Regulation of intestinal epithelial permeability by tight junctions

Abstract

The gastrointestinal epithelium forms the boundary between the body and external environment. It effectively provides a selective permeable barrier that limits the permeation of luminal noxious molecules, such as pathogens, toxins, and antigens, while allowing the appropriate absorption of nutrients and water. This selective permeable barrier is achieved by intercellular tight junction (TJ) structures, which regulate paracellular permeability. Disruption of the intestinal TJ barrier, followed by permeation of luminal noxious molecules, induces a perturbation of the mucosal immune system and inflammation, and can act as a trigger for the development of intestinal and systemic diseases. In this context, much effort has been taken to understand the roles of extracellular factors, including cytokines, pathogens, and food factors, for the regulation of the intestinal TJ barrier. Here, I discuss the regulation of the intestinal TJ barrier together with its implications for the pathogenesis of diseases.

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

Fig. 1
Fig. 2
Fig. 3

Abbreviations

AJ:

Adherens junction

ALD:

Alcoholic liver disease

AMPK:

AMP activated protein kinase

BBDP:

Biobreeding diabetes-prone

BiCM:

Conditioned medium of Bifidobacterium infantis

BT-IgSF:

Brain- and testis-specific immunoglobulin superfamily

C10:

Capric acid

C12:

Lauric acid

CAR:

Coxsacki and adenovirus receptor

CD:

Crohn’s disease

CHO:

Chinese hamster ovary

CPE:

Clostridium perfringen enterotoxin

DHA:

Docosahexaenoic acid

DSS:

Dextran sodium sulfate

ECN:

Escherichia coli Nissle1917

EGF:

Epidermal growth factor

EHEC:

Enterohemorrhagic Escherichia coli

EPA:

Eicosapentaenoic acid

EPEC:

Enteropathogenic Escherichia coli

ERK:

Extracellular signal-regulated kinase

ESAM:

Endothelial selective adhesion molecule

EspF:

Escherichia coli secreted protein F

GPCR:

G-protein-coupled receptor

HA/P:

Hemagglutinin/protease

HS/R:

Hemorrhagic shock and resuscitation

IBD:

Inflammatory bowel disease

IBS:

Irritative bowel syndrome

IFN:

Interferon

Ig:

Immunoglobulin

IL:

Interleukin

JAM:

Junctional adhesion molecule

LA:

Linolec acid

LCFA:

Long chain fatty acid

LIGHT:

Lymphotoxin-like inducible protein

L. plantarum :

Lactobacillus plantarum

L. rhamnosus :

Lactobacillus rhamnosus

MAGUK:

Membrane-associated guanylate kinase homolog

MAP:

Mitochondrial-associated protein

MCFA:

Medium chain fatty acid

MEK:

Mitogen-activated protein kinase

MLC:

Myosin light chain

MLCK:

Myosin light chain kinase

NFκB:

Nuclear factor-κB

PAR:

Proteinase activated receptor

PDZ:

Post-synaptic density 95/Drosophila discs large/zona-occludens 1

PI3K:

Phosphatidyl inositol-3 kinase

PK:

Protein kinase

PKA:

cAMP-dependent kinase

PP:

Protein phosphatase

PPAR:

Peroxisome proliferator-activated receptor

PTP:

Protein tyrosine phosphatase

ROCK:

Rho-associated kinase

SCFA:

Short chain fatty acid

SH:

Src homology

T1D:

Type I diabetes

TER:

Transepithelial electrical resistance

TGF:

Transforming growth factor

TJ:

Tight junction

TLR:

Toll-like receptor

TNF:

Tumor necrosis factor

TNFR:

TNF-α receptor

TPN:

Total parenteral nutrition

VDR:

Vitamin D receptor

ZO:

Zonula occludens

ZOT:

Zonula occludens toxin

References

  1. 1.

    Ferraris RP, Diamond J (1997) Regulation of intestinal sugar transport. Physiol Rev 77:257–302

    PubMed  CAS  Google Scholar 

  2. 2.

    Broer S (2008) Amino acid transport across mammalian intestinal and renal epithelia. Physiol Rev 88:249–286

    PubMed  CAS  Article  Google Scholar 

  3. 3.

    Kiela PR, Ghishan FK (2009) Ion transport in the intestine. Curr Opin Gastroenterol 25:87–91

    PubMed  CAS  Article  Google Scholar 

  4. 4.

    Tsukita S, Furuse M, Itoh M (2001) Multifunctional strands in tight junctions. Nat Rev Mol Cell Biol 2:285–293

    PubMed  CAS  Article  Google Scholar 

  5. 5.

    Van Itallie CM, Anderson JM (2006) Claudins and epithelial paracellular transport. Annu Rev Physiol 68:403–429

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Oda H, Takeichi M (2011) Evolution: structural and functional diversity of cadherin at the adherens junction. J Cell Biol 193:1137–1146

    PubMed  CAS  Article  Google Scholar 

  7. 7.

    Baum B, Georgiou M (2011) Dynamics of adherens junctions in epithelial establishment, maintenance, and remodeling. J Cell Biol 192:907–917

    PubMed  CAS  Article  Google Scholar 

  8. 8.

    Turner JR (2009) Intestinal mucosal barrier function in health and disease. Nat Rev Immunol 9:799–809

    PubMed  CAS  Article  Google Scholar 

  9. 9.

    Nusrat A, Turner JR, Madara JL (2000) Molecular physiology and pathophysiology of tight junctions. IV. Regulation of tight junctions by extracellular stimuli: nutrients, cytokines, and immune cells. Am J Physiol Gastrointest Liver Physiol 279:G851–G857

    PubMed  CAS  Google Scholar 

  10. 10.

    Clayburgh DR, Shen L, Turner JR (2004) A porous defense: the leaky epithelial barrier in intestinal disease. Lab Invest 84:282–291

    PubMed  CAS  Article  Google Scholar 

  11. 11.

    Farhadi A, Banan A, Fields J, Keshavarzian A (2003) Intestinal barrier: an interface between health and disease. J Gastroenterol Hepatol 18:479–497

    PubMed  Article  Google Scholar 

  12. 12.

    Capaldo CT, Nusrat A (2009) Cytokine regulation of tight junctions. Biochim Biophys Acta 1788:864–871

    PubMed  CAS  Article  Google Scholar 

  13. 13.

    Amasheh M, Andres S, Amasheh S, Fromm M, Schulzke JD (2009) Barrier effects of nutritional factors. Ann N Y Acad Sci 1165:267–273

    PubMed  CAS  Article  Google Scholar 

  14. 14.

    Mullin JM, Skrovanek SM, Valenzano MC (2009) Modification of tight junction structure and permeability by nutritional means. Ann N Y Acad Sci 1165:99–112

    PubMed  CAS  Article  Google Scholar 

  15. 15.

    Furuse M, Hirase T, Itoh M, Nagafuchi A, Yonemura S, Tsukita S (1993) Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol 123:1777–1788

    PubMed  CAS  Article  Google Scholar 

  16. 16.

    Furuse M, Fujita K, Hiiragi T, Fujimoto K, Tsukita S (1998) Claudin-1 and -2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J Cell Biol 141:1539–1550

    PubMed  CAS  Article  Google Scholar 

  17. 17.

    Martin-Padura I, Lostaglio S, Schneemann M, Williams L, Romano M, Fruscella P, Panzeri C, Stoppacciaro A, Ruco L, Villa A, Simmons D, Dejana E (1998) Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration. J Cell Biol 142:117–127

    PubMed  CAS  Article  Google Scholar 

  18. 18.

    Ikenouchi J, Furuse M, Furuse K, Sasaki H, Tsukita S (2005) Tricellulin constitutes a novel barrier at tricellular contacts of epithelial cells. J Cell Biol 171:939–945

    PubMed  CAS  Article  Google Scholar 

  19. 19.

    Gonzalez-Mariscal L, Betanzos A, Nava P, Jaramillo BE (2003) Tight junction proteins. Prog Biophys Mol Biol 81:1–44

    PubMed  CAS  Article  Google Scholar 

  20. 20.

    Madara JL, Moore R, Carlson S (1987) Alteration of intestinal tight junction structure and permeability by cytoskeletal contraction. Am J Physiol 253:C854–C861

    PubMed  CAS  Google Scholar 

  21. 21.

    Turner JR, Rill BK, Carlson SL, Carnes D, Kerner R, Mrsny RJ, Madara JL (1997) Physiological regulation of epithelial tight junctions is associated with myosin light-chain phosphorylation. Am J Physiol 273:C1378–C1385

    PubMed  CAS  Google Scholar 

  22. 22.

    Walsh SV, Hopkins AM, Chen J, Narumiya S, Parkos CA, Nusrat A (2001) Rho kinase regulates tight junction function and is necessary for tight junction assembly in polarized intestinal epithelia. Gastroenterology 121:566–579

    PubMed  CAS  Article  Google Scholar 

  23. 23.

    Al-Sadi R, Khatib K, Guo S, Ye D, Youssef M, Ma T (2011) Occludin regulates macromolecule flux across the intestinal epithelial tight junction barrier. Am J Physiol Gastrointest Liver Physiol 300:G1054–G1064

    PubMed  CAS  Article  Google Scholar 

  24. 24.

    Furuse M, Itoh M, Hirase T, Nagafuchi A, Yonemura S, Tsukita S (1994) Direct association of occludin with ZO-1 and its possible involvement in the localization of occludin at tight junctions. J Cell Biol 127:1617–1626

    PubMed  CAS  Article  Google Scholar 

  25. 25.

    Wong V, Gumbiner BM (1997) A synthetic peptide corresponding to the extracellular domain of occludin perturbs the tight junction permeability barrier. J Cell Biol 136:399–409

    PubMed  CAS  Article  Google Scholar 

  26. 26.

    Saitou M, Fujimoto K, Doi Y, Itoh M, Fujimoto T, Furuse M, Takano H, Noda T, Tsukita S (1998) Occludin-deficient embryonic stem cells can differentiate into polarized epithelial cells bearing tight junctions. J Cell Biol 141:397–408

    PubMed  CAS  Article  Google Scholar 

  27. 27.

    Schulzke JD, Gitter AH, Mankertz J, Spiegel S, Seidler U, Amasheh S, Saitou M, Tsukita S, Fromm M (2005) Epithelial transport and barrier function in occludin-deficient mice. Biochim Biophys Acta 1669:34–42

    PubMed  CAS  Article  Google Scholar 

  28. 28.

    Saitou M, Furuse M, Sasaki H, Schulzke JD, Fromm M, Takano H, Noda T, Tsukita S (2000) Complex phenotype of mice lacking occludin, a component of tight junction strands. Mol Biol Cell 11:4131–4142

    PubMed  CAS  Google Scholar 

  29. 29.

    Sakakibara A, Furuse M, Saitou M, Ando-Akatsuka Y, Tsukita S (1997) Possible involvement of phosphorylation of occludin in tight junction formation. J Cell Biol 137:1393–1401

    PubMed  CAS  Article  Google Scholar 

  30. 30.

    Rao R (2009) Occludin phosphorylation in regulation of epithelial tight junctions. Ann N Y Acad Sci 1165:62–68

    PubMed  CAS  Article  Google Scholar 

  31. 31.

    Jain S, Suzuki T, Seth A, Samak G, Rao R (2011) Protein kinase Czeta phosphorylates occludin and promotes assembly of epithelial tight junctions. Biochem J 437:289–299

    PubMed  CAS  Article  Google Scholar 

  32. 32.

