The intestinal epithelial barrier: a therapeutic target?

Key Points

  • The intestinal epithelium is a dynamic cellular layer that serves as a barrier between luminal contents and the underlying immune system while simultaneously supporting water, nutrient and ion transport

  • Tight junctions are the primary determinants of barrier function in intact epithelia and are composed of a complex network of transmembrane and cytosolic proteins accompanied by cytoskeletal and regulatory proteins

  • Two distinct pathways — termed pore and leak — regulate paracellular flux in intact epithelia whereas the unrestricted flux pathway is the dominant route across ulcerated or denuded epithelia

  • Reduced intestinal epithelial barrier function is associated with a variety of gastrointestinal and systemic diseases, including IBD and graft versus host disease, respectively, but is insufficient to cause disease in the absence of other insults

  • Experimental evidence suggests that barrier defects contribute to IBD, as mouse models demonstrate that increased paracellular permeability accelerates experimental colitis and that preservation of tight junction barrier function delays disease progression

  • Although no currently available therapeutics specifically modulate epithelial barrier function, promising approaches to target the pore, leak, and unrestricted pathways are being investigated

Abstract

A fundamental function of the intestinal epithelium is to act as a barrier that limits interactions between luminal contents such as the intestinal microbiota, the underlying immune system and the remainder of the body, while supporting vectorial transport of nutrients, water and waste products. Epithelial barrier function requires a contiguous layer of cells as well as the junctions that seal the paracellular space between epithelial cells. Compromised intestinal barrier function has been associated with a number of disease states, both intestinal and systemic. Unfortunately, most current clinical data are correlative, making it difficult to separate cause from effect in interpreting the importance of barrier loss. Some data from experimental animal models suggest that compromised epithelial integrity might have a pathogenic role in specific gastrointestinal diseases, but no FDA-approved agents that target the epithelial barrier are presently available. To develop such therapies, a deeper understanding of both disease pathogenesis and mechanisms of barrier regulation must be reached. Here, we review and discuss mechanisms of intestinal barrier loss and the role of intestinal epithelial barrier function in pathogenesis of both intestinal and systemic diseases. We conclude with a discussion of potential strategies to restore the epithelial barrier.

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Figure 1: The apical junctional complex is necessary for epithelial barrier formation.
Figure 2: Three distinct paracellular epithelial permeability pathways are disrupted during disease pathogenesis.

References

  1. 1

    Marchiando, A. M., Graham, W. V. & Turner, J. R. Epithelial barriers in homeostasis and disease. Annu. Rev. Pathol. 5, 119–144 (2010).

    CAS  PubMed  Google Scholar 

  2. 2

    Turner, J. R. in Yamada's Textbook of Gastroenterology (eds Podolsky, D. K. et al.) 317–329 (Wiley-Blackwell, 2015).

    Google Scholar 

  3. 3

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

    CAS  PubMed  Google Scholar 

  4. 4

    Fu, J. et al. Loss of intestinal core 1-derived O-glycans causes spontaneous colitis in mice. J. Clin. Invest. 121, 1657–1666 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Johansson, M. E. et al. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc. Natl Acad. Sci. USA 105, 15064–15069 (2008).

    CAS  PubMed  Google Scholar 

  6. 6

    Johansson, M. E. et al. Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis. Gut 63, 281–291 (2014).

    CAS  PubMed  Google Scholar 

  7. 7

    Van der Sluis, M. et al. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 131, 117–129 (2006).

    CAS  PubMed  Google Scholar 

  8. 8

    Shen, L., Weber, C. R., Raleigh, D. R., Yu, D. & Turner, J. R. Tight junction pore and leak pathways: a dynamic duo. Annu. Rev. Physiol. 73, 283–309 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Farquhar, M. & Palade, G. Junctional complexes in various epithelia. J. Cell Biol. 17, 375–412 (1963).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Madara, J. L. Intestinal absorptive cell tight junctions are linked to cytoskeleton. Am. J. Physiol. 253, C171–C175 (1987).

    CAS  PubMed  Google Scholar 

  11. 11

    Mooseker, M. S. et al. Brush border cytoskeleton and integration of cellular functions. J. Cell Biol. 99, 104s–112s (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Takeichi, M. Dynamic contacts: rearranging adherens junctions to drive epithelial remodelling. Nat. Rev. Mol. Cell Biol. 15, 397–410 (2014).

    CAS  PubMed  Google Scholar 

  13. 13

    Hartsock, A. & Nelson, W. J. Adherens and tight junctions: structure, function and connections to the actin cytoskeleton. Biochim. Biophys. Acta 1778, 660–669 (2008).

    CAS  PubMed  Google Scholar 

  14. 14

    Drees, F., Pokutta, S., Yamada, S., Nelson, W. J. & Weis, W. I. α-catenin is a molecular switch that binds E-cadherin-β-catenin and regulates actin-filament assembly. Cell 123, 903–915 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Maiden, S. L. & Hardin, J. The secret life of α-catenin: moonlighting in morphogenesis. J. Cell Biol. 195, 543–552 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Capaldo, C. T. & Macara, I. G. Depletion of E-cadherin disrupts establishment but not maintenance of cell junctions in Madin-Darby canine kidney epithelial cells. Mol. Biol. Cell 18, 189–200 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Maiers, J. L., Peng, X., Fanning, A. S. & DeMali, K. A. ZO-1 recruitment to α-catenin — a novel mechanism for coupling the assembly of tight junctions to adherens junctions. J. Cell Sci. 126, 3904–3915 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Goodenough, D. A. & Revel, J. P. A fine structural analysis of intercellular junctions in the mouse liver. J. Cell Biol. 45, 272–290 (1970).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Kachar, B. & Reese, T. S. Evidence for the lipidic nature of tight junction strands. Nature 296, 464–466 (1982).

    CAS  PubMed  Google Scholar 

  20. 20

    Lingaraju, A. et al. Conceptual barriers to understanding physical barriers. Semin. Cell Dev. Biol. 42, 13–21 (2015).

    PubMed  PubMed Central  Google Scholar 

  21. 21

    Furuse, M. et al. Occludin: a novel integral membrane protein localizing at tight junctions. J. Cell Biol. 123, 1777–1788 (1993).

    CAS  PubMed  Google Scholar 

  22. 22

    Stankewich, M. C., Francis, S. A., Vu, Q. U., Schneeberger, E. E. & Lynch, R. D. Alterations in cell cholesterol content modulate Ca2+-induced tight junction assembly by MDCK cells. Lipids 31, 817–828 (1996).

