll, SA, Ayyadurai, S, Charania, MA, et al. (2012) The role and pathophysiological relevance of membrane transporter PepT1 in intestinal inflammation and inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 302, G484G492.
10. Charrier, L & Merlin, D (2006) The oligopeptide transporter hPepT1: gateway to the innate immune response. Lab Invest 86, 538546.
11. Dalmasso, G, Nguyen, HTT, Charrier-Hisamuddin, L, et al. (2010) PepT1 mediates transport of the proinflammatory bacterial tripeptide l-Ala-γ-d-Glu-meso-DAP in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 299, G687G696.
12. de Medina, FS, Daddaoua, A, Requena, P, et al. (2010) Session 9: Food ingredients, immunity and inflammation: animal and in vitro models. New insights into the immunological effects of food bioactive peptides in animal models of intestinal inflammation. Proc Nutr Soc 69, 454462.
13. Ma, K, Hu, YJ & Smith, DE (2012) Influence of fed-fasted state on intestinal PEPT1 expression and in vivo pharmacokinetics of glycylsarcosine in wild-type and Pept1 knockout mice. Pharm Res 29, 535545.
14. Jowett, SL, Seal, CJ, Phillips, E, et al. (2003) Defining relapse of ulcerative colitis using a symptom-based activity index. Scand J Gastroenterol 38, 164171.
15. Rutherfurd-Markwick, KJ & Moughan, PJ (2005) Bioactive peptides derived from food. J AOAC Int 88, 955966.
16. Jappar, D, Hu, YJ & Smith, DE (2011) Effect of dose escalation on the in vivo oral absorption and disposition of glycylsarcosine in wild-type and Pept1 knockout mice. Drug Metab Dispos 39, 22502257.
17. Nassl, AM, Rubio-Aliaga, I, Sailer, M, et al. (2011) The intestinal peptide transporter PEPT1 is involved in food intake regulation in mice fed a high-protein diet. PLoS ONE 6, e26407.
18. Frank, DN, Zhu, W, Sartor, RB, et al. (2011) Investigating the biological and clinical significance of human dysbioses. Trends Microbiol 19, 427434.
19. Olaison, G, Sjodahl, R & Tagesson, C (1990) Abnormal intestinal permeability in Crohn’s disease: a possible pathogenic factor. Scand J Gastroenterol 25, 321328.
20. Hollander, D (1992) The intestinal permeability barrier. A hypothesis as to its regulation and involvement in Crohn’s disease. Scand J Gastroenterol 27, 721726.
21. Soderholm, JD, Peterson, KH, Olaison, G, et al. (1999) Epithelial permeability to proteins in the noninflamed ileum of Crohn’s disease? Gastroenterology 117, 6572.
22. Hollander, D, Vadheim, CM, Brettholz, E, et al. (1986) Increased intestinal permeability in patients with Crohn’s disease and their relatives: a possible etiologic factor. Ann Intern Med 105, 883885.
23. Travis, S & Menzies, I (1992) Intestinal permeability: functional assessment and significance. Clin Sci 82, 471488.
24. Bjarnason, I, Macpherson, A & Hollander, D (1995) Intestinal permiability: an overview. Gastroenterology 108, 15661581.
25. Wehkamp, J & Stange, EF (2010) Paneth’s disease. J Crohns Colitis 4, 523531.
26. Smith, DE, Clemencon, B & Hediger, MA (2013) Proton-coupled oligopeptide transporter family SLC15: physiological, pharmacological and pathological implications. Mol Aspects Med 34, 323336.
27. Brandsch, M & Brandsch, C (2003) Intestinal transport of amino acids, peptides and proteins. In Progress in Research on Energy and Protein Metabolism, pp. 667680 [WB Souffrant and CC Metges, editors]. Wageningen: Wageningen Academy Press.
28. Menard, S, Cerf-Bensussan, N & Heyman, M (2010) Multiple facets of intestinal permeability and epithelial handling of dietary antigens. Mucosal Immunol 3, 247259.
29. Chabance, B, Marteau, P, Rambaud, JC, et al. (1998) Casein peptide release and passage to the blood in humans during digestion of milk or yogurt. Biochimie 80, 155165.
30. Chabance, B, Jolles, P, Izquierdo, C, et al. (1995) Characterization of an antithrombotic peptide from κ-casein in newborn plasma after milk ingestion. Br J Nutr 73, 583590.
31. Meisel, H & FitzGerald, RJ (2000) Opioid peptides encrypted in intact milk protein sequences. Br J Nutr 84, S27S31.
32. Miner-Williams, WM, Stevens, BR & Moughan, PJ (2014) Are intact peptides absorbed from the healthy gut in the adult human? Nutr Res Rev 27, 308329.
33. Izcue, A, Coombes, JL & Powrie, F (2006) Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation. Immunol Rev 212, 256271.
34. Strobel, S & Mowat, AM (1998) Immune responses to dietary antigens: oral tolerance. Immunol Today 19, 173181.
35. Goll, R & Granlund, AV (2015) Intestinal barrier homeostasis in inflammatory bowel disease. Scand J Gastroenterol 50, 312.
36. Cani, PD, Bibiloni, R, Knauf, C, et al. (2008) Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57, 14701481.
37. Furuse, M, Fujita, K, Hiiragi, T, et al. (1998) Claudin-1 and -2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J Cell Biol 141, 15391550.
38. Furuse, M, Hirase, T, Itoh, M, et al. (1993) Occludin: a novel integral membrane-protein localizing at tight junctions. J Cell Biol 123, 17771788.
39. Mandell, KJ, McCall, IC & Parkos, CA (2004) Involvement of the junctional adhesion molecule-1 (JAM1) homodimer interface in regulation of epithelial barrier function. J Biol Chem 279, 1625416262.
40. Ikenouchi, J, Furuse, M, Furuse, K, et al. (2005) Tricellulin constitutes a novel barrier at tricellular contacts of epithelial cells. J Cell Biol 171, 939945.
41. Vermeirssen, V, Van Camp, J & Verstraete, W (2004) Bioavailability of angiotensin I converting enzyme inhibitory peptides. Br J Nutr 92, 357366.
42. Arrieta, MC, Bistritz, L & Meddings, JB (2006) Alterations in intestinal permeability. Gut 55, 15121520.
43. Madsen, KL, Malfair, D, Gray, D, et al. (1999) Interleukin-10 gene-deficient mice develop a primary intestinal permeability defect in response to enteric microflora. Inflamm Bowel Dis 5, 262270.
44. Raddatz, D, Bockemuhl, M & Ramadori, G (2005) Quantitative measurement of cytokine mRNA in inflammatory bowel disease: relation to clinical and endoscopic activity and outcome. Eur J Gastroenterol Hepatol 17, 547557.
45. Stallmach, A, Giese, T, Schmidt, C, et al. (2004) Cytokine/chemokine transcript profiles reflect mucosal inflammation in Crohn’s disease. Int J Colorectal Dis 19, 308315.
46. Gassler, N, Rohr, C, Schneider, A, et al. (2001) Inflammatory bowel disease is associated with changes of enterocytic junctions. Am J Physiol Gastrointest Liver Physiol 281, G216G228.
47. Kucharzik, T, Walsh, SV, Chen, J, et al. (2001) Neutrophil transmigration in inflammatory bowel disease is associated with differential expression of epithelial intercellular junction proteins. Am J Pathol 159, 20012009.
48. Bruewer, M, Luegering, A, Kucharzik, T, et al. (2003) Proinflammatory cytokines disrupt epithelial barrier function by apoptosis-independent mechanisms. J Immunol 171, 61646172.