    Suzuki T, Elias BC, Seth A, Shen L, Turner JR, Giorgianni F, Desiderio D, Guntaka R, Rao R (2009) PKC eta regulates occludin phosphorylation and epithelial tight junction integrity. Proc Natl Acad Sci USA 106:61–66

    PubMed  CAS  Article  Google Scholar 

  33. 33.

    Dorfel MJ, Westphal JK, Huber O (2009) Differential phosphorylation of occludin and tricellulin by CK2 and CK1. Ann N Y Acad Sci 1165:69–73

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    McKenzie JA, Riento K, Ridley AJ (2006) Casein kinase I epsilon associates with and phosphorylates the tight junction protein occludin. FEBS Lett 580:2388–2394

    PubMed  CAS  Article  Google Scholar 

  35. 35.

    Smales C, Ellis M, Baumber R, Hussain N, Desmond H, Staddon JM (2003) Occludin phosphorylation: identification of an occludin kinase in brain and cell extracts as CK2. FEBS Lett 545:161–166

    PubMed  CAS  Article  Google Scholar 

  36. 36.

    Wong V (1997) Phosphorylation of occludin correlates with occludin localization and function at the tight junction. Am J Physiol 273:C1859–C1867

    PubMed  CAS  Google Scholar 

  37. 37.

    Seth A, Sheth P, Elias BC, Rao R (2007) Protein phosphatases 2A and 1 interact with occludin and negatively regulate the assembly of tight junctions in the CACO-2 cell monolayer. J Biol Chem 282:11487–11498

    PubMed  CAS  Article  Google Scholar 

  38. 38.

    Nunbhakdi-Craig V, Machleidt T, Ogris E, Bellotto D, White CL 3rd, Sontag E (2002) Protein phosphatase 2A associates with and regulates atypical PKC and the epithelial tight junction complex. J Cell Biol 158:967–978

    PubMed  CAS  Article  Google Scholar 

  39. 39.

    Elias BC, Suzuki T, Seth A, Giorgianni F, Kale G, Shen L, Turner JR, Naren A, Desiderio DM, Rao R (2008) Phosphorylation of Y398 and Y402 in occludin prevents its interaction with ZO-1 and destabilizes its assembly at the tight junctions. J Biol Chem 284:1559–1569

    Google Scholar 

  40. 40.

    Rao RK, Basuroy S, Rao VU, Karnaky KJ Jr, Gupta A (2002) Tyrosine phosphorylation and dissociation of occludin-ZO-1 and E-cadherin-beta-catenin complexes from the cytoskeleton by oxidative stress. Biochem J 368:471–481

    PubMed  CAS  Article  Google Scholar 

  41. 41.

    Kale G, Naren AP, Sheth P, Rao RK (2003) Tyrosine phosphorylation of occludin attenuates its interactions with ZO-1, ZO-2, and ZO-3. Biochem Biophys Res Commun 302:324–329

    PubMed  CAS  Article  Google Scholar 

  42. 42.

    Suzuki T, Seth A, Rao R (2008) Role of phospholipase Cgamma-induced activation of protein kinase Cepsilon (PKCepsilon) and PKCbetaI in epidermal growth factor-mediated protection of tight junctions from acetaldehyde in Caco-2 cell monolayers. J Biol Chem 283:3574–3583

    PubMed  CAS  Article  Google Scholar 

  43. 43.

    Atkinson KJ, Rao RK (2001) Role of protein tyrosine phosphorylation in acetaldehyde-induced disruption of epithelial tight junctions. Am J Physiol Gastrointest Liver Physiol 280:G1280–G1288

    PubMed  CAS  Google Scholar 

  44. 44.

    Tsukita S, Furuse M (2000) Pores in the wall: claudins constitute tight junction strands containing aqueous pores. J Cell Biol 149:13–16

    PubMed  CAS  Article  Google Scholar 

  45. 45.

    Furuse M, Hata M, Furuse K, Yoshida Y, Haratake A, Sugitani Y, Noda T, Kubo A, Tsukita S (2002) Claudin-based tight junctions are crucial for the mammalian epidermal barrier: a lesson from claudin-1-deficient mice. J Cell Biol 156:1099–1111

    PubMed  CAS  Article  Google Scholar 

  46. 46.

    Tamura A, Hayashi H, Imasato M, Yamazaki Y, Hagiwara A, Wada M, Noda T, Watanabe M, Suzuki Y, Tsukita S (2011) Loss of claudin-15, but not claudin-2, causes Na+ deficiency and glucose malabsorption in mouse small intestine. Gastroenterology 140:913–923

    PubMed  CAS  Article  Google Scholar 

  47. 47.

    Miyamoto T, Morita K, Takemoto D, Takeuchi K, Kitano Y, Miyakawa T, Nakayama K, Okamura Y, Sasaki H, Miyachi Y, Furuse M, Tsukita S (2005) Tight junctions in Schwann cells of peripheral myelinated axons: a lesson from claudin-19-deficient mice. J Cell Biol 169:527–538

    PubMed  CAS  Article  Google Scholar 

  48. 48.

    Weber S, Hoffmann K, Jeck N, Saar K, Boeswald M, Kuwertz-Broeking E, Meij II, Knoers NV, Cochat P, Sulakova T, Bonzel KE, Soergel M, Manz F, Schaerer K, Seyberth HW, Reis A, Konrad M (2000) Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis maps to chromosome 3q27 and is associated with mutations in the PCLN-1 gene. Eur J Hum Genet 8:414–422

    PubMed  CAS  Article  Google Scholar 

  49. 49.

    Gow A, Southwood CM, Li JS, Pariali M, Riordan GP, Brodie SE, Danias J, Bronstein JM, Kachar B, Lazzarini RA (1999) CNS myelin and sertoli cell tight junction strands are absent in Osp/claudin-11 null mice. Cell 99:649–659

    PubMed  CAS  Article  Google Scholar 

  50. 50.

    Morita K, Sasaki H, Furuse M, Tsukita S (1999) Endothelial claudin: claudin-5/TMVCF constitutes tight junction strands in endothelial cells. J Cell Biol 147:185–194

    PubMed  CAS  Article  Google Scholar 

  51. 51.

    Holmes JL, Van Itallie CM, Rasmussen JE, Anderson JM (2006) Claudin profiling in the mouse during postnatal intestinal development and along the gastrointestinal tract reveals complex expression patterns. In. Gene expr patterns 6:581–588

    CAS  Article  Google Scholar 

  52. 52.

    Inai T, Kobayashi J, Shibata Y (1999) Claudin-1 contributes to the epithelial barrier function in MDCK cells. Eur J Cell Biol 78:849–855

    PubMed  CAS  Article  Google Scholar 

  53. 53.

    Amasheh S, Meiri N, Gitter AH, Schoneberg T, Mankertz J, Schulzke JD, Fromm M (2002) Claudin-2 expression induces cation-selective channels in tight junctions of epithelial cells. J Cell Sci 115:4969–4976

    PubMed  CAS  Article  Google Scholar 

  54. 54.

    Colegio OR, Van Itallie CM, McCrea HJ, Rahner C, Anderson JM (2002) Claudins create charge-selective channels in the paracellular pathway between epithelial cells. Am J Physiol Cell Physiol 283:C142–C147

    PubMed  CAS  Google Scholar 

  55. 55.

    Hou J, Gomes AS, Paul DL, Goodenough DA (2006) Study of claudin function by RNA interference. J Biol Chem 281:36117–36123

    PubMed  CAS  Article  Google Scholar 

  56. 56.

    Milatz S, Krug SM, Rosenthal R, Gunzel D, Muller D, Schulzke JD, Amasheh S, Fromm M (2010) Claudin-3 acts as a sealing component of the tight junction for ions of either charge and uncharged solutes. Biochim Biophys Acta 1798:2048–2057

    PubMed  CAS  Article  Google Scholar 

  57. 57.

    Yu AS, Enck AH, Lencer WI, Schneeberger EE (2003) Claudin-8 expression in Madin–Darby canine kidney cells augments the paracellular barrier to cation permeation. J Biol Chem 278:17350–17359

    PubMed  CAS  Article  Google Scholar 

  58. 58.

    Alexandre MD, Jeansonne BG, Renegar RH, Tatum R, Chen YH (2007) The first extracellular domain of claudin-7 affects paracellular Cl- permeability. Biochem Biophys Res Commun 357:87–91

    PubMed  CAS  Article  Google Scholar 

  59. 59.

    Amasheh S, Schmidt T, Mahn M, Florian P, Mankertz J, Tavalali S, Gitter AH, Schulzke JD, Fromm M (2005) Contribution of claudin-5 to barrier properties in tight junctions of epithelial cells. Cell Tissue Res 321:89–96

    PubMed  CAS  Article  Google Scholar 

  60. 60.

    Van Itallie C, Rahner C, Anderson JM (2001) Regulated expression of claudin-4 decreases paracellular conductance through a selective decrease in sodium permeability. J Clin Invest 107:1319–1327

    PubMed  Article  Google Scholar 

  61. 61.

    Krause G, Winkler L, Piehl C, Blasig I, Piontek J, Muller SL (2009) Structure and function of extracellular claudin domains. Ann N Y Acad Sci 1165:34–43

    PubMed  CAS  Article  Google Scholar 

  62. 62.

    Fujita H, Chiba H, Yokozaki H, Sakai N, Sugimoto K, Wada T, Kojima T, Yamashita T, Sawada N (2006) Differential expression and subcellular localization of claudin-7, -8, -12, -13, and -15 along the mouse intestine. J Histochem Cytochem 54:933–944

    PubMed  CAS  Article  Google Scholar 

  63. 63.

    Fujibe M, Chiba H, Kojima T, Soma T, Wada T, Yamashita T, Sawada N (2004) Thr203 of claudin-1, a putative phosphorylation site for MAP kinase, is required to promote the barrier function of tight junctions. Exp Cell Res 295:36–47

    PubMed  CAS  Article  Google Scholar 

  64. 64.

    Soma T, Chiba H, Kato-Mori Y, Wada T, Yamashita T, Kojima T, Sawada N (2004) Thr(207) of claudin-5 is involved in size-selective loosening of the endothelial barrier by cyclic AMP. Exp Cell Res 300:202–212

    PubMed  CAS  Article  Google Scholar 

  65. 65.

    D’Souza T, Agarwal R, Morin PJ (2005) Phosphorylation of claudin-3 at threonine 192 by cAMP-dependent protein kinase regulates tight junction barrier function in ovarian cancer cells. J Biol Chem 280:26233–26240

    PubMed  Article  CAS  Google Scholar 

  66. 66.

    Tanaka M, Kamata R, Sakai R (2005) EphA2 phosphorylates the cytoplasmic tail of claudin-4 and mediates paracellular permeability. J Biol Chem 280:42375–42382

    PubMed  CAS  Article  Google Scholar 

  67. 67.

    Van Itallie CM, Gambling TM, Carson JL, Anderson JM (2005) Palmitoylation of claudins is required for efficient tight-junction localization. J Cell Sci 118:1427–1436

    PubMed  Article  CAS  Google Scholar 

  68. 68.

    Cunningham SA, Arrate MP, Rodriguez JM, Bjercke RJ, Vanderslice P, Morris AP, Brock TA (2000) A novel protein with homology to the junctional adhesion molecule. Characterization of leukocyte interactions. J Biol Chem 275:34750–34756

    PubMed  CAS  Article  Google Scholar 

  69. 69.