    CAS  PubMed  Google Scholar 

  23. 23

    Francis, S. A. et al. Rapid reduction of MDCK cell cholesterol by methyl-β-cyclodextrin alters steady state transepithelial electrical resistance. Eur. J. Cell Biol. 78, 473–484 (1999).

    CAS  PubMed  Google Scholar 

  24. 24

    Shen, L. et al. Myosin light chain phosphorylation regulates barrier function by remodeling tight junction structure. J. Cell Sci. 119, 2095–2106 (2006).

    CAS  PubMed  Google Scholar 

  25. 25

    Van Itallie, C. M. & Anderson, J. M. Claudins and epithelial paracellular transport. Annu. Rev. Physiol. 68, 403–429 (2006).

    CAS  PubMed  Google Scholar 

  26. 26

    Furuse, M., Furuse, K., Sasaki, H. & Tsukita, S. Conversion of zonulae occludentes from tight to leaky strand type by introducing claudin-2 into Madin-Darby canine kidney I cells. J. Cell Biol. 153, 263–272 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Amasheh, S. et al. Claudin-2 expression induces cation-selective channels in tight junctions of epithelial cells. J. Cell Sci. 115, 4969–4976 (2002).

    CAS  PubMed  Google Scholar 

  28. 28

    Weber, C. R. et al. Claudin-2-dependent paracellular channels are dynamically gated. eLife 4, e09906 (2015).

    PubMed  PubMed Central  Google Scholar 

  29. 29

    Weber, C. R. et al. Epithelial myosin light chain kinase activation induces mucosal interleukin-13 expression to alter tight junction ion selectivity. J. Biol. Chem. 285, 12037–12046 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Raleigh, D. R. et al. Occludin S408 phosphorylation regulates tight junction protein interactions and barrier function. J. Cell Biol. 193, 565–582 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Wada, M., Tamura, A., Takahashi, N. & Tsukita, S. Loss of claudins 2 and 15 from mice causes defects in paracellular Na+ flow and nutrient transport in gut and leads to death from malnutrition. Gastroenterology 144, 369–380 (2013).

    CAS  PubMed  Google Scholar 

  32. 32

    Tamura, A. et al. Loss of claudin-15, but not claudin-2, causes Na+ deficiency and glucose malabsorption in mouse small intestine. Gastroenterology 140, 913–923 (2011).

    CAS  PubMed  Google Scholar 

  33. 33

    Turner, J. R., Buschmann, M. M., Romero-Calvo, I., Sailer, A. & Shen, L. The role of molecular remodeling in differential regulation of tight junction permeability. Semin. Cell Dev. Biol. 36, 204–212 (2014).

    CAS  PubMed  Google Scholar 

  34. 34

    Raleigh, D. R. et al. Tight junction-associated MARVEL proteins marveld3, tricellulin, and occludin have distinct but overlapping functions. Mol. Biol. Cell 21, 1200–1213 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Furuse, M. et al. 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 (1994).

    CAS  PubMed  Google Scholar 

  36. 36

    Cording, J. et al. In tight junctions, claudins regulate the interactions between occludin, tricellulin and marvelD3, which, inversely, modulate claudin oligomerization. J. Cell Sci. 126, 554–564 (2013).

    CAS  PubMed  Google Scholar 

  37. 37

    Fanning, A. S. & Anderson, J. M. Zonula occludens-1 and -2 are cytosolic scaffolds that regulate the assembly of cellular junctions. Ann. N. Y. Acad. Sci. 1165, 113–120 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Anderson, J. M., Fanning, A. S., Lapierre, L. & Van Itallie, C. M. Zonula occludens (ZO)-1 and ZO-2: membrane-associated guanylate kinase homologues (MAGuKs) of the tight junction. Biochem. Soc. Trans. 23, 470–475 (1995).

    CAS  PubMed  Google Scholar 

  39. 39

    Katsuno, T. et al. Deficiency of zonula occludens-1 causes embryonic lethal phenotype associated with defected yolk sac angiogenesis and apoptosis of embryonic cells. Mol. Biol. Cell 19, 2465–2475 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Xu, J. et al. Early embryonic lethality of mice lacking ZO-2, but not ZO-3, reveals critical and nonredundant roles for individual zonula occludens proteins in mammalian development. Mol. Cell. Biol. 28, 1669–1678 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Carlton, V. E. et al. Complex inheritance of familial hypercholanemia with associated mutations in TJP2 and BAAT. Nat. Genet. 34, 91–96 (2003).

    CAS  PubMed  Google Scholar 

  42. 42

    Sambrotta, M. et al. Mutations in TJP2 cause progressive cholestatic liver disease. Nat. Genet. 46, 326–328 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Matsumoto, K. et al. Claudin 2 deficiency reduces bile flow and increases susceptibility to cholesterol gallstone disease in mice. Gastroenterology 147, 1134–1145.e10 (2014).

    CAS  PubMed  Google Scholar 

  44. 44

    Luther, J. et al. Hepatic injury in nonalcoholic steatohepatitis contributes to altered intestinal permeability. Cell. Mol. Gastroenterol. Hepatol. 1, 222–232 (2015).

    PubMed  PubMed Central  Google Scholar 

  45. 45

    Llorente, C. & Schnabl, B. The gut microbiota and liver disease. Cell. Mol. Gastroenterol. Hepatol. 1, 275–284 (2015).

    PubMed  PubMed Central  Google Scholar 

  46. 46

    Van Itallie, C. M., Fanning, A. S., Bridges, A. & Anderson, J. M. ZO-1 stabilizes the tight junction solute barrier through coupling to the perijunctional cytoskeleton. Mol. Biol. Cell 20, 3930–3940 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Nalle, S. C. & Turner, J. R. Intestinal barrier loss as a critical pathogenic link between inflammatory bowel disease and graft-versus-host disease. Mucosal Immunol. 8, 720–730 (2015).

    CAS  PubMed  Google Scholar 

  48. 48

    Su, L. et al. TNFR2 activates MLCK-dependent tight junction dysregulation to cause apoptosis-mediated barrier loss and experimental colitis. Gastroenterology 145, 407–415 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Kiesler, P., Fuss, I. J. & Strober, W. Experimental models of inflammatory bowel diseases. Cell. Mol. Gastroenterol. Hepatol. 1, 154–170 (2015).