49. Utech, M, Ivanov, AI, Samarin, SN, et al. (2005) Mechanism of IFN-γ-induced endocytosis of tight junction proteins: myosin II-dependent vacuolarization of the apical plasma membrane. Mol Biol Cell 16, 50405052.
50. Matsuda, M, Kubo, A, Furuse, M, et al. (2004) A peculiar internalization of claudins, tight junction-specific adhesion molecules, during the intercellular movement of epithelial cells. J Cell Sci 117, 12471257.
51. Bojarski, C, Gitter, AH, Bendfeldt, K, et al. (2001) Permeability of human HT-29/B6 colonic epithelium as a function of apoptosis. J Physiol 535, 541552.
52. Schulzke, JD, Bojarski, C, Zeissig, S, et al. (2006) Disrupted barrier function through epithelial cell apoptosis. Ann N Y Acad Sci 1072, 288299.
53. Begue, B, Wajant, H, Bambou, JC, et al. (2006) Implication of TNF-related apoptosis-inducing ligand in inflammatory intestinal epithelial lesions. Gastroenterology 130, 19621974.
54. Mankertz, J, Tavalali, S, Schmitz, H, et al. (2000) Expression from the human occludin promoter is affected by tumor necrosis factor α and interferon γ. J Cell Sci 113, 20852090.
55. Zolotarevsky, Y, Hecht, G, Koutsouris, A, et al. (2002) A membrane-permeant peptide that inhibits MLC kinase restores barrier function in in vitro models of intestinal disease. Gastroenterology 123, 163172.
56. Turner, JR (2009) Intestinal mucosal barrier function in health and disease. Nat Rev Immunol 9, 799809.
57. Mennigen, R, Nolte, K, Rijcken, E, et al. (2009) Probiotic mixture VSL#3 protects the epithelial barrier by maintaining tight junction protein expression and preventing apoptosis in a murine model of colitis. Am J Physiol Gastrointest Liver Physiol 296, G1140G1149.
58. Gionchetti, P, Rizzello, F, Morselli, C, et al. (2007) High-dose probiotics for the treatment of active pouchitis. Dis Colon Rectum 50, 20752082.
59. Bai, YH, Pak, SC, Lee, SH, et al. (2005) Assessment of a bioactive compound for its potential antiinflammatory property by tight junction permeability. Phytother Res 19, 10091012.
60. Parassol, N, Freitas, M, Thoreux, K, et al. (2005) Lactobacillus casei DN-114 001 inhibits the increase in paracellular permeability of enteropathogenic Escherichia coli-infected T84 cells. Res Microbiol 156, 256262.
61. Resta-Lenert, S & Barrett, KE (2006) Probiotics and commensals reverse TNF-α- and IFN-γ-induced dysfunction in human intestinal epithelial cells. Gastroenterology 130, 731746.
62. Zyrek, AA, Cichon, C, Helms, S, et al. (2007) Molecular mechanisms underlying the probiotic effects of Escherichia coli Nissle 1917 involve ZO-2 and PKC zeta redistribution resulting in tight junction and epithelial barrier repair. Cell Microbiol 9, 804816.
63. Ukena, SN, Singh, A, Dringenberg, U, et al. (2007) Probiotic Escherichia coli Nissle 1917 Inhibits leaky gut by enhancing mucosal integrity. PLoS ONE 2, e1308.
64. Miyauchi, E, Morita, H & Tanabe, S (2009) Lactobacillus rhamnosus alleviates intestinal barrier dysfunction in part by increasing expression of zonula occludens-1 and myosin light-chain kinase in vivo . J Dairy Sci 92, 24002408.
65. Chen, HQ, Yang, J, Zhang, M, et al. (2010) Lactobacillus plantarum ameliorates colonic epithelial barrier dysfunction by modulating the apical junctional complex and PepT1 in IL-10 knockout mice. Am J Physiol Gastrointest Liver Physiol 299, G1287G1297.
66. Ewaschuk, JB, Diaz, H, Meddings, L, et al. (2008) Secreted bioactive factors from Bifidobacterium infantis enhance epithelial cell barrier function. Am J Physiol Gastrointest Liver Physiol 295, G1025G1034.
67. Keita, AV, Gullberg, E, Ericson, AC, et al. (2006) Characterization of antigen and bacterial transport in the follicle-associated epithelium of human ileum. Lab Invest 86, 504516.
68. Keita, AC, Salim, S, Jiang, T, et al. (2008) Increased uptake of non-pathogenic E. coli via the follicle-associated epithelium in longstanding ileal Crohn’s disease. J Pathol 215, 135144.
69. Rescigno, M, Rotta, G, Valzasina, B, et al. (2001) Dendritic cells shuttle microbes across gut epithelial monolayers. Immunobiology 204, 572581.
70. Shimizu, M, Tsunogai, M & Arai, S (1997) Transepithelial transport of oligopeptides in the human intestinal cell, Caco-2. Peptides 18, 681687.
71. Shen, WC, Wan, JS & Ekrami, H (1992) Enhancement of polypeptide and protein-absorption by macromolecular carriers via endocytosis and transcytosis 3. Adv Drug Deliver Rev 8, 93113.
72. Van Niel, G, Mallegol, J, Bevilacqua, C, et al. (2003) Intestinal epithelial exosomes carry MHC class II/peptides able to inform the immune system in mice. Gut 52, 16901697.
73. Mallegol, J, Van Niel, G, Lebreton, C, et al. (2007) T84-intestinal epithelial exosomes bear MHC class II/peptide complexes potentiating antigen presentation by dendritic cells. Gastroenterology 132, 18661876.
74. Fernandez, MI, Pedron, T, Tournebize, R, et al. (2003) Anti-inflammatory role for intracellular dimeric immunoglobulin a by neutralization of lipopolysaccharide in epithelial cells. Immunity 18, 739749.
75. Matysiak-Budnik, T, Moura, IC, Arcos-Fajardo, M, et al. (2008) Secretory IgA mediates retrotranscytosis of intact gliadin peptides via the transferrin receptor in celiac disease. J Exp Med 205, 143154.
76. Brambell, FW (1966) Transmission of immunity from mother to young and catabolism of immunoglobulins. Lancet ii, 10871093.
77. Jones, EA & Waldmann, TA (1971) Mechanism of intestinal uptake and transcellular transport of IgG in neonatal rat. Gut 12, 855856.
78. Yoshida, M, Kobayashi, K, Kuo, TT, et al. (2006) Neonatal Fc receptor for IgG regulates mucosal immune responses to luminal bacteria. J Clin Invest 116, 21422151.
79. Kobayashi, K, Qiao, SW, Yoshida, M, et al. (2009) An FcRn-dependent role for anti-flagellin immunoglobulin G in pathogenesis of colitis in mice. Gastroenterology 137, 17461756.
80. Kaiserlian, D, Lachaux, A, Grosjean, I, et al. (1993) Intestinal epithelial cells express the CD23/Fc epsilon RII molecule: enhanced expression in enteropathies. Immunology 80, 9095.
81. Soderholm, JD, Olaison, G, Hedman, L, et al. (1996) Crohn’s disease: a hyperreactivity of the tight junctions? Gut 39, A167.
82. Soderholm, JD, Streutker, C, Yang, PC, et al. (2004) Increased epithelial uptake of protein antigens in the ileum of Crohn’s disease mediated by tumour necrosis factor α. Gut 53, 18171824.
83. D’Haens, G (2009) Anti-TNF-α treatment strategies: results and clinical perspectives. Gastroenterol Clin Biol 33, S209S216.
84. Terpend, K, Boisgerault, F, Blaton, MA, et al. (1998) Protein transport and processing by human HT29-19A intestinal cells: effect of interferon γ. Gut 42, 538545.