    Arrate MP, Rodriguez JM, Tran TM, Brock TA, Cunningham SA (2001) Cloning of human junctional adhesion molecule 3 (JAM3) and its identification as the JAM2 counter-receptor. J Biol Chem 276:45826–45832

    PubMed  CAS  Article  Google Scholar 

  70. 70.

    Hirabayashi S, Tajima M, Yao I, Nishimura W, Mori H, Hata Y (2003) JAM4, a junctional cell adhesion molecule interacting with a tight junction protein, MAGI-1. Mol Cell Biol 23:4267–4282

    PubMed  CAS  Article  Google Scholar 

  71. 71.

    Bergelson JM, Cunningham JA, Droguett G, Kurt-Jones EA, Krithivas A, Hong JS, Horwitz MS, Crowell RL, Finberg RW (1997) Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5. Science 275:1320–1323

    PubMed  CAS  Article  Google Scholar 

  72. 72.

    Hirata K, Ishida T, Penta K, Rezaee M, Yang E, Wohlgemuth J, Quertermous T (2001) Cloning of an immunoglobulin family adhesion molecule selectively expressed by endothelial cells. J Biol Chem 276:16223–16231

    CAS  Article  Google Scholar 

  73. 73.

    Suzu S, Hayashi Y, Harumi T, Nomaguchi K, Yamada M, Hayasawa H, Motoyoshi K (2002) Molecular cloning of a novel immunoglobulin superfamily gene preferentially expressed by brain and testis. Biochem Biophys Res Commun 296:1215–1221

    PubMed  CAS  Article  Google Scholar 

  74. 74.

    Bazzoni G (2003) The JAM family of junctional adhesion molecules. Curr Opin Cell Biol 15:525–530

    PubMed  CAS  Article  Google Scholar 

  75. 75.

    Liu Y, Nusrat A, Schnell FJ, Reaves TA, Walsh S, Pochet M, Parkos CA (2000) Human junction adhesion molecule regulates tight junction resealing in epithelia. J Cell Sci 113(Pt 13):2363–2374

    PubMed  CAS  Google Scholar 

  76. 76.

    Laukoetter MG, Nava P, Lee WY, Severson EA, Capaldo CT, Babbin BA, Williams IR, Koval M, Peatman E, Campbell JA, Dermody TS, Nusrat A, Parkos CA (2007) JAM-A regulates permeability and inflammation in the intestine in vivo. J Exp Med 204:3067–3076

    PubMed  CAS  Article  Google Scholar 

  77. 77.

    Cohen CJ, Shieh JT, Pickles RJ, Okegawa T, Hsieh JT, Bergelson JM (2001) The coxsackievirus and adenovirus receptor is a transmembrane component of the tight junction. Proc Natl Acad Sci USA 98:15191–15196

    PubMed  CAS  Article  Google Scholar 

  78. 78.

    Westphal JK, Dorfel MJ, Krug SM, Cording JD, Piontek J, Blasig IE, Tauber R, Fromm M, Huber O (2010) Tricellulin forms homomeric and heteromeric tight junctional complexes. Cell Mol Life Sci 67:2057–2068

    PubMed  CAS  Article  Google Scholar 

  79. 79.

    Krug SM, Amasheh S, Richter JF, Milatz S, Gunzel D, Westphal JK, Huber O, Schulzke JD, Fromm M (2009) Tricellulin forms a barrier to macromolecules in tricellular tight junctions without affecting ion permeability. Mol Biol Cell 20:3713–3724

    PubMed  CAS  Article  Google Scholar 

  80. 80.

    Ikenouchi J, Sasaki H, Tsukita S, Furuse M (2008) Loss of occludin affects tricellular localization of tricellulin. Mol Biol Cell 19:4687–4693

    PubMed  CAS  Article  Google Scholar 

  81. 81.

    Gumbiner B, Lowenkopf T, Apatira D (1991) Identification of a 160-kDa polypeptide that binds to the tight junction protein ZO-1. Proc Natl Acad Sci USA 88:3460–3464

    PubMed  CAS  Article  Google Scholar 

  82. 82.

    Willott E, Balda MS, Fanning AS, Jameson B, Van Itallie C, Anderson JM (1993) The tight junction protein ZO-1 is homologous to the Drosophila discs-large tumor suppressor protein of septate junctions. Proc Natl Acad Sci USA 90:7834–7838

    PubMed  CAS  Article  Google Scholar 

  83. 83.

    Haskins J, Gu L, Wittchen ES, Hibbard J, Stevenson BR (1998) ZO-3, a novel member of the MAGUK protein family found at the tight junction, interacts with ZO-1 and occludin. J Cell Biol 141:199–208

    PubMed  CAS  Article  Google Scholar 

  84. 84.

    Fanning AS, Ma TY, Anderson JM (2002) Isolation and functional characterization of the actin binding region in the tight junction protein ZO-1. FASEB J 16:1835–1837

    PubMed  CAS  Google Scholar 

  85. 85.

    Itoh M, Furuse M, Morita K, Kubota K, Saitou M, Tsukita S (1999) Direct binding of three tight junction-associated MAGUKs, ZO-1, ZO-2, and ZO-3, with the COOH termini of claudins. J Cell Biol 147:1351–1363

    PubMed  CAS  Article  Google Scholar 

  86. 86.

    Bazzoni G, Martinez-Estrada OM, Orsenigo F, Cordenonsi M, Citi S, Dejana E (2000) Interaction of junctional adhesion molecule with the tight junction components ZO-1, cingulin, and occludin. J Biol Chem 275:20520–20526

    PubMed  CAS  Article  Google Scholar 

  87. 87.

    Alexandre MD, Lu Q, Chen YH (2005) Overexpression of claudin-7 decreases the paracellular Cl-conductance and increases the paracellular Na+ conductance in LLC-PK1 cells. J Cell Sci 118:2683–2693

    PubMed  CAS  Article  Google Scholar 

  88. 88.

    Wittchen ES, Haskins J, Stevenson BR (2000) Exogenous expression of the amino-terminal half of the tight junction protein ZO-3 perturbs junctional complex assembly. J Cell Biol 151:825–836

    PubMed  CAS  Article  Google Scholar 

  89. 89.

    Balda MS, Matter K (2000) The tight junction protein ZO-1 and an interacting transcription factor regulate ErbB-2 expression. EMBO J 19:2024–2033

    PubMed  CAS  Article  Google Scholar 

  90. 90.

    Umeda K, Matsui T, Nakayama M, Furuse K, Sasaki H, Furuse M, Tsukita S (2004) Establishment and characterization of cultured epithelial cells lacking expression of ZO-1. J Biol Chem 279:44785–44794

    PubMed  CAS  Article  Google Scholar 

  91. 91.

    Cordenonsi M, D’Atri F, Hammar E, Parry DA, Kendrick-Jones J, Shore D, Citi S (1999) Cingulin contains globular and coiled-coil domains and interacts with ZO-1, ZO-2, ZO-3, and myosin. J Cell Biol 147:1569–1582

    PubMed  CAS  Article  Google Scholar 

  92. 92.

    Cordenonsi M, Turco F, D’Atri F, Hammar E, Martinucci G, Meggio F, Citi S (1999) Xenopus laevis occludin. Identification of in vitro phosphorylation sites by protein kinase CK2 and association with cingulin. Eur J Biochem 264:374–384

    PubMed  CAS  Article  Google Scholar 

  93. 93.

    Guillemot L, Hammar E, Kaister C, Ritz J, Caille D, Jond L, Bauer C, Meda P, Citi S (2004) Disruption of the cingulin gene does not prevent tight junction formation but alters gene expression. J Cell Sci 117:5245–5256

    PubMed  CAS  Article  Google Scholar 

  94. 94.

    Niessner M, Volk BA (1995) Altered Th1/Th2 cytokine profiles in the intestinal mucosa of patients with inflammatory bowel disease as assessed by quantitative reversed transcribed polymerase chain reaction (RT-PCR). Clin Exp Immunol 101:428–435

    PubMed  CAS  Article  Google Scholar 

  95. 95.

    Stallmach A, Giese T, Schmidt C, Ludwig B, Mueller-Molaian I, Meuer SC (2004) Cytokine/chemokine transcript profiles reflect mucosal inflammation in Crohn’s disease. Int J Colorectal Dis 19:308–315

    PubMed  Article  Google Scholar 

  96. 96.

    Bruewer M, Luegering A, Kucharzik T, Parkos CA, Madara JL, Hopkins AM, Nusrat A (2003) Proinflammatory cytokines disrupt epithelial barrier function by apoptosis-independent mechanisms. J Immunol 171:6164–6172

    PubMed  CAS  Google Scholar 

  97. 97.

    Bruewer M, Utech M, Ivanov AI, Hopkins AM, Parkos CA, Nusrat A (2005) Interferon-gamma induces internalization of epithelial tight junction proteins via a macropinocytosis-like process. FASEB J 19:923–933

    PubMed  CAS  Article  Google Scholar 

  98. 98.

    Sandborn WJ, Hanauer SB (1999) Antitumor necrosis factor therapy for inflammatory bowel disease: a review of agents, pharmacology, clinical results, and safety. Inflamm Bowel Dis 5:119–133

    PubMed  CAS  Article  Google Scholar 

  99. 99.

    Ricart E, Panaccione R, Loftus EV, Tremaine WJ, Sandborn WJ (1999) Successful management of Crohn’s disease of the ileoanal pouch with infliximab. Gastroenterology 117:429–432

    PubMed  CAS  Article  Google Scholar 

  100. 100.

    Murch SH, Braegger CP, Walker-Smith JA, MacDonald TT (1993) Location of tumour necrosis factor alpha by immunohistochemistry in chronic inflammatory bowel disease. Gut 34:1705–1709

    PubMed  CAS  Article  Google Scholar 

  101. 101.

    Braegger CP, Nicholls S, Murch SH, Stephens S, MacDonald TT (1992) Tumour necrosis factor alpha in stool as a marker of intestinal inflammation. Lancet 339:89–91

    PubMed  CAS  Article  Google Scholar 

  102. 102.

    Schulzke JD, Bojarski C, Zeissig S, Heller F, Gitter AH, Fromm M (2006) Disrupted barrier function through epithelial cell apoptosis. Ann N Y Acad Sci 1072:288–299

    PubMed  CAS  Article  Google Scholar 

  103. 103.

    Ma TY, Iwamoto GK, Hoa NT, Akotia V, Pedram A, Boivin MA, Said HM (2004) TNF-alpha-induced increase in intestinal epithelial tight junction permeability requires NF-kappa B activation. Am J Physiol Gastrointest Liver Physiol 286:G367–G376

    PubMed  CAS  Article  Google Scholar 

  104. 104.

    Ma TY, Boivin MA, Ye D, Pedram A, Said HM (2005) Mechanism of TNF-{alpha} modulation of Caco-2 intestinal epithelial tight junction barrier: role of myosin light-chain kinase protein expression. Am J Physiol Gastrointest Liver Physiol 288:G422–G430

    PubMed  CAS  Article  Google Scholar 

  105. 105.

    Graham WV, Wang F, Clayburgh DR, Cheng JX, Yoon B, Wang Y, Lin A, Turner JR (2006) Tumor necrosis factor-induced long myosin light chain kinase transcription is regulated by differentiation-dependent signaling events. Characterization of the human long myosin light chain kinase promoter. J Biol Chem 281:26205–26215

    PubMed  CAS  Article  Google Scholar 

  106. 106.