    PubMed  PubMed Central  Google Scholar 

  50. 50

    Gitter, A. H., Wullstein, F., Fromm, M. & Schulzke, J. D. Epithelial barrier defects in ulcerative colitis: characterization and quantification by electrophysiological imaging. Gastroenterology 121, 1320–1328 (2001).

    CAS  PubMed  Google Scholar 

  51. 51

    Snippert, H. J. et al. Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143, 134–144 (2010).

    CAS  PubMed  Google Scholar 

  52. 52

    van der Flier, L. G. & Clevers, H. Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu. Rev. Physiol. 71, 241–260 (2009).

    CAS  PubMed  Google Scholar 

  53. 53

    Aoki, R. et al. Foxl1-expressing mesenchymal cells constitute the intestinal stem cell niche. Cell. Mol. Gastroenterol. Hepatol. 2, 175–188 (2016).

    PubMed  Google Scholar 

  54. 54

    Russo, J. M. et al. Distinct temporal-spatial roles for rho kinase and myosin light chain kinase in epithelial purse-string wound closure. Gastroenterology 128, 987–1001 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Marchiando, A. M. et al. The epithelial barrier is maintained by in vivo tight junction expansion during pathologic intestinal epithelial shedding. Gastroenterology 140, 1208–1218.e2 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Rosenblatt, J., Raff, M. C. & Cramer, L. P. An epithelial cell destined for apoptosis signals its neighbors to extrude it by an actin- and myosin-dependent mechanism. Curr. Biol. 11, 1847–1857 (2001).

    CAS  PubMed  Google Scholar 

  57. 57

    Madara, J. L. & Pappenheimer, J. R. Structural basis for physiological regulation of paracellular pathways in intestinal epithelia. J. Membr. Biol. 100, 149–164 (1987).

    CAS  PubMed  Google Scholar 

  58. 58

    Pappenheimer, J. R. Physiological regulation of transepithelial impedance in the intestinal mucosa of rats and hamsters. J. Membr. Biol. 100, 137–148 (1987).

    CAS  PubMed  Google Scholar 

  59. 59

    Pappenheimer, J. R. & Reiss, K. Z. Contribution of solvent drag through intercellular junctions to absorption of nutrients by the small intestine of the rat. J. Membr. Biol. 100, 123–136 (1987).

    CAS  PubMed  Google Scholar 

  60. 60

    Turner, J. R. et al. Physiological regulation of epithelial tight junctions is associated with myosin light-chain phosphorylation. Am. J. Physiol. 273, C1378–C1385 (1997).

    CAS  PubMed  Google Scholar 

  61. 61

    Turner, J. R. Show me the pathway! Regulation of paracellular permeability by Na+-glucose cotransport. Adv. Drug Deliv. Rev. 41, 265–281 (2000).

    CAS  PubMed  Google Scholar 

  62. 62

    Meddings, J. B. & Westergaard, H. Intestinal glucose transport using perfused rat jejunum in vivo: model analysis and derivation of corrected kinetic constants. Clin. Sci. (Lond.) 76, 403–413 (1989).

    CAS  Google Scholar 

  63. 63

    Sadowski, D. C. & Meddings, J. B. Luminal nutrients alter tight-junction permeability in the rat jejunum: an in vivo perfusion model. Can. J. Physiol. Pharmacol. 71, 835–839 (1993).

    CAS  PubMed  Google Scholar 

  64. 64

    Turner, J. R., Cohen, D. E., Mrsny, R. J. & Madara, J. L. Noninvasive in vivo analysis of human small intestinal paracellular absorption: regulation by Na+-glucose cotransport. Dig. Dis. Sci. 45, 2122–2126 (2000).

    CAS  PubMed  Google Scholar 

  65. 65

    Heller, F. et al. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology 129, 550–564 (2005).

    CAS  PubMed  Google Scholar 

  66. 66

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

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Wisner, D. M., Harris, L. R. III, Green, C. L. & Poritz, L. S. Opposing regulation of the tight junction protein claudin-2 by interferon-γ and interleukin-4. J. Surg. Res. 144, 1–7 (2008).

    CAS  PubMed  Google Scholar 

  68. 68

    Mankertz, J. et al. TNFα up-regulates claudin-2 expression in epithelial HT-29/B6 cells via phosphatidylinositol–3-kinase signaling. Cell Tissue Res. 336, 67–77 (2009).

    CAS  PubMed  Google Scholar 

  69. 69

    Gerlach, K. et al. TH9 cells that express the transcription factor PU.1 drive T cell-mediated colitis via IL-9 receptor signaling in intestinal epithelial cells. Nat. Immunol. 15, 676–686 (2014).

    CAS  PubMed  Google Scholar 

  70. 70

    Zeissig, S. et al. 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 (2007).

    CAS  PubMed  Google Scholar 

  71. 71

    Prasad, S. et al. Inflammatory processes have differential effects on claudins 2, 3 and 4 in colonic epithelial cells. Lab. Invest. 85, 1139–1162 (2005).

    CAS  PubMed  Google Scholar 

  72. 72

    Yu, A. S. et al. Molecular basis for cation selectivity in claudin-2-based paracellular pores: identification of an electrostatic interaction site. J. Gen. Physiol. 133, 111–127 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Li, J., Zhuo, M., Pei, L. & Yu, A. S. Conserved aromatic residue confers cation selectivity in claudin-2 and claudin-10b. J. Biol. Chem. 288, 22790–22797 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Li, J., Zhuo, M., Pei, L., Rajagopal, M. & Yu, A. S. Comprehensive cysteine-scanning mutagenesis reveals claudin-2 pore-lining residues with different intrapore locations. J. Biol. Chem. 289, 6475–6484 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Marcial, M. A., Carlson, S. L. & Madara, J. L. Partitioning of paracellular conductance along the ileal crypt–villus axis: a hypothesis based on structural analysis with detailed consideration of tight junction structure-function relationships. J. Membr. Biol. 80, 59–70 (1984).

    CAS  PubMed  Google Scholar 

  76. 76

    Fihn, B. M., Sjoqvist, A. & Jodal, M. Permeability of the rat small intestinal epithelium along the villus–crypt axis: effects of glucose transport. Gastroenterology 119, 1029–1036 (2000).

    CAS  PubMed  Google Scholar 

  77. 77

    Mora-Galindo, J. Maturation of tight junctions in guinea-pig cecal epithelium. Cell Tissue Res. 246, 169–175 (1986).