85. Goodacre, R (2007) Metabolomics of a superorganism. J Nutr 137, 259S266S.
86. Wilson, A, Teft, WA, Morse, BL, et al. (2015) Trimethylamine-N-oxide: a novel biomarker for the identification of inflammatory bowel disease. Dig Dis Sci 60, 36203630.
87. Gill, SR, Pop, M, DeBoy, RT, et al. (2006) Metagenomic analysis of the human distal gut microbiome. Science 312, 13551359.
88. Wu, GD, Chen, J, Hoffmann, C, et al. (2011) Linking long-term dietary patterns with gut microbial enterotypes. Science 334, 105108.
89. Sartor, RB (2008) Microbial influences in inflammatory bowel diseases. Gastroenterology 134, 577594.
90. Matsuoka, K & Kanai, T (2015) The gut microbiota and inflammatory bowel disease. Semin Immunopathol 37, 4755.
91. Jia, WJ, Whitehead, RN, Griffiths, L, et al. (2012) Diversity and distribution of sulphate-reducing bacteria in human faeces from healthy subjects and patients with inflammatory bowel disease. FEMS Immunol Med Microbiol 65, 5568.
92. Bibiloni, R, Mangold, M, Madsen, KL, et al. (2006) The bacteriology of biopsies differs between newly diagnosed, untreated, Crohn’s disease and ulcerative colitis patients. J Med Microbiol 55, 11411149.
93. Chassaing, B & Darfeuille-Michaud, A (2011) The commensal microbiota and enteropathogens in the pathogenesis of inflammatory bowel diseases. Gastroenterology 140, 17201728.
94. Frank, DN, Amand, ALS, Feldman, RA, et al. (2007) Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci U S A 104, 1378013785.
95. van der Waaij, LA, Kroese, FGM, Visser, A, et al. (2004) Immunoglobulin coating of faecal bacteria in inflammatory bowel disease. Eur J Gastroenterol Hepatol 16, 669674.
96. Pitcher, MCL, Beatty, ER & Cummings, JH (2000) The contribution of sulphate reducing bacteria and 5-aminosalicylic acid to faecal sulphide in patients with ulcerative colitis. Gut 46, 6472.
97. Zinkevich, V & Beech, IB (2000) Screening of sulfate-reducing bacteria in colonoscopy samples from healthy and colitic human gut mucosa. FEMS Microbiol Ecol 34, 147155.
98. Duffy, M, O’Mahony, L, Coffey, JC, et al. (2002) Sulfate-reducing bacteria colonize pouches formed for ulcerative colitis but not for familial adenomatous polyposis. Dis Colon Rectum 45, 384388.
99. Ohge, H, Furne, JK, Springfield, J, et al. (2005) Association between fecal hydrogen sulfide production and pouchitis. Dis Colon Rectum 48, 469475.
100. Manichanh, C, Rigottier-Gois, L, Bonnaud, E, et al. (2006) Reduced diversity of faecal microbiota in Crohn’s disease revealed by a metagenomic approach. Gut 55, 205211.
101. Carmen Collado, M & Sanz, Y (2007) Quantification of mucosa-adhered microbiota of lambs and calves by the use of culture methods and fluorescent in situ hybridization coupled with flow cytometry techniques. Vet Microbiol 121, 299306.
102. Shatalin, K, Shatalina, A, Mironov, A, et al. (2011) H2S: a universal defense against antibiotics in bacteria. Science 335, 986990.
103. Marquet, P, Duncan, SH, Chassard, C, et al. (2009) Lactate has the potential to promote hydrogen sulphide formation in the human colon. FEMS Microbiol Lett 299, 128134.
104. Giaffer, MH, Clark, A & Holdsworth, CD (1992) Antibodies to Saccharomyces cerevisiae in patients with Crohn’s disease and their possible pathogenic importance. Gut 33, 10711075.
105. Rescigno, M (2011) The intestinal epithelial barrier in the control of homeostasis and immunity. Trends Immunol 32, 256264.
106. Qin, JJ, Li, RQ, Raes, J, et al. (2010) A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 5965.
107. Willing, BP, Dicksved, J, Halfvarson, J, et al. (2010) A pyrosequencing study in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel disease phenotypes. Gastroenterology 139, 18441854.e1.
108. Willing, B, Halfvarson, J, Dicksved, J, et al. (2009) Twin studies reveal specific imbalances in the mucosa-associated microbiota of patients with ileal Crohn’s disease. Inflamm Bowel Dis 15, 653660.
109. Frank, DN, Robertson, CE, Hamm, CM, et al. (2011) Disease phenotype and genotype are associated with shifts in intestinal-associated microbiota in inflammatory bowel diseases. Inflamm Bowel Dis 17, 179184.
110. Packey, CD & Sartor, RB (2009) Commensal bacteria, traditional and opportunistic pathogens, dysbiosis and bacterial killing in inflammatory bowel diseases. Curr Opin Infect Dis 22, 292301.
111. Sokol, H, Lay, C, Seksik, P, et al. (2008) Analysis of bacterial bowel communities of IBD patients: what has it revealed? Inflamm Bowel Dis 14, 858867.
112. Feng, T & Elson, CO (2011) Adaptive immunity in the host–microbiota dialog. Mucosal Immunol 4, 1521.
113. Konrad, A, Cong, YZ, Duck, W, et al. (2006) Tight mucosal compartmentation of the murine immune response to antigens of the enteric microbiota. Gastroenterology 130, 20502059.
114. Slack, E, Hapfelmeier, S, Stecher, B, et al. (2009) Innate and adaptive immunity cooperate flexibly to maintain host–microbiota mutualism. Science 325, 617620.
115. Sartor, RB (2010) Genetics and environmental interactions shape the intestinal microbiome to promote inflammatory bowel disease versus mucosal homeostasis. Gastroenterology 139, 18161819.
116. Abraham, C & Cho, JH (2009) Inflammatory bowel disease. New Engl J Med 361, 20662078.
117. 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, 259263.
118. Wehkamp, J, Salzman, NH, Porter, E, et al. (2005) Reduced Paneth cell α-defensins in ileal Crohn’s disease. Proc Natl Acad Sci U S A 102, 1812918134.
119. Hill, AB (1965) Environment and disease: association or causation? Proc R Soc Med 58, 295300.
120. Evans, AS (1976) Causation and disease: Henle–Koch postulates revisited. Yale J Biol Med 49, 175195.
121. Fredricks, DN & Relman, DA (1996) Sequence-based identification of microbial pathogens: a reconsideration of Koch’s postulates. Clin Microbiol Rev 9, 1833.
122. Sepehri, S, Kotlowski, R, Bernstein, CN, et al. (2007) Microbial diversity of inflamed and noninflamed gut biopsy tissues in inflammatory bowel disease. Inflamm Bowel Dis 13, 675683.
123. Seksik, P, Lepage, P, de la Cochetiere, MF, et al. (2005) Search for localized dysbiosis in Crohn’s disease ulcerations by temporal temperature gradient gel electrophoresis of 16S rRNA. J Clin Microbiol 43, 46544658.
124. Walker, AW, Sanderson, JD, Churcher, C, et al. (2011) High-throughput clone library analysis of the mucosa-associated microbiota reveals dysbiosis and differences between inflamed and non-inflamed regions of the intestine in inflammatory bowel disease. BMC Microbiol 11, 7.
125. Quigley, EMM (2011) Commensal bacteria: the link between IBS and IBD? Curr Opin Clin Nutr Metab Care 14, 497503.
126. Sartor, RB (2011) Key questions to guide a better understanding of host–commensal microbiota interactions in intestinal inflammation. Mucosal Immunol 4, 127132.
127. Sokol, H, Pigneur, B, Watterlot, L, et al. (2008) Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A 105, 1673116736.