    Ye D, Ma I, Ma TY (2006) Molecular mechanism of tumor necrosis factor-alpha modulation of intestinal epithelial tight junction barrier. Am J Physiol Gastrointest Liver Physiol 290:G496–G504

    PubMed  CAS  Article  Google Scholar 

  107. 107.

    Mankertz J, Amasheh M, Krug SM, Fromm A, Amasheh S, Hillenbrand B, Tavalali S, Fromm M, Schulzke JD (2009) TNFalpha up-regulates claudin-2 expression in epithelial HT-29/B6 cells via phosphatidylinositol-3-kinase signaling. Cell Tissue Res 336:67–77

    PubMed  CAS  Article  Google Scholar 

  108. 108.

    Reinecker HC, Steffen M, Witthoeft T, Pflueger I, Schreiber S, MacDermott RP, Raedler A (1993) Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1 beta by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn’s disease. Clin Exp Immunol 94:174–181

    PubMed  CAS  Article  Google Scholar 

  109. 109.

    Wang F, Graham WV, Wang Y, Witkowski ED, Schwarz BT, Turner JR (2005) Interferon-gamma and tumor necrosis factor-alpha synergize to induce intestinal epithelial barrier dysfunction by up-regulating myosin light chain kinase expression. Am J Pathol 166:409–419

    PubMed  CAS  Article  Google Scholar 

  110. 110.

    Wang F, Schwarz BT, Graham WV, Wang Y, Su L, Clayburgh DR, Abraham C, Turner JR (2006) IFN-gamma-induced TNFR2 expression is required for TNF-dependent intestinal epithelial barrier dysfunction. Gastroenterology 131:1153–1163

    PubMed  CAS  Article  Google Scholar 

  111. 111.

    Schwarz BT, Wang F, Shen L, Clayburgh DR, Su L, Wang Y, Fu YX, Turner JR (2007) LIGHT signals directly to intestinal epithelia to cause barrier dysfunction via cytoskeletal and endocytic mechanisms. Gastroenterology 132:2383–2394

    PubMed  CAS  Article  Google Scholar 

  112. 112.

    Dinarello CA (1994) The interleukin-1 family: 10 years of discovery. FASEB J 8:1314–1325

    PubMed  CAS  Google Scholar 

  113. 113.

    Carty E, De Brabander M, Feakins RM, Rampton DS (2000) Measurement of in vivo rectal mucosal cytokine and eicosanoid production in ulcerative colitis using filter paper. Gut 46:487–492

    PubMed  CAS  Article  Google Scholar 

  114. 114.

    Barksby HE, Lea SR, Preshaw PM, Taylor JJ (2007) The expanding family of interleukin-1 cytokines and their role in destructive inflammatory disorders. Clin Exp Immunol 149:217–225

    PubMed  CAS  Article  Google Scholar 

  115. 115.

    Dinarello CA (2003) Anti-cytokine therapeutics and infections. Vaccine 21(Suppl 2):S24–S34

    PubMed  Article  CAS  Google Scholar 

  116. 116.

    Al-Sadi RM, Ma TY (2007) IL-1beta causes an increase in intestinal epithelial tight junction permeability. J Immunol 178:4641–4649

    PubMed  CAS  Google Scholar 

  117. 117.

    Al-Sadi R, Ye D, Dokladny K, Ma TY (2008) Mechanism of IL-1beta-induced increase in intestinal epithelial tight junction permeability. J Immunol 180:5653–5661

    PubMed  CAS  Google Scholar 

  118. 118.

    Al-Sadi R, Ye D, Said HM, Ma TY (2010) IL-1beta-induced increase in intestinal epithelial tight junction permeability is mediated by MEKK-1 activation of canonical NF-kappaB pathway. Am J Pathol 177:2310–2322

    PubMed  CAS  Article  Google Scholar 

  119. 119.

    Oliphant CJ, Barlow JL, McKenzie AN (2011) Insights into the initiation of type 2 immune responses. Immunology 134:378–385

    PubMed  CAS  Article  Google Scholar 

  120. 120.

    Okoye IS, Wilson MS (2011) CD4+ T helper 2 cells-microbial triggers, differentiation requirements and effector functions. Immunology 134:368–377

    PubMed  CAS  Article  Google Scholar 

  121. 121.

    Wisner DM, Harris LR 3rd, Green CL, Poritz LS (2008) Opposing regulation of the tight junction protein claudin-2 by interferon-gamma and interleukin-4. J Surg Res 144:1–7

    PubMed  CAS  Article  Google Scholar 

  122. 122.

    Colgan SP, Resnick MB, Parkos CA, Delp-Archer C, McGuirk D, Bacarra AE, Weller PF, Madara JL (1994) IL-4 directly modulates function of a model human intestinal epithelium. J Immunol 153:2122–2129

    PubMed  CAS  Google Scholar 

  123. 123.

    Ceponis PJ, Botelho F, Richards CD, McKay DM (2000) Interleukins 4 and 13 increase intestinal epithelial permeability by a phosphatidylinositol 3-kinase pathway. Lack of evidence for STAT 6 involvement. J Biol Chem 275:29132–29137

    PubMed  CAS  Article  Google Scholar 

  124. 124.

    Tilg H, Dinarello CA, Mier JW (1997) IL-6 and APPs: anti-inflammatory and immunosuppressive mediators. Immunol Today 18:428–432

    PubMed  CAS  Article  Google Scholar 

  125. 125.

    Alonzi T, Fattori E, Lazzaro D, Costa P, Probert L, Kollias G, De Benedetti F, Poli V, Ciliberto G (1998) Interleukin 6 is required for the development of collagen-induced arthritis. J Exp Med 187:461–468

    PubMed  CAS  Article  Google Scholar 

  126. 126.

    Louis E, Belaiche J, van Kemseke C, Franchimont D, de Groote D, Gueenen V, Mary JY (1997) A high serum concentration of interleukin-6 is predictive of relapse in quiescent Crohn’s disease. Eur J Gastroenterol Hepatol 9:939–944

    PubMed  CAS  Article  Google Scholar 

  127. 127.

    Kusugami K, Fukatsu A, Tanimoto M, Shinoda M, Haruta J, Kuroiwa A, Ina K, Kanayama K, Ando T, Matsuura T et al (1995) Elevation of interleukin-6 in inflammatory bowel disease is macrophage- and epithelial cell-dependent. Dig Dis Sci 40:949–959

    PubMed  CAS  Article  Google Scholar 

  128. 128.

    Suzuki T, Yoshinaga N, Tanabe S (2011) Interleukin-6 (IL-6) regulates claudin-2 expression and tight junction permeability in intestinal epithelium. J Biol Chem 286:31263–31271

    PubMed  CAS  Article  Google Scholar 

  129. 129.

    Yang R, Han X, Uchiyama T, Watkins SK, Yaguchi A, Delude RL, Fink MP (2003) IL-6 is essential for development of gut barrier dysfunction after hemorrhagic shock and resuscitation in mice. Am J Physiol Gastrointest Liver Physiol 285:G621–G629

    PubMed  CAS  Google Scholar 

  130. 130.

    Ouyang W, Rutz S, Crellin NK, Valdez PA, Hymowitz SG (2011) Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu Rev Immunol 29:71–109

    PubMed  CAS  Article  Google Scholar 

  131. 131.

    Saraiva M, O’Garra A (2010) The regulation of IL-10 production by immune cells. Nat Rev Immunol 10:170–181

    PubMed  CAS  Article  Google Scholar 

  132. 132.

    Kucharzik T, Lugering N, Pauels HG, Domschke W, Stoll R (1998) IL-4, IL-10 and IL-13 down-regulate monocyte-chemoattracting protein-1 (MCP-1) production in activated intestinal epithelial cells. Clin Exp Immunol 111:152–157

    PubMed  CAS  Article  Google Scholar 

  133. 133.

    Madsen KL, Malfair D, Gray D, Doyle JS, Jewell LD, Fedorak RN (1999) Interleukin-10 gene-deficient mice develop a primary intestinal permeability defect in response to enteric microflora. Inflamm Bowel Dis 5:262–270

    PubMed  CAS  Article  Google Scholar 

  134. 134.

    Madsen KL, Lewis SA, Tavernini MM, Hibbard J, Fedorak RN (1997) Interleukin 10 prevents cytokine-induced disruption of T84 monolayer barrier integrity and limits chloride secretion. Gastroenterology 113:151–159

    PubMed  CAS  Article  Google Scholar 

  135. 135.

    Duran B (2005) The effects of long-term total parenteral nutrition on gut mucosal immunity in children with short bowel syndrome: a systematic review. BMC Nurs 4:2

    PubMed  Article  Google Scholar 

  136. 136.

    Wildhaber BE, Yang H, Spencer AU, Drongowski RA, Teitelbaum DH (2005) Lack of enteral nutrition–effects on the intestinal immune system. J Surg Res 123:8–16

    PubMed  CAS  Article  Google Scholar 

  137. 137.

    Kansagra K, Stoll B, Rognerud C, Niinikoski H, Ou CN, Harvey R, Burrin D (2003) Total parenteral nutrition adversely affects gut barrier function in neonatal piglets. Am J Physiol Gastrointest Liver Physiol 285:G1162–G1170

    PubMed  CAS  Google Scholar 

  138. 138.

    Sun X, Yang H, Nose K, Nose S, Haxhija EQ, Koga H, Feng Y, Teitelbaum DH (2008) Decline in intestinal mucosal IL-10 expression and decreased intestinal barrier function in a mouse model of total parenteral nutrition. Am J Physiol Gastrointest Liver Physiol 294:G139–G147

    PubMed  CAS  Article  Google Scholar 

  139. 139.

    Heller F, Florian P, Bojarski C, Richter J, Christ M, Hillenbrand B, Mankertz J, Gitter AH, Burgel N, Fromm M, Zeitz M, Fuss I, Strober W, Schulzke JD (2005) Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology 129:550–564

    PubMed  CAS  Google Scholar 

  140. 140.

    Fuss IJ, Heller F, Boirivant M, Leon F, Yoshida M, Fichtner-Feigl S, Yang Z, Exley M, Kitani A, Blumberg RS, Mannon P, Strober W (2004) Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Invest 113:1490–1497

    PubMed  CAS  Google Scholar 

  141. 141.

    Prasad S, Mingrino R, Kaukinen K, Hayes KL, Powell RM, MacDonald TT, Collins JE (2005) Inflammatory processes have differential effects on claudins 2, 3 and 4 in colonic epithelial cells. Lab Invest 85:1139–1162

    PubMed  CAS  Article  Google Scholar 

  142. 142.

    Weber CR, Raleigh DR, Su L, Shen L, Sullivan EA, Wang Y, Turner JR (2010) Epithelial myosin light chain kinase activation induces mucosal interleukin-13 expression to alter tight junction ion selectivity. J Biol Chem 285:12037–12046

    PubMed  CAS  Article  Google Scholar 

  143. 143.

    Pappu R, Ramirez-Carrozzi V, Sambandam A (2011) The interleukin-17 cytokine family: critical players in host defence and inflammatory diseases. Immunology 134:8–16

    PubMed  CAS  Article  Google Scholar 

  144. 144.

    Chang SH, Dong C (2011) Signaling of interleukin-17 family cytokines in immunity and inflammation. Cell Signal 23:1069–1075

    PubMed  CAS  Article  Google Scholar 

  145. 145.

    Cosmi L, Liotta F, Maggi E, Romagnani S, Annunziato F (2011) Th17 cells: new players in asthma pathogenesis. Allergy 66:989–998

    PubMed  CAS  Article  Google Scholar 

  146. 146.