    CAS  PubMed  Google Scholar 

  78. 78

    Suenaert, P. et al. Anti-tumor necrosis factor treatment restores the gut barrier in Crohn's disease. Am. J. Gastroenterol. 97, 2000–2004 (2002).

    CAS  PubMed  Google Scholar 

  79. 79

    Baert, F. J. et al. Tumor necrosis factor alpha antibody (infliximab) therapy profoundly down-regulates the inflammation in Crohn's ileocolitis. Gastroenterology 116, 22–28 (1999).

    CAS  PubMed  Google Scholar 

  80. 80

    Zolotarevsky, Y. et al. A membrane-permeant peptide that inhibits MLC kinase restores barrier function in in vitro models of intestinal disease. Gastroenterology 123, 163–172 (2002).

    CAS  PubMed  Google Scholar 

  81. 81

    Wang, F. et al. Interferon-γ and tumor necrosis factor-α synergize to induce intestinal epithelial barrier dysfunction by up-regulating myosin light chain kinase expression. Am. J. Pathol. 166, 409–419 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Clayburgh, D. R., Musch, M. W., Leitges, M., Fu, Y. X. & Turner, J. R. Coordinated epithelial NHE3 inhibition and barrier dysfunction are required for TNF-mediated diarrhea in vivo. J. Clin. Invest. 116, 2682–2694 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Wang, F. et al. IFN-γ-induced TNFR2 expression is required for TNF-dependent intestinal epithelial barrier dysfunction. Gastroenterology 131, 1153–1163 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Clayburgh, D. R. et al. Epithelial myosin light chain kinase-dependent barrier dysfunction mediates T cell activation-induced diarrhea in vivo. J. Clin. Invest. 115, 2702–2715 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Graham, W. V. et al. 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 (2006).

    CAS  PubMed  Google Scholar 

  86. 86

    Su, L. et al. Targeted epithelial tight junction dysfunction causes immune activation and contributes to development of experimental colitis. Gastroenterology 136, 551–563 (2009).

    CAS  PubMed  Google Scholar 

  87. 87

    Marchiando, A. M. et al. Caveolin-1-dependent occludin endocytosis is required for TNF-induced tight junction regulation in vivo. J. Cell Biol. 189, 111–126 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Buschmann, M. M. et al. Occludin OCEL-domain interactions are required for maintenance and regulation of the tight junction barrier to macromolecular flux. Mol. Biol. Cell 24, 3056–3068 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Van Itallie, C. M., Fanning, A. S., Holmes, J. & Anderson, J. M. Occludin is required for cytokine-induced regulation of tight junction barriers. J. Cell Sci. 123, 2844–2852 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Westphal, J. K. et al. Tricellulin forms homomeric and heteromeric tight junctional complexes. Cell. Mol. Life Sci. 67, 2057–2068 (2010).

    CAS  PubMed  Google Scholar 

  91. 91

    Krug, S. M. et al. Tricellulin forms a barrier to macromolecules in tricellular tight junctions without affecting ion permeability. Mol. Biol. Cell 20, 3713–3724 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

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

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Kojima, T. et al. c-Jun N-terminal kinase is largely involved in the regulation of tricellular tight junctions via tricellulin in human pancreatic duct epithelial cells. J. Cell. Physiol. 225, 720–733 (2010).

    CAS  PubMed  Google Scholar 

  94. 94

    Nayak, G. et al. Tricellulin deficiency affects tight junction architecture and cochlear hair cells. J. Clin. Invest. 123, 4036–4049 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Riazuddin, S. et al. Tricellulin is a tight-junction protein necessary for hearing. Am. J. Hum. Genet. 79, 1040–1051 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Chishti, M. S. et al. Splice-site mutations in the TRIC gene underlie autosomal recessive nonsyndromic hearing impairment in Pakistani families. J. Hum. Genet. 53, 101–105 (2008).

    CAS  PubMed  Google Scholar 

  97. 97

    Kitajiri, S. I. et al. Deafness in occludin-deficient mice with dislocation of tricellulin and progressive apoptosis of the hair cells. Biol. Open 3, 759–766 (2014).

    PubMed  PubMed Central  Google Scholar 

  98. 98

    Saitou, M. et al. Complex phenotype of mice lacking occludin, a component of tight junction strands. Mol. Biol. Cell 11, 4131–4142 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Schulzke, J. D. et al. Epithelial transport and barrier function in occludin-deficient mice. Biochim. Biophys. Acta 1669, 34–42 (2005).

    CAS  PubMed  Google Scholar 

  100. 100

    Olson, T. S. et al. The primary defect in experimental ileitis originates from a nonhematopoietic source. J. Exp. Med. 203, 541–552 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Maes, M. & Leunis, J. C. Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of LPS from gram-negative bacteria. Neuro Endocrinol. Lett. 29, 902–910 (2008).

    PubMed  Google Scholar 

  102. 102

    Quigley, E. M. Leaky gut — concept or clinical entity? Curr. Opin. Gastroenterol. 32, 74–79 (2016).

    PubMed  Google Scholar 

  103. 103

    Odenwald, M. A. & Turner, J. R. Intestinal permeability defects: is it time to treat? Clin. Gastroenterol. Hepatol. 11, 1075–1083 (2013).

    PubMed  PubMed Central  Google Scholar 

  104. 104

    In, J. et al. Enterohemorrhagic Escherichia coli reduces mucus and intermicrovillar bridges in human stem cell-derived colonoids. Cell. Mol. Gastroenterol. Hepatol. 2, 48–62.e3 (2016).

    PubMed  Google Scholar 

  105. 105

    Yuhan, R., Koutsouris, A., Savkovic, S. D. & Hecht, G. Enteropathogenic Escherichia coli-induced myosin light chain phosphorylation alters intestinal epithelial permeability. Gastroenterology 113, 1873–1882 (1997).

    CAS  PubMed  Google Scholar 

  106. 106

    Sonoda, N. et al. 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 (1999).

    PubMed  PubMed Central  Google Scholar 

  107. 107

    Saitoh, Y. et al. Tight junctions. Structural insight into tight junction disassembly by Clostridium perfringens enterotoxin. Science 347, 775–778 (2015).

    CAS  PubMed  Google Scholar 

  108. 108

    Hecht, G., Koutsouris, A., Pothoulakis, C., LaMont, J. T. & Madara, J. L. Clostridium difficile toxin B disrupts the barrier function of T84 monolayers. Gastroenterology 102, 416–423 (1992).