128. Swidsinski, A, Loening-Baucke, V, Vaneechoutte, M, et al. (2008) Active Crohn’s disease and ulcerative colitis can be specifically diagnosed and monitored based on the biostructure of the fecal flora. Inflamm Bowel Dis 14, 147161.
129. Maldonado-Contreras, AL & McCormick, BA (2011) Intestinal epithelial cells and their role in innate mucosal immunity. Cell Tissue Res 343, 512.
130. Fyderek, K, Strus, M, Kowalska-Duplaga, K, et al. (2009) Mucosal bacterial microflora and mucus layer thickness in adolescents with inflammatory bowel disease. World J Gastroenterol 15, 52875294.
131. Corfield, AP (2015) Mucins: a biologically relevant glycan barrier in mucosal protection. Biochim Biophys Acta 1850, 236252.
132. Joossens, M, Huys, G, Cnockaert, M, et al. (2011) Dysbiosis of the faecal microbiota in patients with Crohn’s disease and their unaffected relatives. Gut 60, 631637.
133. Kufer, TA & Sansonetti, PJ (2007) Sensing of bacteria: NOD a lonely job. Curr Opin Microbiol 10, 6269.
134. Wilmanski, JM, Petnicki-Ocwieja, T & Kobayashi, KS (2008) NLR proteins: integral members of innate immunity and mediators of inflammatory diseases. J Leukoc Biol 83, 1330.
135. Girardin, SE, Travassos, LH, Herve, M, et al. (2003) Peptidoglycan molecular requirements allowing detection by Nod1 and Nod2. J Biol Chem 278, 4170241708.
136. Girardin, SE, Boneca, IG, Carneiro, LAM, et al. (2003) Nod1 detects a unique muropeptide from Gram-negative bacterial peptidoglycan. Science 300, 15841587.
137. Chamaillard, M, Hashimoto, M, Horie, Y, et al. (2003) An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat Immunol 4, 702707.
138. Girardin, SE, Boneca, IG, Viala, J, et al. (2003) Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem 278, 88698872.
139. Inohara, N, Ogura, Y, Fontalba, A, et al. (2003) Host recognition of bacterial muramyl dipeptide mediated through NOD2. J Biol Chem 278, 55095512.
140. Le Bourhis, L, Benko, S & Girardin, SE (2007) Nod1 and Nod2 in innate immunity and human inflammatory disorders. Biochem Soc Trans 35, 14791484.
141. Hugot, JP, Chamaillard, M, Zouali, H, et al. (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411, 599603.
142. Ogura, Y, Bonen, DK, Inohara, N, et al. (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411, 603606.
143. Wehkamp, J, Schmid, M & Stange, EF (2007) Defensins and other antimicrobial peptides in inflammatory bowel disease. Curr Opin Gastroenterol 23, 370378.
144. Bevins, CL, Martin-Porter, E & Ganz, T (1999) Defensins and innate host defence of the gastrointestinal tract. Gut 271, 1403814045.
145. Ayabe, T, Satchell, DP, Wilson, CL, et al. (2000) Secretion of microbicidal α-defensins by intestinal Paneth cells in response to bacteria. Nat Immunol 1, 113118.
146. Khan, J & Islam, MN (2011) Intestinal barrier function: impairment and possible modulation. Int Med J 18, 212216.
147. Astwood, JD, Leach, JN & Fuchs, RL (1996) Stability of food allergens to digestion in vitro . Nat Biotechnol 14, 12691273.
148. Mahé, S, Messing, B, Thuillier, F, et al. (1991) Digestion of bovine milk proteins in patients with a high jejunostomy. Am J Clin Nutr 54, 534538.
149. Shan, L, Molberg, O, Parrot, I, et al. (2002) Structural basis for gluten intolerance in celiac sprue. Science 297, 22752279.
150. Shan, L, Qiao, SW, Arentz-Hansen, H, et al. (2005) Identification and analysis of multivalent proteolytically resistant peptides from gluten: implications for celiac sprue. J Proteome Res 4, 17321741.
151. Diesner, SC, Knittelfelder, R, Krishnamurthy, D, et al. (2008) Dose-dependent food allergy induction against ovalbumin under acid-suppression: a murine food allergy model. Immunol Lett 121, 4551.
152. Estaki, M, DeCoffe, D & Gibson, DL (2014) Interplay between intestinal alkaline phosphatase, diet, gut microbes and immunity. World J Gastroenterol 20, 1565015656.
153. Lalles, JP (2014) Intestinal alkaline phosphatase: novel functions and protective effects. Nutr Rev 72, 8294.
154. Wang, W, Chen, SW, Zhu, J, et al. (2015) Intestinal alkaline phosphatase inhibits the translocation of bacteria of gut-origin in mice with peritonitis: mechanism of action. PLOS ONE 10, e0124835.
155. Martínez-Augustin, O, López-Posadas, R, González, R, et al. (2010) It may not be intestinal, but tissue non-specific alkaline phosphatase. Gut 59, 560.
156. Molnar, K, Vannay, A, Sziksz, E, et al. (2012) Decreased mucosal expression of intestinal alkaline phosphatase in children with coeliac disease. Virchows Archiv 460, 157161.
157. Tuin, A, Poelstra, K, de Jager-Krikken, A, et al. (2009) Role of alkaline phosphatase in colitis in man and rats. Gut 58, 379387.
158. Lukas, M, Drastich, P, Konecny, M, et al. (2010) Exogenous alkaline phosphatase for the treatment of patients with moderate to severe ulcerative colitis. Inflamm Bowel Dis 16, 11801186.
159. Weersma, RK, Stokkers, PCF, van Bodegraven, AA, et al. (2009) Molecular prediction of disease risk and severity in a large Dutch Crohn’s disease cohort. Gut 58, 388395.
160. Ellinghaus, D, Bethune, J, Petersen, BS, et al. (2015) The genetics of Crohn’s disease and ulcerative colitis – status quo and beyond. Scand J Gastroenterol 50, 1323.
161. Qin, XF (2012) Etiology of inflammatory bowel disease: a unified hypothesis. World J Gastroenterol 18, 17081722.
162. Ferguson, LR (2013) Nutrigenetics, nutrigenomics and inflammatory bowel diseases. Expert Rev Clin Immunol 9, 717726.
163. Ferguson, LR (2010) Nutrigenomics and inflammatory bowel diseases. Expert Rev Clin Immunol 6, 573583.
164. Graham, DB & Xavier, RJ (2013) From genetics of inflammatory bowel disease towards mechanistic insights. Trends Immunol 34, 371378.
165. Neuman, MG & Nanau, RM (2012) Single-nucleotide polymorphisms in inflammatory bowel disease. Transl Res 160, 4564.
166. Gardet, A & Xavier, RJ (2012) Common alleles that influence autophagy and the risk for inflammatory bowel disease. Curr Opin Immunol 24, 522529.
167. Cheon, JH (2013) Genetics of inflammatory bowel diseases: a comparison between Western and Eastern perspectives. J Gastroenterol Hepatol 28, 220226.
168. Stange, EF (2013) Inflammatory bowel disease: the past 50 years [article in German]. Z Gastroenterol 51, 371377.
169. Boirivant, M & Cossu, A (2012) Inflammatory bowel disease. Oral Dis 18, 115.
170. Satokari, R (2015) Contentious host–microbiota relationship in inflammatory bowel disease – can foes become friends again? Scand J Gastroenterol 50, 3442.
171. Jostins, L, Ripke, S, Weersma, RK, et al. (2012) Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119124.
172. Thompson, AI & Lees, CW (2011) Genetics of ulcerative colitis. Inflamm Bowel Dis 17, 831848.
173. Rivas, MA, Beaudoin, M, Gardet, A, et al. (2011) Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat Genet 43, 10661073.