    Kinugasa T, Sakaguchi T, Gu X, Reinecker HC (2000) Claudins regulate the intestinal barrier in response to immune mediators. Gastroenterology 118:1001–1011

    PubMed  CAS  Article  Google Scholar 

  147. 147.

    Harris RC, Chung E, Coffey RJ (2003) EGF receptor ligands. Exp Cell Res 284:2–13

    PubMed  CAS  Article  Google Scholar 

  148. 148.

    Booth BW, Smith GH (2007) Roles of transforming growth factor-alpha in mammary development and disease. Growth Factors 25:227–235

    PubMed  CAS  Article  Google Scholar 

  149. 149.

    Forsyth CB, Banan A, Farhadi A, Fields JZ, Tang Y, Shaikh M, Zhang LJ, Engen PA, Keshavarzian A (2007) Regulation of oxidant-induced intestinal permeability by metalloprotease-dependent epidermal growth factor receptor signaling. J Pharmacol Exp Ther 321:84–97

    PubMed  CAS  Article  Google Scholar 

  150. 150.

    Rao R, Baker RD, Baker SS (1999) Inhibition of oxidant-induced barrier disruption and protein tyrosine phosphorylation in Caco-2 cell monolayers by epidermal growth factor. Biochem Pharmacol 57:685–695

    PubMed  CAS  Article  Google Scholar 

  151. 151.

    Howe KL, Reardon C, Wang A, Nazli A, McKay DM (2005) Transforming growth factor-beta regulation of epithelial tight junction proteins enhances barrier function and blocks enterohemorrhagic Escherichia coli O157:H7-induced increased permeability. Am J Pathol 167:1587–1597

    PubMed  CAS  Article  Google Scholar 

  152. 152.

    Hering NA, Andres S, Fromm A, van Tol EA, Amasheh M, Mankertz J, Fromm M, Schulzke JD (2011) Transforming growth factor-beta, a whey protein component, strengthens the intestinal barrier by upregulating claudin-4 in HT-29/B6 cells. J Nutr 141:783–789

    PubMed  CAS  Article  Google Scholar 

  153. 153.

    Roche JK, Martins CA, Cosme R, Fayer R, Guerrant RL (2000) Transforming growth factor beta1 ameliorates intestinal epithelial barrier disruption by Cryptosporidium parvum in vitro in the absence of mucosal T lymphocytes. Infect Immun 68:5635–5644

    PubMed  CAS  Article  Google Scholar 

  154. 154.

    Rao R (2008) Oxidative stress-induced disruption of epithelial and endothelial tight junctions. Front Biosci 13:7210–7226

    PubMed  CAS  Article  Google Scholar 

  155. 155.

    Basuroy S, Seth A, Elias B, Naren AP, Rao R (2006) MAPK interacts with occludin and mediates EGF-induced prevention of tight junction disruption by hydrogen peroxide. Biochem J 393:69–77

    PubMed  CAS  Article  Google Scholar 

  156. 156.

    Banan A, Fields JZ, Talmage DA, Zhang L, Keshavarzian A (2002) PKC-zeta is required in EGF protection of microtubules and intestinal barrier integrity against oxidant injury. Am J Physiol Gastrointest Liver Physiol 282:G794–G808

    PubMed  CAS  Google Scholar 

  157. 157.

    Banan A, Fields JZ, Talmage DA, Zhang Y, Keshavarzian A (2001) PKC-beta1 mediates EGF protection of microtubules and barrier of intestinal monolayers against oxidants. Am J Physiol Gastrointest Liver Physiol 281:G833–G847

    PubMed  CAS  Google Scholar 

  158. 158.

    Banan A, Keshavarzian A, Zhang L, Shaikh M, Forsyth CB, Tang Y, Fields JZ (2007) NF-kappaB activation as a key mechanism in ethanol-induced disruption of the F-actin cytoskeleton and monolayer barrier integrity in intestinal epithelium. Alcohol 41:447–460

    PubMed  CAS  Article  Google Scholar 

  159. 159.

    Samak G, Aggarwal S, Rao RK (2011) ERK is involved in EGF-mediated protection of tight junctions, but not adherens junctions, in acetaldehyde-treated Caco-2 cell monolayers. Am J Physiol Gastrointest Liver Physiol 301:G50–G59

    PubMed  CAS  Article  Google Scholar 

  160. 160.

    Baudry B, Fasano A, Ketley J, Kaper JB (1992) Cloning of a gene (zot) encoding a new toxin produced by Vibrio cholerae. Infect Immun 60:428–434

    PubMed  CAS  Google Scholar 

  161. 161.

    Fasano A, Baudry B, Pumplin DW, Wasserman SS, Tall BD, Ketley JM, Kaper JB (1991) Vibrio cholerae produces a second enterotoxin, which affects intestinal tight junctions. Proc Natl Acad Sci USA 88:5242–5246

    PubMed  CAS  Article  Google Scholar 

  162. 162.

    Di Pierro M, Lu R, Uzzau S, Wang W, Margaretten K, Pazzani C, Maimone F, Fasano A (2001) Zonula occludens toxin structure-function analysis. Identification of the fragment biologically active on tight junctions and of the zonulin receptor binding domain. J Biol Chem 276:19160–19165

    PubMed  Article  Google Scholar 

  163. 163.

    Goldblum SE, Rai U, Tripathi A, Thakar M, De Leo L, Di Toro N, Not T, Ramachandran R, Puche AC, Hollenberg MD, Fasano A (2011) The active Zot domain (aa 288–293) increases ZO-1 and myosin 1C serine/threonine phosphorylation, alters interaction between ZO-1 and its binding partners, and induces tight junction disassembly through proteinase activated receptor 2 activation. FASEB J 25:144–158

    PubMed  CAS  Article  Google Scholar 

  164. 164.

    Mel SF, Fullner KJ, Wimer-Mackin S, Lencer WI, Mekalanos JJ (2000) Association of protease activity in Vibrio cholerae vaccine strains with decreases in transcellular epithelial resistance of polarized T84 intestinal epithelial cells. Infect Immun 68:6487–6492

    PubMed  CAS  Article  Google Scholar 

  165. 165.

    Wu Z, Nybom P, Magnusson KE (2000) Distinct effects of Vibrio cholerae haemagglutinin/protease on the structure and localization of the tight junction-associated proteins occludin and ZO-1. Cell Microbiol 2:11–17

    PubMed  CAS  Article  Google Scholar 

  166. 166.

    Muza-Moons MM, Schneeberger EE, Hecht GA (2004) Enteropathogenic Escherichia coli infection leads to appearance of aberrant tight junctions strands in the lateral membrane of intestinal epithelial cells. Cell Microbiol 6:783–793

    PubMed  CAS  Article  Google Scholar 

  167. 167.

    Philpott DJ, McKay DM, Sherman PM, Perdue MH (1996) Infection of T84 cells with enteropathogenic Escherichia coli alters barrier and transport functions. Am J Physiol 270:G634–G645

    PubMed  CAS  Google Scholar 

  168. 168.

    Shifflett DE, Clayburgh DR, Koutsouris A, Turner JR, Hecht GA (2005) Enteropathogenic E. coli disrupts tight junction barrier function and structure in vivo. Lab Invest 85:1308–1324

    PubMed  CAS  Article  Google Scholar 

  169. 169.

    Simonovic I, Rosenberg J, Koutsouris A, Hecht G (2000) Enteropathogenic Escherichia coli dephosphorylates and dissociates occludin from intestinal epithelial tight junctions. Cell Microbiol 2:305–315

    PubMed  CAS  Article  Google Scholar 

  170. 170.

    Spitz J, Yuhan R, Koutsouris A, Blatt C, Alverdy J, Hecht G (1995) Enteropathogenic Escherichia coli adherence to intestinal epithelial monolayers diminishes barrier function. Am J Physiol 268:G374–G379

    PubMed  CAS  Google Scholar 

  171. 171.

    Tomson FL, Koutsouris A, Viswanathan VK, Turner JR, Savkovic SD, Hecht G (2004) Differing roles of protein kinase C-zeta in disruption of tight junction barrier by enteropathogenic and enterohemorrhagic Escherichia coli. Gastroenterology 127:859–869

    PubMed  CAS  Article  Google Scholar 

  172. 172.

    Dean P, Kenny B (2004) Intestinal barrier dysfunction by enteropathogenic Escherichia coli is mediated by two effector molecules and a bacterial surface protein. Mol Microbiol 54:665–675

    PubMed  CAS  Article  Google Scholar 

  173. 173.

    Philpott DJ, McKay DM, Mak W, Perdue MH, Sherman PM (1998) Signal transduction pathways involved in enterohemorrhagic Escherichia coli-induced alterations in T84 epithelial permeability. Infect Immun 66:1680–1687

    PubMed  CAS  Google Scholar 

  174. 174.

    Brynestad S, Granum PE (2002) Clostridium perfringens and foodborne infections. Int J Food Microbiol 74:195–202

    PubMed  Article  Google Scholar 

  175. 175.

    McClane BA, Wnek AP, Hulkower KI, Hanna PC (1988) Divalent cation involvement in the action of Clostridium perfringens type A enterotoxin. Early events in enterotoxin action are divalent cation-independent. J Biol Chem 263:2423–2435

    PubMed  CAS  Google Scholar 

  176. 176.

    Hanna PC, Mietzner TA, Schoolnik GK, McClane BA (1991) Localization of the receptor-binding region of Clostridium perfringens enterotoxin utilizing cloned toxin fragments and synthetic peptides. The 30 C-terminal amino acids define a functional binding region. J Biol Chem 266:11037–11043

    PubMed  CAS  Google Scholar 

  177. 177.

    Hanna PC, Wieckowski EU, Mietzner TA, McClane BA (1992) Mapping of functional regions of Clostridium perfringens type A enterotoxin. Infect Immun 60:2110–2114

    PubMed  CAS  Google Scholar 

  178. 178.

    Katahira J, Sugiyama H, Inoue N, Horiguchi Y, Matsuda M, Sugimoto N (1997) Clostridium perfringens enterotoxin utilizes two structurally related membrane proteins as functional receptors in vivo. J Biol Chem 272:26652–26658

    PubMed  CAS  Article  Google Scholar 

  179. 179.

    Katahira J, Inoue N, Horiguchi Y, Matsuda M, Sugimoto N (1997) Molecular cloning and functional characterization of the receptor for Clostridium perfringens enterotoxin. J Cell Biol 136:1239–1247

    PubMed  CAS  Article  Google Scholar 

  180. 180.

    Sonoda N, Furuse M, Sasaki H, Yonemura S, Katahira J, Horiguchi Y, Tsukita S (1999) Clostridium perfringens enterotoxin fragment removes specific claudins from tight junction strands: evidence for direct involvement of claudins in tight junction barrier. J Cell Biol 147:195–204

    PubMed  Article  Google Scholar 

  181. 181.

    Takahashi A, Kondoh M, Masuyama A, Fujii M, Mizuguchi H, Horiguchi Y, Watanabe Y (2005) Role of C-terminal regions of the C-terminal fragment of Clostridium perfringens enterotoxin in its interaction with claudin-4. J Controlled Release 108:56–62

    CAS  Article  Google Scholar 

  182. 182.

    Singh U, Van Itallie CM, Mitic LL, Anderson JM, McClane BA (2000) CaCo-2 cells treated with Clostridium perfringens enterotoxin form multiple large complex species, one of which contains the tight junction protein occludin. J Biol Chem 275:18407–18417

    PubMed  CAS  Article  Google Scholar 

  183. 183.