    CAS  PubMed  Google Scholar 

  109. 109

    Just, I. et al. Glucosylation of Rho proteins by Clostridium difficile toxin B. Nature 375, 500–503 (1995).

    CAS  PubMed  Google Scholar 

  110. 110

    Hollander, D. Crohn's disease — a permeability disorder of the tight junction? Gut 29, 1621–1624 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Pearson, A. D., Eastham, E. J., Laker, M. F., Craft, A. W. & Nelson, R. Intestinal permeability in children with Crohn's disease and coeliac disease. Br. Med. J. (Clin. Res. Ed.) 285, 20–21 (1982).

    CAS  Google Scholar 

  112. 112

    Ukabam, S. O., Clamp, J. R. & Cooper, B. T. Abnormal small intestinal permeability to sugars in patients with Crohn's disease of the terminal ileum and colon. Digestion 27, 70–74 (1983).

    CAS  PubMed  Google Scholar 

  113. 113

    Schmitz, H. et al. Altered tight junction structure contributes to the impaired epithelial barrier function in ulcerative colitis. Gastroenterology 116, 301–309 (1999).

    CAS  PubMed  Google Scholar 

  114. 114

    Weber, C. R., Nalle, S. C., Tretiakova, M., Rubin, D. T. & Turner, J. R. Claudin-1 and claudin-2 expression is elevated in inflammatory bowel disease and may contribute to early neoplastic transformation. Lab. Invest. 88, 1110–1120 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Blair, S. A., Kane, S. V., Clayburgh, D. R. & Turner, J. R. Epithelial myosin light chain kinase expression and activity are upregulated in inflammatory bowel disease. Lab. Invest. 86, 191–201 (2006).

    CAS  PubMed  Google Scholar 

  116. 116

    Wyatt, J., Vogelsang, H., Hubl, W., Waldhoer, T. & Lochs, H. Intestinal permeability and the prediction of relapse in Crohn's disease. Lancet 341, 1437–1439 (1993).

    CAS  PubMed  Google Scholar 

  117. 117

    D'Inca, R. et al. Intestinal permeability test as a predictor of clinical course in Crohn's disease. Am. J. Gastroenterol. 94, 2956–2960 (1999).

    CAS  PubMed  Google Scholar 

  118. 118

    Tibble, J. A., Sigthorsson, G., Bridger, S., Fagerhol, M. K. & Bjarnason, I. Surrogate markers of intestinal inflammation are predictive of relapse in patients with inflammatory bowel disease. Gastroenterology 119, 15–22 (2000).

    CAS  PubMed  Google Scholar 

  119. 119

    Kiesslich, R. et al. Local barrier dysfunction identified by confocal laser endomicroscopy predicts relapse in inflammatory bowel disease. Gut 61, 1146–1153 (2012).

    CAS  PubMed  Google Scholar 

  120. 120

    Madara, J. L. Maintenance of the macromolecular barrier at cell extrusion sites in intestinal epithelium: physiological rearrangement of tight junctions. J. Membr. Biol. 116, 177–184 (1990).

    CAS  PubMed  Google Scholar 

  121. 121

    Hollander, D. et al. Increased intestinal permeability in patients with Crohn's disease and their relatives. A possible etiologic factor. Ann. Intern. Med. 105, 883–885 (1986).

    CAS  PubMed  Google Scholar 

  122. 122

    Jacobs, J. P. et al. A disease-associated microbial and metabolomics state in relatives of pediatric inflammatory bowel disease patients. Cell. Mol. Gastroenterol. Hepatol. 2, 750–766 (2016).

    PubMed  PubMed Central  Google Scholar 

  123. 123

    Li, X. et al. Microgeographic proteomic networks of the human colonic mucosa and their association with inflammatory bowel disease. Cell. Mol. Gastroenterol. Hepatol. 2, 567–583 (2016).

    PubMed  PubMed Central  Google Scholar 

  124. 124

    Buhner, S. et al. Genetic basis for increased intestinal permeability in families with Crohn's disease: role of CARD15 3020insC mutation? Gut 55, 342–347 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Bjarnason, I., MacPherson, A. & Hollander, D. Intestinal permeability: an overview. Gastroenterology 108, 1566–1581 (1995).

    CAS  PubMed  Google Scholar 

  126. 126

    Irvine, E. J. & Marshall, J. K. Increased intestinal permeability precedes the onset of Crohn's disease in a subject with familial risk. Gastroenterology 119, 1740–1744 (2000).

    CAS  PubMed  Google Scholar 

  127. 127

    Vetrano, S. et al. Unique role of junctional adhesion molecule-A in maintaining mucosal homeostasis in inflammatory bowel disease. Gastroenterology 135, 173–184 (2008).

    CAS  PubMed  Google Scholar 

  128. 128

    Turner, J. R. in Robbins and Cotran Pathologic Basis of Disease (eds Kumar, V., Abbas, A. K. & Aster, J. C.) 749–819 (Elsevier, 2014).

    Google Scholar 

  129. 129

    Hamilton, I., Cobden, I., Rothwell, J. & Axon, A. T. Intestinal permeability in coeliac disease: the response to gluten withdrawal and single-dose gluten challenge. Gut 23, 202–210 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Smecuol, E. et al. Gastrointestinal permeability in celiac disease. Gastroenterology 112, 1129–1136 (1997).

    CAS  PubMed  Google Scholar 

  131. 131

    van Elburg, R. M., Uil, J. J., Mulder, C. J. & Heymans, H. S. Intestinal permeability in patients with coeliac disease and relatives of patients with coeliac disease. Gut 34, 354–357 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Cummins, A. G. et al. Improvement in intestinal permeability precedes morphometric recovery of the small intestine in coeliac disease. Clin. Sci. (Lond.) 100, 379–386 (2001).

    CAS  Google Scholar 

  133. 133

    Vazquez-Roque, M. I. et al. A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function. Gastroenterology 144, 903–911.e3 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Hall, E. J. & Batt, R. M. Abnormal permeability precedes the development of a gluten sensitive enteropathy in Irish setter dogs. Gut 32, 749–753 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Verdu, E. F. et al. Gliadin-dependent neuromuscular and epithelial secretory responses in gluten-sensitive HLA-DQ8 transgenic mice. Am. J. Physiol. Gastrointest. Liver Physiol. 294, G217–G225 (2008).