174. Khor, B, Gardet, A & Xavier, RJ (2011) Genetics and pathogenesis of inflammatory bowel disease. Nature 474, 307317.
175. Viennois, E, Baker, MT, Xiao, B, et al. (2015) Longitudinal study of circulating protein biomarkers in inflammatory bowel disease. J Proteomics 112, 166179.
176. Hu, YG, Smith, DE, Ma, K, et al. (2008) Targeted disruption of peptide transporter pept1 gene in mice significantly reduces dipeptide absorption in intestine. Mol Pharm 5, 11221130.
177. Russel, MG (2000) Changes in the incidence of inflammatory bowel disease: what does it mean? Eur J Intern Med 11, 191196.
178. Steel, A, Nussberger, S, Romero, MF, et al. (1997) Stoichiometry and pH dependence of the rabbit proton-dependent oligopeptide transporter PepT1. J Physiol 498, 563569.
179. Boll, M, Markovich, D, Weber, WM, et al. (1994) Expression cloning of a cDNA from rabbit small intestine related to proton-coupled transport of peptides, β-lactam antibiotics and ACE-inhibitors. Pflugers Arch 429, 146149.
180. Qin, X (2007) Inactivation of digestive proteases by deconjugated bilirubin: the possible evolutionary driving force for bilirubin or biliverdin predominance in animals. Gut 56, 16411642.
181. Qin, XF (2002) Impaired inactivation of digestive proteases by deconjugated bilirubin: the possible mechanism for inflammatory bowel disease. Med Hypotheses 59, 159163.
182. Ogihara, H, Saito, H, Shin, BC, et al. (1996) Immuno-localization of H+/peptide cotransporter in rat digestive tract. Biochem Biophys Res Commun 220, 848852.
183. Ismair, MG, Vavricka, SR, Kullak-Ublick, GA, et al. (2006) hPepT1 selectively transports muramyl dipeptide but not Nod1-activating muramyl peptides. Can J Physiol Pharmacol 84, 13131319.
184. Weitz, D, Harder, D, Casagrande, F, et al. (2007) Functional and structural characterization of a prokaryotic peptide transporter with features similar to mammalian PEPT1. J Biol Chem 282, 28322839.
185. Daniel, H (2004) Molecular and integrative physiology of intestinal peptide transport. Annu Rev Physiol 66, 361384.
186. Bailey, PD, Boyd, CAR, Collier, ID, et al. (2006) Affinity prediction for substrates of the peptide transporter PepT1. Chem Commun 21, 323325.
187. Spanier, B (2014) Transcriptional and functional regulation of the intestinal peptide transporter PEPT1. J Physiol 592, 871879.
188. Watanabe, C, Kato, Y, Ito, S, et al. (2005) Na+/H+ exchanger 3 affects transport property of H+/oligopeptide transporter 1. Drug Metab Pharmacokinet 20, 443451.
189. Vavricka, SR, Musch, MW, Fujiya, M, et al. (2006) Tumor necrosis factor-α and interferon-γ increase PepT1 expression and activity in the human colon carcinoma cell line Caco-2/bbe and in mouse intestine. Pflugers Arch 452, 7180.
190. Zucchelli, M, Torkvist, L, Bresso, F, et al. (2009) PepT1 oligopeptide transporter (SLC15A1) gene polymorphism in inflammatory bowel disease. Inflamm Bowel Dis 15, 15621569.
191. Strober, W, Asano, N, Fuss, I, et al. (2014) Cellular and molecular mechanisms underlying NOD2 risk-associated polymorphisms in Crohn’s disease. Immunol Rev 260, 249260.
192. Freeman, HJ (2015) Clinical relevance of intestinal peptide uptake. World J Gastrointest Pharm Ther 6, 2227.
193. Nassl, A-M, Rubio-Aliaga, I, Fenselau, H, et al. (2011) Amino acid absorption and homeostasis in mice lacking the intestinal peptide transporter PEPT1. Am J Physiol Gastrointest Liver Physiol 301, G128G137.
194. Nataro, JP & Kaper, JB (1998) Diarrheagenic Escherichia coli . Clin Microbiol Rev 11, 142201.
195. Nguyen, HTT, Dalmasso, G, Powell, KR, et al. (2009) Pathogenic bacteria induce colonic PepT1 expression: an implication in host defense response. Gastroenterology 137, 14351447.
196. Merlin, D, Steel, A, Gewirtz, AT, et al. (1998) hPepT1-mediated epithelial transport of bacteria-derived chemotactic peptides enhances neutrophil–epithelial interactions. J Clin Invest 102, 20112018.
197. Vavricka, SR, Musch, MW, Chang, JE, et al. (2004) hPepT1 transports muramyl dipeptide, activating NF-κB and stimulating IL-8 secretion in human colonic Caco2/bbe cells. Gastroenterology 127, 14011409.
198. Dalmasso, G, Hang, TTN, Ingersoll, SA, et al. (2011) The PepT1-NOD2 signaling pathway aggravates induced colitis in mice. Gastroenterology 141, 13341345.
199. Foster, DR & Zheng, X (2007) Cephalexin inhibits N-formylated peptide transport and intestinal hyperpermeability in Caco2 cells. J Pharm Pharm Sci 10, 299310.
200. Dalmasso, G, Yan, Y, Charrier, L, et al. (2007) Butyrate transcriptionally enhances peptide transporter (hPepT1) expression and activity. FASEB J 21, A586A586.
201. Bhardwaj, RK, Herrera-Ruiz, D, Eltoukhy, N, et al. (2006) The functional evaluation of human peptide/histidine transporter 1 (hPHT1) in transiently transfected COS-7 cells. Eur J Pharm Sci 27, 533542.
202. Wu, SP & Smith, DE (2013) Impact of intestinal PepT1 on the kinetics and dynamics of N-formyl-methionyl-leucyl-phenylalanine, a bacterially-produced chemotactic peptide. Mol Pharm 10, 677684.
203. Tsuji, A, Nakashima, E, Deguchi, Y, et al. (1981) Degradation kinetics and mechanism of aminocephalosporins in aqueous solution: cefadroxil. J Pharm Sci 70, 11201128.
204. Walker, D, Thwaites, DT, Simmons, NL, et al. (1998) Substrate upregulation of the human small intestinal peptide transporter, hPepT1. J Physiol 507, 697706.
205. Huebner, C, Browning, BL, Petermann, I, et al. (2009) Genetic analysis of MDR1 and inflammatory bowel disease reveals protective effect of heterozygous variants for ulcerative colitis. Inflamm Bowel Dis 15, 17841793.
206. Sakata, K, Yamashita, T, Maeda, M, et al. (2001) Cloning of a lymphatic peptide/histidine transporter. Biochem J 356, 5360.
207. Potocnik, U, Ferkolj, I, Glavac, D, et al. (2004) Polymorphisms in multidrug resistance 1 (MDR1) gene are associated with refractory Crohn disease and ulcerative colitis. Genes Immun 5, 530539.
208. Sabbah, A, Chang, TH, Harnack, R, et al. (2009) Activation of innate immune antiviral responses by Nod2. Nat Immunol 10, 10731080.
209. Garrett, WS, Gallini, CA, Yatsunenko, T, et al. (2010) Enterobacteriaceae act in concert with the gut microbiota to induce spontaneous and maternally transmitted colitis. Cell Host Microbe 8, 292300.