    Peng X, Yan H, You Z, Wang P, Wang S (2004) Effects of enteral supplementation with glutamine granules on intestinal mucosal barrier function in severe burned patients. Burns 30:135–139

    PubMed  Article  Google Scholar 

  184. 184.

    Ding LA, Li JS (2003) Effects of glutamine on intestinal permeability and bacterial translocation in TPN-rats with endotoxemia. World J Gastroenterol 9:1327–1332

    PubMed  CAS  Google Scholar 

  185. 185.

    Li J, Langkamp-Henken B, Suzuki K, Stahlgren LH (1994) Glutamine prevents parenteral nutrition-induced increases in intestinal permeability. JPEN J Parenter Enteral Nutr 18:303–307

    PubMed  CAS  Article  Google Scholar 

  186. 186.

    Foitzik T, Stufler M, Hotz HG, Klinnert J, Wagner J, Warshaw AL, Schulzke JD, Fromm M, Buhr HJ (1997) Glutamine stabilizes intestinal permeability and reduces pancreatic infection in acute experimental pancreatitis. J Gastrointest Surg 1:40–46 (discussion 46–47)

    PubMed  CAS  Google Scholar 

  187. 187.

    Li N, Lewis P, Samuelson D, Liboni K, Neu J (2004) Glutamine regulates Caco-2 cell tight junction proteins. Am J Physiol Gastrointest Liver Physiol 287:G726–G733

    PubMed  CAS  Article  Google Scholar 

  188. 188.

    Li N, Neu J (2009) Glutamine deprivation alters intestinal tight junctions via a PI3-K/Akt mediated pathway in Caco-2 cells. J Nutr 139:710–714

    PubMed  CAS  Article  Google Scholar 

  189. 189.

    Seth A, Basuroy S, Sheth P, Rao RK (2004) l-Glutamine ameliorates acetaldehyde-induced increase in paracellular permeability in Caco-2 cell monolayer. Am J Physiol Gastrointest Liver Physiol 287:G510–G517

    PubMed  CAS  Article  Google Scholar 

  190. 190.

    Basuroy S, Sheth P, Mansbach CM, Rao RK (2005) Acetaldehyde disrupts tight junctions and adherens junctions in human colonic mucosa: protection by EGF and l-glutamine. Am J Physiol Gastrointest Liver Physiol 289:G367–G375

    PubMed  CAS  Article  Google Scholar 

  191. 191.

    Watanabe J, Fukumoto K, Fukushi E, Sonoyama K, Kawabata J (2004) Isolation of tryptophan as an inhibitor of ovalbumin permeation and analysis of its suppressive effect on oral sensitization. Biosci Biotechnol Biochem 68:59–65

    PubMed  CAS  Article  Google Scholar 

  192. 192.

    Isobe N, Suzuki M, Oda M, Tanabe S (2008) Enzyme-modified cheese exerts inhibitory effects on allergen permeation in rats suffering from indomethacin-induced intestinal inflammation. Biosci Biotechnol Biochem 72:1740–1745

    PubMed  CAS  Article  Google Scholar 

  193. 193.

    Tanabe S (2012) Short peptide modules for enhancing intestinal barrier function. Curr Pharm Des 18:776–781

    PubMed  CAS  Article  Google Scholar 

  194. 194.

    Yasumatsu H, Tanabe S (2010) The casein peptide Asn-Pro-Trp-Asp-Gln enforces the intestinal tight junction partly by increasing occludin expression in Caco-2 cells. Br J Nutr 104:951–956

    PubMed  CAS  Article  Google Scholar 

  195. 195.

    Usami M, Muraki K, Iwamoto M, Ohata A, Matsushita E, Miki A (2001) Effect of eicosapentaenoic acid (EPA) on tight junction permeability in intestinal monolayer cells. Clin Nutr 20:351–359

    PubMed  CAS  Article  Google Scholar 

  196. 196.

    Usami M, Komurasaki T, Hanada A, Kinoshita K, Ohata A (2003) Effect of gamma-linolenic acid or docosahexaenoic acid on tight junction permeability in intestinal monolayer cells and their mechanism by protein kinase C activation and/or eicosanoid formation. Nutrition 19:150–156

    PubMed  CAS  Article  Google Scholar 

  197. 197.

    Willemsen LE, Koetsier MA, Balvers M, Beermann C, Stahl B, van Tol EA (2008) Polyunsaturated fatty acids support epithelial barrier integrity and reduce IL-4 mediated permeability in vitro. Eur J Nutr 47:183–191

    PubMed  CAS  Article  Google Scholar 

  198. 198.

    Anderberg EK, Lindmark T, Artursson P (1993) Sodium caprate elicits dilatations in human intestinal tight junctions and enhances drug absorption by the paracellular route. Pharm Res 10:857–864

    PubMed  CAS  Article  Google Scholar 

  199. 199.

    Lindmark T, Nikkila T, Artursson P (1995) Mechanisms of absorption enhancement by medium chain fatty acids in intestinal epithelial Caco-2 cell monolayers. J Pharmacol Exp Ther 275:958–964

    PubMed  CAS  Google Scholar 

  200. 200.

    Soderholm JD, Oman H, Blomquist L, Veen J, Lindmark T, Olaison G (1998) Reversible increase in tight junction permeability to macromolecules in rat ileal mucosa in vitro by sodium caprate, a constituent of milk fat. Dig Dis Sci 43:1547–1552

    PubMed  CAS  Article  Google Scholar 

  201. 201.

    Mortensen PB, Clausen MR (1996) Short-chain fatty acids in the human colon: relation to gastrointestinal health and disease. Scand J Gastroenterol Suppl 216:132–148

    PubMed  CAS  Article  Google Scholar 

  202. 202.

    Topping DL, Clifton PM (2001) Short-chain fatty acids and human colonic function: roles of resistant starch and nonstarch polysaccharides. Physiol Rev 81:1031–1064

    PubMed  CAS  Google Scholar 

  203. 203.

    Mariadason JM, Barkla DH, Gibson PR (1997) Effect of short-chain fatty acids on paracellular permeability in Caco-2 intestinal epithelium model. Am J Physiol 272:G705–G712

    PubMed  CAS  Google Scholar 

  204. 204.

    Kinoshita M, Suzuki Y, Saito Y (2002) Butyrate reduces colonic paracellular permeability by enhancing PPARgamma activation. Biochem Biophys Res Commun 293:827–831

    PubMed  CAS  Article  Google Scholar 

  205. 205.

    Peng L, Li ZR, Green RS, Holzman IR, Lin J (2009) Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers. J Nutr 139:1619–1625

    PubMed  CAS  Article  Google Scholar 

  206. 206.

    Suzuki T, Yoshida S, Hara H (2008) Physiological concentrations of short-chain fatty acids immediately suppress colonic epithelial permeability. Br J Nutr 100:297–305

    PubMed  CAS  Article  Google Scholar 

  207. 207.

    Le Poul E, Loison C, Struyf S, Springael JY, Lannoy V, Decobecq ME, Brezillon S, Dupriez V, Vassart G, Van Damme J, Parmentier M, Detheux M (2003) Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. J Biol Chem 278:25481–25489

    PubMed  Article  CAS  Google Scholar 

  208. 208.

    Brown AJ, Goldsworthy SM, Barnes AA, Eilert MM, Tcheang L, Daniels D, Muir AI, Wigglesworth MJ, Kinghorn I, Fraser NJ, Pike NB, Strum JC, Steplewski KM, Murdock PR, Holder JC, Marshall FH, Szekeres PG, Wilson S, Ignar DM, Foord SM, Wise A, Dowell SJ (2003) The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem 278:11312–11319

    PubMed  CAS  Article  Google Scholar 

  209. 209.

    Karaki S, Mitsui R, Hayashi H, Kato I, Sugiya H, Iwanaga T, Furness JB, Kuwahara A (2006) Short-chain fatty acid receptor, GPR43, is expressed by enteroendocrine cells and mucosal mast cells in rat intestine. Cell Tissue Res 324:353–360

    PubMed  CAS  Article  Google Scholar 

  210. 210.

    Karaki S, Tazoe H, Hayashi H, Kashiwabara H, Tooyama K, Suzuki Y, Kuwahara A (2008) Expression of the short-chain fatty acid receptor, GPR43, in the human colon. J Mol Histol 39:135–142

    PubMed  CAS  Article  Google Scholar 

  211. 211.

    Rowe A (1997) Retinoid X receptors. Int J Biochem Cell Biol 29:275–278

    PubMed  CAS  Article  Google Scholar 

  212. 212.

    Dusso AS, Brown AJ (1998) Mechanism of vitamin D action and its regulation. Am J Kidney Dis 32:S13–S24

    PubMed  CAS  Article  Google Scholar 

  213. 213.

    Maciel AA, Oria RB, Braga-Neto MB, Braga AB, Carvalho EB, Lucena HB, Brito GA, Guerrant RL, Lima AA (2007) Role of retinol in protecting epithelial cell damage induced by Clostridium difficile toxin A. Toxicon 50:1027–1040

    PubMed  CAS  Article  Google Scholar 

  214. 214.

    Kong J, Zhang Z, Musch MW, Ning G, Sun J, Hart J, Bissonnette M, Li YC (2008) Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier. Am J Physiol Gastrointest Liver Physiol 294:G208–G216

    PubMed  CAS  Article  Google Scholar 

  215. 215.

    Kandaswami C, Middleton E Jr (1994) Free radical scavenging and antioxidant activity of plant flavonoids. Adv Exp Med Biol 366:351–376

    PubMed  CAS  Article  Google Scholar 

  216. 216.

    Hamalainen M, Nieminen R, Vuorela P, Heinonen M, Moilanen E (2007) Anti-inflammatory effects of flavonoids: genistein, kaempferol, quercetin, and daidzein inhibit STAT-1 and NF-kappaB activations, whereas flavone, isorhamnetin, naringenin, and pelargonidin inhibit only NF-kappaB activation along with their inhibitory effect on iNOS expression and NO production in activated macrophages. Mediat Inflamm 2007:45673

    Google Scholar 

  217. 217.

    Suzuki T, Hara H (2009) Quercetin enhances intestinal barrier function through the assembly of zonula occludens-2, occludin, and claudin-1 and the expression of claudin-4 in Caco-2 cells. J Nutr 139:965–974

    PubMed  CAS  Article  Google Scholar 

  218. 218.

    Suzuki T, Tanabe S, Hara H (2011) Kaempferol enhances intestinal barrier function through the cytoskeletal association and expression of tight junction proteins in Caco-2 cells. J Nutr 141:87–94

    PubMed  CAS  Article  Google Scholar 

  219. 219.

    Amasheh M, Schlichter S, Amasheh S, Mankertz J, Zeitz M, Fromm M, Schulzke JD (2008) Quercetin enhances epithelial barrier function and increases claudin-4 expression in Caco-2 cells. J Nutr 138:1067–1073

    PubMed  CAS  Google Scholar 

  220. 220.

    Sheth P, Seth A, Atkinson KJ, Gheyi T, Kale G, Giorgianni F, Desiderio DM, Li C, Naren A, Rao R (2007) Acetaldehyde dissociates the PTP1B-E-cadherin-beta-catenin complex in Caco-2 cell monolayers by a phosphorylation-dependent mechanism. Biochem J 402:291–300

    PubMed  CAS  Article  Google Scholar 

  221. 221.