    CAS  PubMed  Google Scholar 

  136. 136

    Natividad, J. M. et al. Host responses to intestinal microbial antigens in gluten-sensitive mice. PLoS ONE 4, e6472 (2009).

    PubMed  PubMed Central  Google Scholar 

  137. 137

    Clemente, M. G. et al. Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function. Gut 52, 218–223 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Sander, G. R., Cummins, A. G., Henshall, T. & Powell, B. C. Rapid disruption of intestinal barrier function by gliadin involves altered expression of apical junctional proteins. FEBS Lett. 579, 4851–4855 (2005).

    CAS  PubMed  Google Scholar 

  139. 139

    Fasano, A. et al. Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease. Lancet 355, 1518–1519 (2000).

    CAS  PubMed  Google Scholar 

  140. 140

    Gopalakrishnan, S. et al. Larazotide acetate regulates epithelial tight junctions in vitro and in vivo. Peptides 35, 86–94 (2012).

    CAS  PubMed  Google Scholar 

  141. 141

    Kelly, C. P. et al. Larazotide acetate in patients with coeliac disease undergoing a gluten challenge: a randomised placebo-controlled study. Aliment. Pharmacol. Ther. 37, 252–262 (2013).

    CAS  PubMed  Google Scholar 

  142. 142

    Monsuur, A. J. et al. Myosin IXB variant increases the risk of celiac disease and points toward a primary intestinal barrier defect. Nat. Genet. 37, 1341–1344 (2005).

    CAS  PubMed  Google Scholar 

  143. 143

    Van Belzen, M. J. et al. A major non-HLA locus in celiac disease maps to chromosome 19. Gastroenterology 125, 1032–1041 (2003).

    CAS  PubMed  Google Scholar 

  144. 144

    Wirth, J. A., Jensen, K. A., Post, P. L., Bement, W. M. & Mooseker, M. S. Human myosin-IXb, an unconventional myosin with a chimerin-like rho/rac GTPase-activating protein domain in its tail. J. Cell Sci. 109, 653–661 (1996).

    CAS  PubMed  Google Scholar 

  145. 145

    Post, P. L., Bokoch, G. M. & Mooseker, M. S. Human myosin-IXb is a mechanochemically active motor and a GAP for rho. J. Cell Sci. 111, 941–950 (1998).

    CAS  PubMed  Google Scholar 

  146. 146

    Hunt, K. A. et al. Lack of association of MYO9B genetic variants with coeliac disease in a British cohort. Gut 55, 969–972 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147

    Amundsen, S. S. et al. Association analysis of MYO9B gene polymorphisms with celiac disease in a Swedish/Norwegian cohort. Hum. Immunol. 67, 341–345 (2006).

    CAS  PubMed  Google Scholar 

  148. 148

    Wolters, V. M. et al. Replication of genetic variation in the MYO9B gene in Crohn's disease. Hum. Immunol. 72, 592–597 (2011).

    CAS  PubMed  Google Scholar 

  149. 149

    van Bodegraven, A. A. et al. Genetic variation in myosin IXB is associated with ulcerative colitis. Gastroenterology 131, 1768–1774 (2006).

    CAS  PubMed  Google Scholar 

  150. 150

    Cooney, R. et al. Association between genetic variants in myosin IXB and Crohn's disease. Inflamm. Bowel Dis. 15, 1014–1021 (2009).

    PubMed  Google Scholar 

  151. 151

    Chandhoke, S. K. & Mooseker, M. S. A role for myosin IXb, a motor-RhoGAP chimera, in epithelial wound healing and tight junction regulation. Mol. Biol. Cell 23, 2468–2480 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152

    Hegan, P. S. et al. Mice lacking myosin IXb, an inflammatory bowel disease susceptibility gene, have impaired intestinal barrier function and superficial ulceration in the ileum. Cytoskeleton (Hoboken) 73, 163–179 (2016).

    CAS  Google Scholar 

  153. 153

    Schumann, M. et al. Cell polarity-determining proteins Par-3 and PP-1 are involved in epithelial tight junction defects in coeliac disease. Gut 61, 220–228 (2012).

    CAS  PubMed  Google Scholar 

  154. 154

    Szakal, D. N. et al. 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 (2010).

    PubMed  Google Scholar 

  155. 155

    Menzies, I. S. et al. Abnormal intestinal permeability to sugars in villous atrophy. Lancet 2, 1107–1109 (1979).

    CAS  PubMed  Google Scholar 

  156. 156

    Keating, J. et al. Intestinal absorptive capacity, intestinal permeability and jejunal histology in HIV and their relation to diarrhoea. Gut 37, 623–629 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157

    Hermiston, M. L. & Gordon, J. I. Inflammatory bowel disease and adenomas in mice expressing a dominant negative N-cadherin. Science 270, 1203–1207 (1995).

    CAS  PubMed  Google Scholar 

  158. 158

    Jankowski, J. A. et al. Alterations in classical cadherins associated with progression in ulcerative and Crohn's colitis. Lab. Invest. 78, 1155–1167 (1998).

    CAS  PubMed  Google Scholar 

  159. 159

    Smalley-Freed, W. G. et al. p120-catenin is essential for maintenance of barrier function and intestinal homeostasis in mice. J. Clin. Invest. 120, 1824–1835 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. 160

    Schneider, M. R. et al. A key role for E-cadherin in intestinal homeostasis and Paneth cell maturation. PLoS ONE 5, e14325 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. 161

    Barrett, J. C. et al. Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. Nat. Genet. 41, 1330–1334 (2009).

    CAS  PubMed  Google Scholar 

  162. 162

    Moran, C. J. et al. IL-10R polymorphisms are associated with very-early-onset ulcerative colitis. Inflamm. Bowel Dis. 19, 115–123 (2013).

    PubMed  PubMed Central  Google Scholar 

  163. 163

    Glocker, E. O. et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N. Engl. J. Med. 361, 2033–2045 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164

    Doecke, J. D. et al. Genetic susceptibility in IBD: overlap between ulcerative colitis and Crohn's disease. Inflamm. Bowel Dis. 19, 240–245 (2013).

    PubMed  Google Scholar 

  165. 165

    Madsen, K. L. Inflammatory bowel disease: lessons from the IL-10 gene-deficient mouse. Clin. Invest. Med. 24, 250–257 (2001).

    CAS  PubMed  Google Scholar 

  166. 166

    Kuhn, R., Lohler, J., Rennick, D., Rajewsky, K. & Muller, W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75, 263–274 (1993).