210. Molodecky, NA, Soon, IS, Rabi, DM, et al. (2012) Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 142, 4654.
211. Merlin, D, Si-Tahar, M, Sitaraman, SV, et al. (2001) Colonic epithelial hPepT1 expression occurs in inflammatory bowel disease: transport of bacterial peptides influences expression of MHC class 1 molecules. Gastroenterology 120, 16661679.
212. Nduati, V, Yan, YT, Dalmasso, G, et al. (2007) Leptin transcriptionally enhances peptide transporter (hPepT1) expression and activity via the cAMP-response element-binding protein and Cdx2 transcription factors. J Biol Chem 282, 13591373.
213. Ziegler, TR, Fernández-Estívariz, C, Gu, LH, et al. (2002) Distribution of the H+/peptide transporter PepT1 in human intestine: up-regulated expression in the colonic mucosa of patients with short-bowel syndrome. Am J Clin Nutr 75, 922930.
214. Shimakura, J, Terada, T, Shimada, Y, et al. (2006) The transcription factor Cdx2 regulates the intestine-specific expression of human peptide transporter 1 through functional interaction with Sp1. Biochem Pharmacol 71, 15811588.
215. Metges, CC (2000) Contribution of microbial amino acids to amino acid homeostasis of the host. J Nutr 130, 1857S1864S.
216. Whitman, WB, Coleman, DC & Wiebe, WJ (1998) Prokaryotes: the unseen majority. Proc Natl Acad Sci U S A 95, 65786583.
217. Garrett, WS, Lord, GM, Punit, S, et al. (2007) Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell 131, 3345.
218. Davies, PS & Rhodes, J (1978) Maintenance of remission in ulcerative colitis with sulphasalazine or a high-fibre diet: a clinical trial. Br Med J i, 15241525.
219. Fernandez-Banares, F, Hinojosa, J, Sanchez-Lombrana, JL, et al. (1999) Randomized clinical trial of Plantago ovata seeds (dietary fiber) as compared with mesalamine in maintaining remission in ulcerative colitis. Am J Gastroenterol 94, 427433.
220. Wright, R & Truelove, SC (1965) A controlled therapeutic trial of various diets in ulcerative colitis. Br Med J ii, 138141.
221. Samuelsson, SM, Ekbom, A, Zack, M, et al. (1991) Risk factors for extensive ulcerative colitis and ulcerative proctitis: a population based case–control study. Gut 32, 15261530.
222. Pithadia, AB & Jain, S (2011) Treatment of inflammatory bowel disease (IBD). Pharmacol Rep 63, 629642.
223. Roediger, WEW, Duncan, A, Kapaniris, O, et al. (1993) Reducing sulfur compounds of the colon impair colonocyte nutrition: implications for ulcerative colitis. Gastroenterology 104, 802809.
224. Sakamoto, N, Kono, S, Wakai, K, et al. (2005) Dietary risk factors for inflammatory bowel disease: a multicenter case–control study in Japan. Inflamm Bowel Dis 11, 154163.
225. King, TS, Woolner, JT & Hunter, JO (1997) The dietary management of Crohn’s disease. Aliment Pharmacol Ther 11, 1731.
226. Choi, J, Sabikhi, L, Hassan, A, et al. (2012) Bioactive peptides in dairy products. Int J Dairy Technol 65, 112.
227. Meisel, H & FitzGerald, RJ (2003) Biofunctional peptides from milk proteins: mineral binding and cytomodulatory effects. Curr Pharm Des 9, 12891295.
228. Meisel, H (2004) Multifunctional peptides encrypted in milk proteins. Biofactors 21, 5561.
229. Schmid, A (2009) Bioactive substances in meat and meat products. Fleischwirtschaft 89, 8390.
230. Ryan, JT, Ross, RP, Bolton, D, et al. (2011) Bioactive peptides from muscle sources: meat and fish. Nutrients 3, 765791.
231. Toldra, F & Reig, M (2011) Innovations for healthier processed meats. Trends Food Sci Technol 22, 517522.
232. Minkiewicz, P, Dziuba, J & Michalska, J (2011) Bovine meat proteins as potential precursors of biologically active peptides: a computational study based on the BIOPEP Database. Food Sci Technol Int 17, 3945.
233. Chatterton, DEW, Nguyen, DN, Bering, SB, et al. (2013) Anti-inflammatory mechanisms of bioactive milk proteins in the intestine of newborns. Int J Biochem Cell Biol 45, 17301747.
234. Letterio, JJ, Geiser, AG, Kulkarni, AB, et al. (1994) Maternal rescue of transforming growth factor-β1 null mice. Science 264, 19361938.
235. Fei, YJ, Kanai, Y, Nussberger, S, et al. (1994) Expression cloning of a mammalian proton-coupled oligopeptide transporter. Nature 368, 563566.
236. Tanida, S, Kataoka, H, Mizoshita, T, et al. (2010) Intranuclear translocation signaling of HB-EGF carboxy-terminal fragment and mucosal defense through cell proliferation and migration in digestive tracts. Digestion 82, 145149.
237. Mehta, VB & Besner, GE (2005) Heparin-binding epidermal growth factor-like growth factor inhibits cytokine-induced NF-κB activation and nitric oxide production via activation of the phosphatidylinositol 3-kinase pathway. J Immunol 175, 19111918.
238. Mehta, VB & Besner, GE (2003) Inhibition of NF-κB activation and its target genes by heparin-binding epidermal growth factor-like growth factor. J Immunol 171, 60146022.
239. Montagne, L, Toullec, R, Formal, M, et al. (2000) Influence of dietary protein level and origin on the flow of mucin along the small intestine of the preruminant calf. J Dairy Sci 83, 28202828.
240. Lien, KA, Sauer, WC & He, JM (2001) Dietary influences on the secretion into and degradation of mucin in the digestive tract of monogastric animals and humans. J Anim Feed Sci 10, 223245.
241. Claustre, J, Toumi, F, Trompette, A, et al. (2002) Effects of peptides derived from dietary proteins on mucus secretion in rat jejunum. Am J Physiol Gastrointest Liver Physiol 283, G521G528.
242. Han, KS, Deglaire, A, Sengupta, R, et al. (2008) Hydrolyzed casein influences intestinal mucin gene expression in the rat. J Agric Food Chem 56, 55725576.
243. Miner-Williams, W (2012) The protein composition of endogenous losses in the human gut. http://mro.massey.ac.nz/handle/10179/3401 (accessed April 2016).
244. Trompette, A, Claustre, J, Caillon, F, et al. (2003) Milk bioactive peptides and β-casomorphins induce mucus release in rat jejunum. J Nutr 133, 34993503.
245. Clare, DA & Swaisgood, HE (2000) Bioactive milk peptides: a prospectus. J Dairy Sci 83, 11871195.
246. Zoghbi, S, Trompette, A, Claustre, J, et al. (2006) β-Casomorphin-7 regulates the secretion and expression of gastrointestinal mucins through a mu-opioid pathway. Am J Physiol Gastrointest Liver Physiol 290, G1105G1113.
247. van Klinken, BJW, Einerhand, AWC, van der Wal, JWG, et al. (1998) Quantitative analysis of MUC2 secretion in ulcerative colitis. Gastroenterology 114, A1106A1106.
248. Van Klinken, BJW, Van der Wal, JWG, Einerhand, AWC, et al. (1999) Sulphation and secretion of the predominant secretory human colonic mucin MUC2 in ulcerative colitis. Gut 44, 387393.
249. Tytgat, KM, Opdam, FJM, Einerhand, AWC, et al. (1996) MUC2 is the prominent colonic mucin expressed in ulcerative colitis. Gut 38, 554563.
250. Tytgat, KM, vanderWal, JWG, Einerhand, AWC, et al. (1996) Quantitative analysis of MUC2 synthesis in ulcerative colitis. Biochem Biophys Res Commun 224, 397405.