    Watson JL, Ansari S, Cameron H, Wang A, Akhtar M, McKay DM (2004) Green tea polyphenol (−)-epigallocatechin gallate blocks epithelial barrier dysfunction provoked by IFN-gamma but not by IL-4. Am J Physiol Gastrointest Liver Physiol 287:G954–G961

    PubMed  CAS  Article  Google Scholar 

  222. 222.

    Sanders ME (2003) Probiotics: considerations for human health. Nutr Rev 61:91–99

    PubMed  Article  Google Scholar 

  223. 223.

    Ukena SN, Singh A, Dringenberg U, Engelhardt R, Seidler U, Hansen W, Bleich A, Bruder D, Franzke A, Rogler G, Suerbaum S, Buer J, Gunzer F, Westendorf AM (2007) Probiotic Escherichia coli Nissle 1917 inhibits leaky gut by enhancing mucosal integrity. PLoS One 2:e1308

    PubMed  Article  CAS  Google Scholar 

  224. 224.

    Garrido-Mesa N, Utrilla P, Comalada M, Zorrilla P, Garrido-Mesa J, Zarzuelo A, Rodriguez-Cabezas ME, Galvez J (2011) The association of minocycline and the probiotic Escherichia coli Nissle 1917 results in an additive beneficial effect in a DSS model of reactivated colitis in mice. Biochem Pharmacol 82:1891–1900

    PubMed  CAS  Article  Google Scholar 

  225. 225.

    Zyrek AA, Cichon C, Helms S, Enders C, Sonnenborn U, Schmidt MA (2007) Molecular mechanisms underlying the probiotic effects of Escherichia coli Nissle 1917 involve ZO-2 and PKCzeta redistribution resulting in tight junction and epithelial barrier repair. Cell Microbiol 9:804–816

    PubMed  CAS  Article  Google Scholar 

  226. 226.

    Resta-Lenert S, Barrett KE (2003) Live probiotics protect intestinal epithelial cells from the effects of infection with enteroinvasive Escherichia coli (EIEC). Gut 52:988–997

    PubMed  CAS  Article  Google Scholar 

  227. 227.

    Resta-Lenert S, Barrett KE (2006) Probiotics and commensals reverse TNF-alpha- and IFN-gamma-induced dysfunction in human intestinal epithelial cells. Gastroenterology 130:731–746

    PubMed  CAS  Article  Google Scholar 

  228. 228.

    Mennigen R, Nolte K, Rijcken E, Utech M, Loeffler B, Senninger N, Bruewer M (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:G1140–G1149

    PubMed  CAS  Article  Google Scholar 

  229. 229.

    Dai C, Zhao DH, Jiang M (2012) VSL#3 probiotics regulate the intestinal epithelial barrier in vivo and in vitro via the p38 and ERK signaling pathways. Int J Mol Med 29:202–208

    PubMed  CAS  Google Scholar 

  230. 230.

    Chen HQ, Yang J, Zhang M, Zhou YK, Shen TY, Chu ZX, Hang XM, Jiang YQ, Qin HL (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:G1287–G1297

    PubMed  CAS  Article  Google Scholar 

  231. 231.

    Ko JS, Yang HR, Chang JY, Seo JK (2007) Lactobacillus plantarum inhibits epithelial barrier dysfunction and interleukin-8 secretion induced by tumor necrosis factor-alpha. World J Gastroenterol 13:1962–1965

    PubMed  CAS  Google Scholar 

  232. 232.

    Karczewski J, Troost FJ, Konings I, Dekker J, Kleerebezem M, Brummer RJ, Wells JM (2010) Regulation of human epithelial tight junction proteins by Lactobacillus plantarum in vivo and protective effects on the epithelial barrier. Am J Physiol Gastrointest Liver Physiol 298:G851–G859

    PubMed  CAS  Article  Google Scholar 

  233. 233.

    Cario E, Gerken G, Podolsky DK (2004) Toll-like receptor 2 enhances ZO-1-associated intestinal epithelial barrier integrity via protein kinase C. Gastroenterology 127:224–238

    PubMed  CAS  Article  Google Scholar 

  234. 234.

    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 Res 92:2400–2408

    CAS  Article  Google Scholar 

  235. 235.

    Donato KA, Gareau MG, Wang YJ, Sherman PM (2010) Lactobacillus rhamnosus GG attenuates interferon-{gamma} and tumour necrosis factor-alpha-induced barrier dysfunction and pro-inflammatory signalling. Microbiology 156:3288–3297

    PubMed  CAS  Article  Google Scholar 

  236. 236.

    Johnson-Henry KC, Donato KA, Shen-Tu G, Gordanpour M, Sherman PM (2008) Lactobacillus rhamnosus strain GG prevents enterohemorrhagic Escherichia coli O157:H7-induced changes in epithelial barrier function. Infect Immun 76:1340–1348

    PubMed  CAS  Article  Google Scholar 

  237. 237.

    Yan F, Cao H, Cover TL, Whitehead R, Washington MK, Polk DB (2007) Soluble proteins produced by probiotic bacteria regulate intestinal epithelial cell survival and growth. Gastroenterology 132:562–575

    PubMed  CAS  Article  Google Scholar 

  238. 238.

    Seth A, Yan F, Polk DB, Rao RK (2008) Probiotics ameliorate the hydrogen peroxide-induced epithelial barrier disruption by a PKC- and MAP kinase-dependent mechanism. Am J Physiol Gastrointest Liver Physiol 294:G1060–G1069

    PubMed  CAS  Article  Google Scholar 

  239. 239.

    Yan F, Cao H, Cover TL, Washington MK, Shi Y, Liu L, Chaturvedi R, Peek RM Jr, Wilson KT, Polk DB (2011) Colon-specific delivery of a probiotic-derived soluble protein ameliorates intestinal inflammation in mice through an EGFR-dependent mechanism. J Clin Invest 121:2242–2253

    PubMed  CAS  Article  Google Scholar 

  240. 240.

    Ewaschuk JB, Diaz H, Meddings L, Diederichs B, Dmytrash A, Backer J, Looijer-van Langen M, Madsen KL (2008) Secreted bioactive factors from Bifidobacterium infantis enhance epithelial cell barrier function. Am J Physiol Gastrointest Liver Physiol 295:G1025–G1034

    PubMed  CAS  Article  Google Scholar 

  241. 241.

    Keshavarzian A, Farhadi A, Forsyth CB, Rangan J, Jakate S, Shaikh M, Banan A, Fields JZ (2009) Evidence that chronic alcohol exposure promotes intestinal oxidative stress, intestinal hyperpermeability and endotoxemia prior to development of alcoholic steatohepatitis in rats. J Hepatol 50:538–547

    PubMed  CAS  Article  Google Scholar 

  242. 242.

    Ferrier L, Berard F, Debrauwer L, Chabo C, Langella P, Bueno L, Fioramonti J (2006) Impairment of the intestinal barrier by ethanol involves enteric microflora and mast cell activation in rodents. Am J Pathol 168:1148–1154

    PubMed  CAS  Article  Google Scholar 

  243. 243.

    Tamai H, Kato S, Horie Y, Ohki E, Yokoyama H, Ishii H (2000) Effect of acute ethanol administration on the intestinal absorption of endotoxin in rats. Alcohol Clin Exp Res 24:390–394

    PubMed  CAS  Article  Google Scholar 

  244. 244.

    Ma TY, Nguyen D, Bui V, Nguyen H, Hoa N (1999) Ethanol modulation of intestinal epithelial tight junction barrier. Am J Physiol 276:G965–G974

    PubMed  CAS  Google Scholar 

  245. 245.

    Visapaa JP, Jokelainen K, Nosova T, Salaspuro M (1998) Inhibition of intracolonic acetaldehyde production and alcoholic fermentation in rats by ciprofloxacin. Alcohol Clin Exp Res 22:1161–1164

    PubMed  CAS  Article  Google Scholar 

  246. 246.

    Rao RK (1998) Acetaldehyde-induced increase in paracellular permeability in Caco-2 cell monolayer. Alcohol Clin Exp Res 22:1724–1730

    PubMed  CAS  Article  Google Scholar 

  247. 247.

    Soderholm JD, Peterson KH, Olaison G, Franzen LE, Westrom B, Magnusson KE, Sjodahl R (1999) Epithelial permeability to proteins in the noninflamed ileum of Crohn’s disease? Gastroenterology 117:65–72

    PubMed  CAS  Article  Google Scholar 

  248. 248.

    Hollander D, Vadheim CM, Brettholz E, Petersen GM, Delahunty T, Rotter JI (1986) Increased intestinal permeability in patients with Crohn’s disease and their relatives. A possible etiologic factor. Ann Intern Med 105:883–885

    PubMed  CAS  Google Scholar 

  249. 249.

    Suenaert P, Bulteel V, Lemmens L, Noman M, Geypens B, Van Assche G, Geboes K, Ceuppens JL, Rutgeerts P (2002) Anti-tumor necrosis factor treatment restores the gut barrier in Crohn’s disease. Am J Gastroenterol 97:2000–2004

    PubMed  CAS  Article  Google Scholar 

  250. 250.

    Zeissig S, Burgel N, Gunzel D, Richter J, Mankertz J, Wahnschaffe U, Kroesen AJ, Zeitz M, Fromm M, Schulzke JD (2007) Changes in expression and distribution of claudin 2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn’s disease. Gut 56:61–72

    PubMed  CAS  Article  Google Scholar 

  251. 251.

    Vetrano S, Rescigno M, Cera MR, Correale C, Rumio C, Doni A, Fantini M, Sturm A, Borroni E, Repici A, Locati M, Malesci A, Dejana E, Danese S (2008) Unique role of junctional adhesion molecule-a in maintaining mucosal homeostasis in inflammatory bowel disease. Gastroenterology 135:173–184

    PubMed  CAS  Article  Google Scholar 

  252. 252.

    Blair SA, Kane SV, Clayburgh DR, Turner JR (2006) Epithelial myosin light chain kinase expression and activity are upregulated in inflammatory bowel disease. Lab Invest 86:191–201

    PubMed  CAS  Article  Google Scholar 

  253. 253.

    Smecuol E, Bai JC, Vazquez H, Kogan Z, Cabanne A, Niveloni S, Pedreira S, Boerr L, Maurino E, Meddings JB (1997) Gastrointestinal permeability in celiac disease. Gastroenterology 112:1129–1136

    PubMed  CAS  Article  Google Scholar 

  254. 254.

    Schulzke JD, Bentzel CJ, Schulzke I, Riecken EO, Fromm M (1998) Epithelial tight junction structure in the jejunum of children with acute and treated celiac sprue. Pediatr Res 43:435–441

    PubMed  CAS  Article  Google Scholar 

  255. 255.

    van Elburg RM, Uil JJ, Mulder CJ, Heymans HS (1993) Intestinal permeability in patients with coeliac disease and relatives of patients with coeliac disease. Gut 34:354–357

    PubMed  Article  Google Scholar 

  256. 256.

    Lammers KM, Lu R, Brownley J, Lu B, Gerard C, Thomas K, Rallabhandi P, Shea-Donohue T, Tamiz A, Alkan S, Netzel-Arnett S, Antalis T, Vogel SN, Fasano A (2008) Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology 135(194–204):e193

    Google Scholar 

  257. 257.

    Lu R, Wang W, Uzzau S, Vigorito R, Zielke HR, Fasano A (2000) Affinity purification and partial characterization of the zonulin/zonula occludens toxin (Zot) receptor from human brain. J Neurochem 74:320–326

    PubMed  CAS  Article  Google Scholar 

  258. 258.