    CAS  PubMed  Google Scholar 

  167. 167

    Matharu, K. S. et al. Toll-like receptor 4-mediated regulation of spontaneous Helicobacter-dependent colitis in IL-10-deficient mice. Gastroenterology 137, 1380–1390.e3 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. 168

    Madsen, K. L. et al. Interleukin-10 gene-deficient mice develop a primary intestinal permeability defect in response to enteric microflora. Inflamm. Bowel Dis. 5, 262–270 (1999).

    CAS  PubMed  Google Scholar 

  169. 169

    Madsen, K. L. et al. Antibiotic therapy attenuates colitis in interleukin 10 gene-deficient mice. Gastroenterology 118, 1094–1105 (2000).

    CAS  PubMed  Google Scholar 

  170. 170

    Kostic, A. D., Xavier, R. J. & Gevers, D. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology 146, 1489–1499 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. 171

    Berg, D. J. et al. Rapid development of colitis in NSAID-treated IL-10-deficient mice. Gastroenterology 123, 1527–1542 (2002).

    CAS  PubMed  Google Scholar 

  172. 172

    Arrieta, M. C., Madsen, K. L., Field, C. J. & Meddings, J. B. Increasing small intestinal permeability worsens colitis in the IL-10−/− mouse and prevents the induction of oral tolerance to ovalbumin. Inflamm. Bowel Dis. 21, 8–18 (2015).

    PubMed  Google Scholar 

  173. 173

    Arrieta, M. C., Madsen, K., Doyle, J. & Meddings, J. Reducing small intestinal permeability attenuates colitis in the IL10 gene-deficient mouse. Gut 58, 41–48 (2009).

    CAS  PubMed  Google Scholar 

  174. 174

    Storb, R. et al. Graft-versus-host disease and survival in patients with aplastic anemia treated by marrow grafts from HLA-identical siblings — beneficial effect of a protective environment. N. Engl. J. Med. 308, 302–307 (1983).

    CAS  PubMed  Google Scholar 

  175. 175

    Brown, G. R. et al. Tumor necrosis factor inhibitor ameliorates murine intestinal graft-versus-host disease. Gastroenterology 116, 593–601 (1999).

    CAS  PubMed  Google Scholar 

  176. 176

    Cooke, K. R. et al. Tumor necrosis factor- α production to lipopolysaccharide stimulation by donor cells predicts the severity of experimental acute graft-versus-host disease. J. Clin. Invest. 102, 1882–1891 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. 177

    Nalle, S. C. et al. Recipient NK cell inactivation and intestinal barrier loss are required for MHC-matched graft-versus-host disease. Sci. Transl Med. 6, 243ra87 (2014).

    PubMed  PubMed Central  Google Scholar 

  178. 178

    Bosi, E. et al. Increased intestinal permeability precedes clinical onset of type 1 diabetes. Diabetologia 49, 2824–2827 (2006).

    CAS  PubMed  Google Scholar 

  179. 179

    Meddings, J. B., Jarand, J., Urbanski, S. J., Hardin, J. & Gall, D. G. Increased gastrointestinal permeability is an early lesion in the spontaneously diabetic BB rat. Am. J. Physiol. 276, G951–G957 (1999).

    CAS  PubMed  Google Scholar 

  180. 180

    Tennyson, C. A. & Friedman, G. Microecology, obesity, and probiotics. Curr. Opin. Endocrinol. Diabetes Obes. 15, 422–427 (2008).

    PubMed  Google Scholar 

  181. 181

    Pound, L. D. et al. Cathelicidin antimicrobial peptide: a novel regulator of islet function, islet regeneration, and selected gut bacteria. Diabetes 64, 4135–4147 (2015).

    CAS  PubMed  Google Scholar 

  182. 182

    Daft, J. G. & Lorenz, R. G. Role of the gastrointestinal ecosystem in the development of Type 1 diabetes. Pediatr. Diabetes 16, 407–418 (2015).

    PubMed  PubMed Central  Google Scholar 

  183. 183

    Wen, L. et al. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature 455, 1109–1113 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. 184

    Pozzilli, P., Signore, A., Williams, A. J. & Beales, P. E. NOD mouse colonies around the world — recent facts and figures. Immunol. Today 14, 193–196 (1993).

    CAS  PubMed  Google Scholar 

  185. 185

    Watts, T. et al. 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 (2005).

    CAS  PubMed  Google Scholar 

  186. 186

    Sapone, A. et al. Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives. Diabetes 55, 1443–1449 (2006).

    CAS  PubMed  Google Scholar 

  187. 187

    Leffler, D. A. et al. A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge. Am. J. Gastroenterol. 107, 1554–1562 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. 188

    Avansino, J. R., Chen, D. C., Woolman, J. D., Hoagland, V. D. & Stelzner, M. Engraftment of mucosal stem cells into murine jejunum is dependent on optimal dose of cells. J. Surg. Res. 132, 74–79 (2006).

    CAS  PubMed  Google Scholar 

  189. 189

    Tait, I. S., Evans, G. S., Flint, N. & Campbell, F. C. Colonic mucosal replacement by syngeneic small intestinal stem cell transplantation. Am. J. Surg. 167, 67–72 (1994).

    CAS  PubMed  Google Scholar 

  190. 190

    Sato, T. et al. Single Lgr5 stem cells build crypt–villus structures in vitro without a mesenchymal niche. Nature 459, 262–265 (2009).

    CAS  PubMed  Google Scholar 

  191. 191

    Aihara, E. et al. Epithelial regeneration after gastric ulceration causes prolonged cell-type alterations. Cell. Mol. Gastroenterol. Hepatol. 2, 625–647 (2016).

    PubMed  PubMed Central  Google Scholar 

  192. 192

    Engevik, A. C. et al. The development of spasmolytic polypeptide/TFF2-expressing metaplasia (SPEM) during gastric repair is absent in the aged stomach. Cell. Mol. Gastroenterol. Hepatol. 2, 605–624 (2016).

    PubMed  PubMed Central  Google Scholar 

  193. 193

    Yui, S. et al. Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5+ stem cell. Nat. Med. 18, 618–623 (2012).

    CAS  PubMed  Google Scholar 

  194. 194

    Schepers, A. G. et al. Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science 337, 730–735 (2012).

    CAS  PubMed  Google Scholar 

  195. 195

    Barker, N. et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–611 (2009).