251. Shaoul, R, Okada, Y, Cutz, E, et al. (2004) Colonic expression of MUC2, MUC5AC, and TFF1 in inflammatory bowel disease in children. J Pediatric Gastroenterol Nutr 38, 488493.
252. Boltin, D, Perets, TT, Vilkin, A, et al. (2013) Mucin function in inflammatory bowel disease: an update. J Clin Gastroenterol 47, 106111.
253. Xie, B & Costello, CE (2008) Carbohydrate structure determination by mass spectrometry. In Carbohydrate Chemistry, Biology and Medical Applications, pp. 2957 [HG Garg, MK Cowman and CA Hales, editors]. Oxford: Elsevier.
254. Baugh, MD, Perry, MJ, Hollander, AP, et al. (1999) Matrix metalloproteinase levels are elevated in inflammatory bowel disease. Gastroenterology 117, 814822.
255. Kirkegaard, T, Hansen, A, Bruun, E, et al. (2004) Expression and localisation of matrix metalloproteinases and their natural inhibitors in fistulae of patients with Crohn’s disease. Gut 53, 701709.
256. Castaneda, FE, Walia, B, Vijay-Kumar, M, et al. (2005) Targeted deletion of metalloproteinase 9 attenuates experimental colitis in mice: central role of epithelial-derived MMP. Gastroenterology 129, 19912008.
257. Baugh, MD, Evans, GS, Hollander, AP, et al. (1998) Expression of matrix metalloproteases in inflammatory bowel disease. Ann N Y Acad Sci 859, 249253.
258. Kossakowska, AE, Medlicott, SAC, Edwards, DR, et al. (1999) Elevated plasma gelatinase A (MMP-2) activity is associated with quiescent Crohn’s disease. Ann N Y Acad Sci 878, 578580.
259. Garg, P, Ravi, A, Patel, NR, et al. (2007) Matrix metalloproteinase-9 regulates MUC-2 expression through its effect on goblet cell differentiation. Gastroenterology 132, 18771889.
260. Shields, JM, Christy, RJ & Yang, VW (1996) Identification and characterization of a gene encoding a gut-enriched Kruppel-like factor expressed during growth arrest. J Biol Chem 271, 2000920017.
261. Ng, AYN, Waring, P, Ristevski, S, et al. (2002) Inactivation of the transcript ion factor Elf3 in mice results in dysmorphogenesis and altered differentiation of intestinal epithelium. Gastroenterology 122, 14551466.
262. Lammers, KM, Lu, R, Brownley, J, et al. (2008) Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology 135, 194204.
263. Fasano, A, Not, T, Wang, W, et al. (2000) Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease. Lancet 355, 15181519.
264. Green, PHR, Lebwohl, B & Greywoode, R (2015) Celiac disease. J Allergy Clin Immunol 135, 10991106.
265. Heyman, M (2005) Gut barrier dysfunction in food allergy. Eur J Gastroenterol Hepatol 17, 12791285.
266. Heyman, M, Abed, J, Lebreton, C, et al. (2012) Intestinal permeability in coeliac disease: insight into mechanisms and relevance to pathogenesis. Gut 61, 13551364.
267. Perez, LC, de Villasante, GC, Ruiz, AC, et al. (2012) Non-dietary therapeutic clinical trials in coeliac disease. Eur J Intern Med 23, 914.
268. Crowe, SE (2014) Management of celiac disease: beyond the gluten-free diet. Gastroenterology 146, 15941596.
269. Leffler, DA, Kelly, CP, Abdallah, HZ, et al. (2012) A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge. Am J Gastroenterol 107, 15541562.
270. Kelly, CP, Green, PHR, Murray, JA, et al. (2013) Larazotide acetate in patients with coeliac disease undergoing a gluten challenge: a randomised placebo-controlled study. Aliment Pharmacol Ther 37, 252262.
271. Spaenij-Dekking, L, Kooy-Winkelaar, Y, Van Veelen, P, et al. (2005) Natural variation in toxicity of wheat: potential for selection of nontoxic varieties for celiac disease patients. Gastroenterology 129, 797806.
272. Carroccio, A, Di Prima, L, Noto, D, et al. (2011) Searching for wheat plants with low toxicity in celiac disease: between direct toxicity and immunologic activation. Dig Liver Dis 43, 3439.
273. Pinier, M, Fuhrmann, G, Galipeau, HJ, et al. (2012) The copolymer P(HEMA-co-SS) binds gluten and reduces immune response in gluten-sensitized mice and human tissues. Gastroenterology 142, U316U325.e12.
274. Mitea, C, Havenaar, R, Drijfhout, JW, et al. (2008) Efficient degradation of gluten by a prolyl endoprotease in a gastrointestinal model: implications for coeliac disease. Gut 57, 2532.
275. Tack, GJ, Van de Water, JMW, Bruins, MJ, et al. (2013) Consumption of gluten with gluten-degrading enzyme by celiac patients: A pilot-study. World J Gastroenterol 19, 58375847.
276. Schuppan, D, Junker, Y & Barisani, D (2009) Celiac disease: from pathogenesis to novel therapies. Gastroenterology 137, 19121933.
277. Rauhavirta, T, Oittinen, M, Kivisto, R, et al. (2013) Are transglutaminase 2 inhibitors able to reduce gliadin-induced toxicity related to celiac disease? A proof-of-concept study. J Clin Immunol 33, 134142.
278. Xia, J, Siegel, M, Bergseng, E, et al. (2006) Inhibition of HLA-DQ2-mediated antigen presentation by analogues of a high affinity 33-residue peptide from α2-gliadin. J Am Chem Soc 128, 18591867.
279. Keech, CL, Dromey, J, Chen, ZJ, et al. (2009) Immune tolerance induced by peptide immunotherapy in an HLA Dq2-dependent mouse model of gluten immunity. Gastroenterology 136, A57A57.
280. Brown, GJ, Daveson, J, Marjason, JK, et al. (2011) A phase 1 study to determine safety, tolerability and bioactivity of Nexvax2® in HLA DQ2+ volunteers with celiac disease following a long-term, strict gluten-free diet. Gastroenterology 140, S437S438.
281. Heyman, M, Grasset, E, Ducroc, R, et al. (1988) Antigen absorption by the jejunal epithelium of children with cow’s milk allergy. Pediatr Res 24, 197202.
282. Stene, LC, Honeyman, MC, Hoffenberg, EJ, et al. (2006) Rotavirus infection frequency and risk of celiac disease autoimmunity in early childhood: a longitudinal study. Am J Gastroenterol 101, 23332340.
283. Matysiak-Budnik, T, Candalh, C, Dugave, C, et al. (2003) Alterations of the intestinal transport and processing of gliadin peptides in celiac disease. Gastroenterology 125, 696707.
284. Van Limbergen, J, Wilson, DC & Satsangi, J (2009) The genetics of Crohn’s disease. In Annual Review of Genomics and Human Genetics vol. 10, pp. 89116 [A Charavati and ED Green, editors]. Palo Alto, CA: Annual Reviews Inc.
285. Latiano, A, Palmieri, O, Valvano, MR, et al. (2008) The association of MY09B gene in Italian patients with inflammatory bowel diseases. Aliment Pharmacol Ther 27, 241248.
286. Van Bodegraven, AA, Curley, CR, Hunt, KA, et al. (2006) Genetic variation in myosin IXB is associated with ulcerative colitis. Gastroenterology 131, 17681774.
287. Monsuur, AJ, de Bakker, PIW, Alizadeh, BZ, et al. (2005) Myosin IXB variant increases the risk of celiac disease and points toward a primary intestinal barrier defect. Nat Genet 37, 13411344.