    Wang W, Uzzau S, Goldblum SE, Fasano A (2000) Human zonulin, a potential modulator of intestinal tight junctions. J Cell Sci 113(Pt 24):4435–4440

    PubMed  CAS  Google Scholar 

  259. 259.

    Drago S, El Asmar R, Di Pierro M, Grazia Clemente M, Tripathi A, Sapone A, Thakar M, Iacono G, Carroccio A, D’Agate C, Not T, Zampini L, Catassi C, Fasano A (2006) Gliadin, zonulin and gut permeability: effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scand J Gastroenterol 41:408–419

    PubMed  CAS  Article  Google Scholar 

  260. 260.

    Szakal DN, Gyorffy H, Arato A, Cseh A, Molnar K, Papp M, Dezsofi A, Veres G (2010) Mucosal expression of claudins 2, 3 and 4 in proximal and distal part of duodenum in children with coeliac disease. Virchows Arch 456:245–250

    PubMed  Article  CAS  Google Scholar 

  261. 261.

    Louka AS, Sollid LM (2003) HLA in coeliac disease: unravelling the complex genetics of a complex disorder. Tissue Antigens 61:105–117

    PubMed  CAS  Article  Google Scholar 

  262. 262.

    Mooradian AD, Morley JE, Levine AS, Prigge WF, Gebhard RL (1986) Abnormal intestinal permeability to sugars in diabetes mellitus. Diabetologia 29:221–224

    PubMed  CAS  Article  Google Scholar 

  263. 263.

    Bosi E, Molteni L, Radaelli MG, Folini L, Fermo I, Bazzigaluppi E, Piemonti L, Pastore MR, Paroni R (2006) Increased intestinal permeability precedes clinical onset of type 1 diabetes. Diabetologia 49:2824–2827

    PubMed  CAS  Article  Google Scholar 

  264. 264.

    Vaarala O (2008) Leaking gut in type 1 diabetes. Curr Opin Gastroenterol 24:701–706

    PubMed  Article  Google Scholar 

  265. 265.

    Westerholm-Ormio M, Vaarala O, Pihkala P, Ilonen J, Savilahti E (2003) Immunologic activity in the small intestinal mucosa of pediatric patients with type 1 diabetes. Diabetes 52:2287–2295

    PubMed  CAS  Article  Google Scholar 

  266. 266.

    Watts T, Berti I, Sapone A, Gerarduzzi T, Not T, Zielke R, Fasano A (2005) Role of the intestinal tight junction modulator zonulin in the pathogenesis of type I diabetes in BB diabetic-prone rats. Proc Natl Acad Sci USA 102:2916–2921

    PubMed  CAS  Article  Google Scholar 

  267. 267.

    Meddings JB, Jarand J, Urbanski SJ, Hardin J, Gall DG (1999) Increased gastrointestinal permeability is an early lesion in the spontaneously diabetic BB rat. Am J Physiol 276:G951–G957

    PubMed  CAS  Google Scholar 

  268. 268.

    Sapone A, de Magistris L, Pietzak M, Clemente MG, Tripathi A, Cucca F, Lampis R, Kryszak D, Carteni M, Generoso M, Iafusco D, Prisco F, Laghi F, Riegler G, Carratu R, Counts D, Fasano A (2006) Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives. Diabetes 55:1443–1449

    PubMed  CAS  Article  Google Scholar 

  269. 269.

    Rao RK, Seth A, Sheth P (2004) Recent Advances in Alcoholic Liver Disease I. Role of intestinal permeability and endotoxemia in alcoholic liver disease. Am J Physiol Gastrointest Liver Physiol 286:G881–G884

    PubMed  CAS  Article  Google Scholar 

  270. 270.

    Keshavarzian A, Holmes EW, Patel M, Iber F, Fields JZ, Pethkar S (1999) Leaky gut in alcoholic cirrhosis: a possible mechanism for alcohol-induced liver damage. Am J Gastroenterol 94:200–207

    PubMed  CAS  Article  Google Scholar 

  271. 271.

    Fujimoto M, Uemura M, Nakatani Y, Tsujita S, Hoppo K, Tamagawa T, Kitano H, Kikukawa M, Ann T, Ishii Y, Kojima H, Sakurai S, Tanaka R, Namisaki T, Noguchi R, Higashino T, Kikuchi E, Nishimura K, Takaya A, Fukui H (2000) Plasma endotoxin and serum cytokine levels in patients with alcoholic hepatitis: relation to severity of liver disturbance. Alcohol Clin Exp Res 24:48S–54S

    PubMed  CAS  Article  Google Scholar 

  272. 272.

    Nanji AA, Jokelainen K, Fotouhinia M, Rahemtulla A, Thomas P, Tipoe GL, Su GL, Dannenberg AJ (2001) Increased severity of alcoholic liver injury in female rats: role of oxidative stress, endotoxin, and chemokines. Am J Physiol Gastrointest Liver Physiol 281:G1348–G1356

    PubMed  CAS  Google Scholar 

  273. 273.

    Mathurin P, Deng QG, Keshavarzian A, Choudhary S, Holmes EW, Tsukamoto H (2000) Exacerbation of alcoholic liver injury by enteral endotoxin in rats. Hepatology 32:1008–1017

    PubMed  CAS  Article  Google Scholar 

  274. 274.

    Nanji AA, Khettry U, Sadrzadeh SM (1994) Lactobacillus feeding reduces endotoxemia and severity of experimental alcoholic liver (disease). Proc Soc Exp Biol Med 205:243–247

    PubMed  CAS  Google Scholar 

  275. 275.

    Adachi Y, Moore LE, Bradford BU, Gao W, Thurman RG (1995) Antibiotics prevent liver injury in rats following long-term exposure to ethanol. Gastroenterology 108:218–224

    PubMed  CAS  Article  Google Scholar 

  276. 276.

    Bode C, Bode JC (2003) Effect of alcohol consumption on the gut. Best Pract Res Clin Gastroenterol 17:575–592

    PubMed  CAS  Article  Google Scholar 

  277. 277.

    Parlesak A, Schafer C, Schutz T, Bode JC, Bode C (2000) Increased intestinal permeability to macromolecules and endotoxemia in patients with chronic alcohol abuse in different stages of alcohol-induced liver disease. J Hepatol 32:742–747

    PubMed  CAS  Article  Google Scholar 

  278. 278.

    Keshavarzian A, Fields JZ, Vaeth J, Holmes EW (1994) The differing effects of acute and chronic alcohol on gastric and intestinal permeability. Am J Gastroenterol 89:2205–2211

    PubMed  CAS  Google Scholar 

  279. 279.

    Camilleri M, Gorman H (2007) Intestinal permeability and irritable bowel syndrome. Neurogastroenterol Motil 19:545–552

    PubMed  CAS  Article  Google Scholar 

  280. 280.

    Barbara G, Stanghellini V, De Giorgio R, Cremon C, Cottrell GS, Santini D, Pasquinelli G, Morselli-Labate AM, Grady EF, Bunnett NW, Collins SM, Corinaldesi R (2004) Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 126:693–702

    PubMed  Article  Google Scholar 

  281. 281.

    Collins SM (2005) Dysregulation of peripheral cytokine production in irritable bowel syndrome. Am J Gastroenterol 100:2517–2518

    PubMed  CAS  Article  Google Scholar 

  282. 282.

    Piche T, Barbara G, Aubert P, Bruley des Varannes S, Dainese R, Nano JL, Cremon C, Stanghellini V, De Giorgio R, Galmiche JP, Neunlist M. (2009) Impaired intestinal barrier integrity in the colon of patients with irritable bowel syndrome: involvement of soluble mediators. Gut 58:196–201

    Google Scholar 

  283. 283.

    Alonso C, Guilarte M, Vicario M, Ramos L, Ramadan Z, Antolin M, Martinez C, Rezzi S, Saperas E, Kochhar S, Santos J, Malagelada JR (2008) Maladaptive intestinal epithelial responses to life stress may predispose healthy women to gut mucosal inflammation. Gastroenterology 135(163–172):e161

    Google Scholar 

  284. 284.

    Mazzon E, Crisafulli C, Galuppo M, Cuzzocrea S (2009) Role of peroxisome proliferator-activated receptor-alpha in ileum tight junction alteration in mouse model of restraint stress. Am J Physiol Gastrointest Liver Physiol 297:G488–G505

    PubMed  CAS  Article  Google Scholar 

  285. 285.

    Estienne M, Claustre J, Clain-Gardechaux G, Paquet A, Tache Y, Fioramonti J, Plaisancie P (2010) Maternal deprivation alters epithelial secretory cell lineages in rat duodenum: role of CRF-related peptides. Gut 59:744–751

    PubMed  CAS  Article  Google Scholar 

  286. 286.

    Soderholm JD, Yang PC, Ceponis P, Vohra A, Riddell R, Sherman PM, Perdue MH (2002) Chronic stress induces mast cell-dependent bacterial adherence and initiates mucosal inflammation in rat intestine. Gastroenterology 123:1099–1108

    PubMed  Article  Google Scholar 

  287. 287.

    Berin MC, Sicherer S (2011) Food allergy: mechanisms and therapeutics. Curr Opin Immunol 23:794–800

    PubMed  CAS  Article  Google Scholar 

  288. 288.

    Ventura MT, Polimeno L, Amoruso AC, Gatti F, Annoscia E, Marinaro M, Di Leo E, Matino MG, Buquicchio R, Bonini S, Tursi A, Francavilla A (2006) Intestinal permeability in patients with adverse reactions to food. Dig Liver Dis 38:732–736

    PubMed  CAS  Article  Google Scholar 

  289. 289.

    Andre C, Andre F, Colin L, Cavagna S (1987) Measurement of intestinal permeability to mannitol and lactulose as a means of diagnosing food allergy and evaluating therapeutic effectiveness of disodium cromoglycate. Ann Allergy 59:127–130

    PubMed  CAS  Google Scholar 

  290. 290.

    Brandt EB, Strait RT, Hershko D, Wang Q, Muntel EE, Scribner TA, Zimmermann N, Finkelman FD, Rothenberg ME (2003) Mast cells are required for experimental oral allergen-induced diarrhea. J Clin Invest 112:1666–1677

    PubMed  CAS  Google Scholar 

  291. 291.

    Moneret-Vautrin DA, de Korwin JD, Tisserant J, Grignon M, Claudot N (1984) Ultrastructural study of the mast cells of the human duodenal mucosa. Clin Allergy 14:471–481

    PubMed  CAS  Article  Google Scholar 

  292. 292.

    Banan A, Zhang LJ, Farhadi A, Fields JZ, Shaikh M, Keshavarzian A (2004) PKC-beta1 isoform activation is required for EGF-induced NF-kappaB inactivation and IkappaBalpha stabilization and protection of F-actin assembly and barrier function in enterocyte monolayers. Am J Physiol Cell Physiol 286:C723–C738

    PubMed  CAS  Article  Google Scholar 

Download references

Acknowledgments

This work was supported by Japan Society for the Promotion of Science, a Grant-in-Aid for Young Scientists (B) 23780135 to T. Suzuki.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Takuya Suzuki.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Suzuki, T. Regulation of intestinal epithelial permeability by tight junctions. Cell. Mol. Life Sci. 70, 631–659 (2013). https://doi.org/10.1007/s00018-012-1070-x

Download citation

Keywords

  • Tight junction
  • Intestinal epithelium
  • Cytokine
  • Pathogen
  • Nutrient