    CAS  PubMed  Google Scholar 

  196. 196

    Kieckhaefer, J. et al. The RNA polymerase III subunit Polr3b is required for the maintenance of small intestinal crypts in mice. Cell. Mol. Gastroenterol. Hepatol. 2, 783–795 (2016).

    PubMed  PubMed Central  Google Scholar 

  197. 197

    Watanabe, N. et al. Requirement of Gαq/Gα11 signaling in the preservation of mouse intestinal epithelial homeostasis. Cell. Mol. Gastroenterol. Hepatol. 2, 767–782 (2016).

    PubMed  PubMed Central  Google Scholar 

  198. 198

    Yamaoka, T. et al. Transactivation of EGF receptor and ErbB2 protects intestinal epithelial cells from TNF-induced apoptosis. Proc. Natl Acad. Sci. USA 105, 11772–11777 (2008).

    CAS  PubMed  Google Scholar 

  199. 199

    Zhao, J. et al. R-spondin1, a novel intestinotrophic mitogen, ameliorates experimental colitis in mice. Gastroenterology 132, 1331–1343 (2007).

    CAS  PubMed  Google Scholar 

  200. 200

    Pinto, D. & Clevers, H. Wnt, stem cells and cancer in the intestine. Biol. Cell 97, 185–196 (2005).

    CAS  PubMed  Google Scholar 

  201. 201

    Sansom, O. J. et al. Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation, and migration. Genes Dev. 18, 1385–1390 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. 202

    Powell, A. E. et al. The pan-ErbB negative regulator Lrig1 is an intestinal stem cell marker that functions as a tumor suppressor. Cell 149, 146–158 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. 203

    Wong, V. W. et al. Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signalling. Nat. Cell Biol. 14, 401–408 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. 204

    Dube, P. E. et al. Epidermal growth factor receptor inhibits colitis-associated cancer in mice. J. Clin. Invest. 122, 2780–2792 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. 205

    He, W. Q. et al. Role of myosin light chain kinase in regulation of basal blood pressure and maintenance of salt-induced hypertension. Am. J. Physiol. Heart Circ. Physiol. 301, H584–H591 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. 206

    He, W. Q. et al. Myosin light chain kinase is central to smooth muscle contraction and required for gastrointestinal motility in mice. Gastroenterology 135, 610–620 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. 207

    Zhang, W. C. et al. Myosin light chain kinase is necessary for tonic airway smooth muscle contraction. J. Biol. Chem. 285, 5522–5531 (2010).

    CAS  PubMed  Google Scholar 

  208. 208

    Schumann, M. et al. Defective tight junctions in refractory celiac disease. Ann. N. Y. Acad. Sci. 1258, 43–51 (2012).

    CAS  PubMed  Google Scholar 

  209. 209

    Noth, R. et al. Increased intestinal permeability and tight junction disruption by altered expression and localization of occludin in a murine graft versus host disease model. BMC Gastroenterol. 11, 109 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. 210

    Becker, C., Watson, A. J. & Neurath, M. F. Complex roles of caspases in the pathogenesis of inflammatory bowel disease. Gastroenterology 144, 283–293 (2013).

    CAS  PubMed  Google Scholar 

  211. 211

    Washington, K. & Jagasia, M. Pathology of graft-versus-host disease in the gastrointestinal tract. Hum. Pathol. 40, 909–917 (2009).

    PubMed  Google Scholar 

  212. 212

    Andre, F. et al. Assessment of the lactulose–mannitol test in Crohn's disease. Gut 29, 511–515 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. 213

    Peeters, M. et al. Increased permeability of macroscopically normal small bowel in Crohn's disease. Dig. Dis. Sci. 39, 2170–2176 (1994).

    CAS  PubMed  Google Scholar 

  214. 214

    Sundqvist, T., Magnusson, K. E., Sjodahl, R., Stjernstrom, I. & Tagesson, C. Passage of molecules through the wall of the gastrointestinal tract. II. Application of low-molecular weight polyethyleneglycol and a deterministic mathematical model for determining intestinal permeability in man. Gut 21, 208–214 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  215. 215

    Arnott, I. D., Kingstone, K. & Ghosh, S. Abnormal intestinal permeability predicts relapse in inactive Crohn disease. Scand. J. Gastroenterol. 35, 1163–1169 (2000).

    CAS  PubMed  Google Scholar 

  216. 216

    May, G. R., Sutherland, L. M. & Meddings, J. B. Lactulose/mannitol permeability is increased in relatives of patients with Crohn's disease. Gastroenterology 102, A934 (1992).

    Google Scholar 

  217. 217

    Smecuol, E. et al. Sugar tests detect celiac disease among first-degree relatives. Am. J. Gastroenterol. 94, 3547–3552 (1999).

    CAS  PubMed  Google Scholar 

  218. 218

    Secondulfo, M. et al. Ultrastructural mucosal alterations and increased intestinal permeability in non-celiac, type I diabetic patients. Dig. Liver Dis. 36, 35–45 (2004).

    CAS  PubMed  Google Scholar 

  219. 219

    Poritz, L. S. et al. Loss of the tight junction protein ZO-1 in dextran sulfate sodium induced colitis. J. Surg. Res. 140, 12–19 (2007).

    CAS  PubMed  Google Scholar 

  220. 220

    Yan, Y. et al. Temporal and spatial analysis of clinical and molecular parameters in dextran sodium sulfate induced colitis. PLoS ONE 4, e6073 (2009).

    PubMed  PubMed Central  Google Scholar 

  221. 221

    Johansson, J. E. & Ekman, T. Gut toxicity during hemopoietic stem cell transplantation may predict acute graft-versus-host disease severity in patients. Dig. Dis. Sci. 52, 2340–2345 (2007).

    PubMed  Google Scholar 

  222. 222

    Lee, A. S. et al. Gut barrier disruption by an enteric bacterial pathogen accelerates insulitis in NOD mice. Diabetologia 53, 741–748 (2010).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors acknowledge NIH grants F30DK103511 (M.A.O.), T32HD007009 (M.A.O.), R01DK61931 (J.R.T.) and R01DK68271 (J.R.T.).

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Correspondence to Jerrold R. Turner.

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Odenwald, M., Turner, J. The intestinal epithelial barrier: a therapeutic target?. Nat Rev Gastroenterol Hepatol 14, 9–21 (2017). https://doi.org/10.1038/nrgastro.2016.169

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