288. Foster, DR, Landowski, CP & Welage, LS (2002) Interferon-γ increases dipeptide transport via increased expression of the oligopeptide transporter h-PEPT1 in cultured human intestinal monolayers. Pharmacotherapy 10, 1334.
289. Bryant, RV, Brain, O & Travis, SPL (2015) Conventional drug therapy for inflammatory bowel disease. Scand J Gastroenterol 50, 90112.
290. Teml, A, Schaeffeler, E, Herrlinger, KR, et al. (2007) Thiopurine treatment in inflammatory bowel disease: clinical pharmacology and implication of pharmacogenetically guided dosing. Clin Pharmacokinet 46, 187208.
291. Darfeuille-Michaud, A, Boudeau, J, Bulois, P, et al. (2004) High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn’s disease. Gastroenterology 127, 412421.
292. Wehkamp, J, Harder, J, Wehkamp, K, et al. (2004) NF-κB- and AP-1-mediated induction of human β defensin-2 in intestinal epithelial cells by Escherichia coli Nissle 1917: a novel effect of a probiotic bacterium. Infect Immun 72, 57505758.
293. Moendel, M, Schroeder, BO, Zimmermann, K, et al. (2009) Probiotic E. coli treatment mediates antimicrobial human β-defensin synthesis and fecal excretion in humans. Mucosal Immunol 2, 166172.
294. Schlee, M, Wehkamp, J, Altenhoefer, A, et al. (2007) Induction of human β-defensin 2 by the probiotic Escherichia coli Nissle 1917 is mediated through flagellin. Infect Immun 75, 23992407.
295. Kruis, W, Frič, P, Pokrotnieks, J, et al. (2004) Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine. Gut 53, 16171623.
296. Fiorino, G, Danese, S & Peyrin-Biroulet, L (2010) Anti-TNF therapy in inflammatory bowel diseases. In Clinical Update on Inflammatory Disorders of the Gastrointestinal Tract vol. 26, pp. 95107 [J Mayerle and H Tilg, editors]. New York: Karger.
297. Blonski, W & Lichtenstein, GR (2006) Complications of biological therapy for inflammatory bowel diseases. Curr Opin Gastroenterol 22, 3043.
298. Rutgeerts, P, Van Assche, G & Vermeire, S (2004) Optimizing anti-TNF treatment in inflammatory bowel disease. Gastroenterology 126, 15931610.
299. Vermeire, S, Noman, M, Van Assche, G, et al. (2003) Autoimmunity associated with anti-tumor necrosis factor α treatment in Crohn’s disease: a prospective cohort study. Gastroenterology 125, 3239.
300. Siegel, CA, Hur, C, Korzenik, JR, et al. (2006) Risks and benefits of infliximab for the treatment of Crohn’s disease. Clin Gastroenterol Hepatol 4, 10171024.
301. 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, 661673.
302. Madsen, KL, Doyle, JS, Jewell, LD, et al. (1999) Lactobacillus species prevents colitis in interleukin 10 gene-deficient mice. Gastroenterology 116, 11071114.
303. Madsen, K, Cornish, A, Soper, P, et al. (2001) Probiotic bacteria enhance murine and human intestinal epithelial barrier function. Gastroenterology 121, 580591.
304. Triantafillidis, JK, Merikas, E & Georgopoulos, F (2011) Current and emerging drugs for the treatment of inflammatory bowel disease. Drug Design Dev Ther 5, 185210.
305. Nielsen, CU, Brodin, B, Jorgensen, FS, et al. (2002) Human peptide transporters: therapeutic applications. Expert Opin Ther Pat 12, 13291350.
306. Nielsen, CU, Vabeno, J, Andersen, R, et al. (2005) Recent advances in therapeutic applications of human peptide transporters. Expert Opin Ther Pat 15, 153166.
307. Rubio-Aliaga, I & Daniel, H (2008) Peptide transporters and their roles in physiological processes and drug disposition. Xenobiotica 38, 10221042.
308. Knutter, I, Theis, S, Hartrodt, B, et al. (2001) A novel inhibitor of the mammalian peptide transporter PEPT1. Biochemistry 40, 44544458.
309. Kovacs-Nolan, J, Zhang, H, Ibuki, M, et al. (2012) The PepT1-transportable soy tripeptide VPY reduces intestinal inflammation. Biochim Biophys Acta 1820, 17531763.
310. Dalmasso, G, Charrier-Hisamuddin, L, Nguyen, HTT, et al. (2008) PepT1-mediated tripeptide KPV uptake reduces intestinal inflammation. Gastroenterology 134, 166178.
311. Ito, H, Takazoe, M, Fukuda, Y, et al. (2004) A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn’s disease. Gastroenterology 126, 989996.
312. Choy, EHS, Isenberg, DA, Garrood, T, et al. (2002) Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin-6 receptor monoclonal antibody in rheumatoid arthritis: a randomized, double-blind, placebo-controlled, dose-escalation trial. Arthritis Rheum 46, 31433150.
313. Mitsuyama, K, Sata, M & Rose-John, S (2006) Interleukin-6 trans-signaling in inflammatory bowel disease. Cytokine Growth Factor Rev 17, 451461.
314. Navas-López, VM, Blasco-Alonso, J, Maseri, SL, et al. (2015) Exclusive enteral nutrition continues to be first line therapy for pediatric Crohn’s disease in the era of biologics [article in Spanish]. An Pediatr 83, 4754.
315. Konno, M, Takahashi, M, Toita, N, et al. (2015) Long-term therapeutic effectiveness of maintenance enteral nutrition for Crohn’s disease. Pediatr Int 57, 276280.
316. Hirai, F, Ishihara, H, Yada, S, et al. (2013) Effectiveness of concomitant enteral nutrition therapy and infliximab for maintenance treatment of Crohn’s disease in adults. Dig Dis Sci 58, 13291334.
317. Yamamoto, T, Nakahigashi, M, Umegae, S, et al. (2010) Prospective clinical trial: enteral nutrition during maintenance infliximab in Crohn’s disease. J Gastroenterol 45, 2429.
318. Chiba, M, Tsuji, T & Komatsu, M (2014) Conflicting results on the efficacy of enteral nutrition during infliximab maintenance therapy for Crohn’s disease are correct. Dig Dis Sci 59, 227228.
319. Picariello, G, Ferranti, P, Fierro, O, et al. (2010) Peptides surviving the simulated gastrointestinal digestion of milk proteins: biological and toxicological implications. J Chromatogr B Analyt Technol Biomed Life Sci 878, 295308.
320. Schaafsma, G (2009) Safety of protein hydrolysates, fractions thereof and bioactive peptides in human nutrition. Eur J Clin Nutr 63, 11611168.
321. Walker, WA, Wu, M, Isselbacher, KJ, et al. (1975) Intestinal uptake of macromolecules 4. Effect of pancreatic duct ligation on breakdown of antigen and antigen-antibody complexes on intestinal surface. Gastroenterology 69, 12231229.
322. Terada, T, Sawada, K, Saito, H, et al. (1999) Functional characteristics of basolateral peptide transporter in the human intestinal cell line Caco-2. Am J Physiol 276, G1435G1441.
323. Terada, T & Inui, K (2004) Peptide transporters: structure, function, regulation and application for drug delivery. Curr Drug Metab 5, 8594.
324. Shepherd, EJ, Lister, N, Affleck, JA, et al. (2002) Identification of a candidate membrane protein for the basolateral peptide transporter of rat small intestine. Biochem Biophys Res Comm 296, 918922.
325. Irie, M, Terada, T, Okuda, M, et al. (2004) Efflux properties of basolateral peptide transporter in human intestinal cell line Caco-2. Pflugers Arch 449, 186194.