The intestinal epithelial barrier: a therapeutic target? (original) (raw)

• 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
• Turner, J. R. in Yamada's Textbook of Gastroenterology (eds Podolsky, D. K. et al.) 317–329 (Wiley-Blackwell, 2015).
  Google Scholar
• Turner, J. R. Intestinal mucosal barrier function in health and disease. Nat. Rev. Immunol. 9, 799–809 (2009).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• Farquhar, M. & Palade, G. Junctional complexes in various epithelia. J. Cell Biol. 17, 375–412 (1963).
  CAS PubMed PubMed Central Google Scholar
• Madara, J. L. Intestinal absorptive cell tight junctions are linked to cytoskeleton. Am. J. Physiol. 253, C171–C175 (1987).
  CAS PubMed Google Scholar
• 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
• Takeichi, M. Dynamic contacts: rearranging adherens junctions to drive epithelial remodelling. Nat. Rev. Mol. Cell Biol. 15, 397–410 (2014).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• Kachar, B. & Reese, T. S. Evidence for the lipidic nature of tight junction strands. Nature 296, 464–466 (1982).
  CAS PubMed Google Scholar
• Lingaraju, A. et al. Conceptual barriers to understanding physical barriers. Semin. Cell Dev. Biol. 42, 13–21 (2015).
  PubMed PubMed Central Google Scholar
• 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
• 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
• 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
• 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
• Van Itallie, C. M. & Anderson, J. M. Claudins and epithelial paracellular transport. Annu. Rev. Physiol. 68, 403–429 (2006).
  CAS PubMed Google Scholar
• 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
• 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
• Weber, C. R. et al. Claudin-2-dependent paracellular channels are dynamically gated. eLife 4, e09906 (2015).
  PubMed PubMed Central Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Sambrotta, M. et al. Mutations in TJP2 cause progressive cholestatic liver disease. Nat. Genet. 46, 326–328 (2014).
  CAS PubMed PubMed Central Google Scholar
• 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
• 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
• Llorente, C. & Schnabl, B. The gut microbiota and liver disease. Cell. Mol. Gastroenterol. Hepatol. 1, 275–284 (2015).
  PubMed PubMed Central Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Mora-Galindo, J. Maturation of tight junctions in guinea-pig cecal epithelium. Cell Tissue Res. 246, 169–175 (1986).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Quigley, E. M. Leaky gut — concept or clinical entity? Curr. Opin. Gastroenterol. 32, 74–79 (2016).
  PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• Just, I. et al. Glucosylation of Rho proteins by Clostridium difficile toxin B. Nature 375, 500–503 (1995).
  CAS PubMed Google Scholar
• Hollander, D. Crohn's disease — a permeability disorder of the tight junction? Gut 29, 1621–1624 (1988).
  CAS PubMed PubMed Central Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Bjarnason, I., MacPherson, A. & Hollander, D. Intestinal permeability: an overview. Gastroenterology 108, 1566–1581 (1995).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• Smecuol, E. et al. Gastrointestinal permeability in celiac disease. Gastroenterology 112, 1129–1136 (1997).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Gopalakrishnan, S. et al. Larazotide acetate regulates epithelial tight junctions in vitro and in vivo. Peptides 35, 86–94 (2012).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Menzies, I. S. et al. Abnormal intestinal permeability to sugars in villous atrophy. Lancet 2, 1107–1109 (1979).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Madsen, K. L. et al. Antibiotic therapy attenuates colitis in interleukin 10 gene-deficient mice. Gastroenterology 118, 1094–1105 (2000).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Bosi, E. et al. Increased intestinal permeability precedes clinical onset of type 1 diabetes. Diabetologia 49, 2824–2827 (2006).
  CAS PubMed Google Scholar
• 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
• Tennyson, C. A. & Friedman, G. Microecology, obesity, and probiotics. Curr. Opin. Endocrinol. Diabetes Obes. 15, 422–427 (2008).
  PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Barker, N. et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–611 (2009).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• Zhao, J. et al. R-spondin1, a novel intestinotrophic mitogen, ameliorates experimental colitis in mice. Gastroenterology 132, 1331–1343 (2007).
  CAS PubMed Google Scholar
• Pinto, D. & Clevers, H. Wnt, stem cells and cancer in the intestine. Biol. Cell 97, 185–196 (2005).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Schumann, M. et al. Defective tight junctions in refractory celiac disease. Ann. N. Y. Acad. Sci. 1258, 43–51 (2012).
  CAS PubMed Google Scholar
• 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
• 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
• Washington, K. & Jagasia, M. Pathology of graft-versus-host disease in the gastrointestinal tract. Hum. Pathol. 40, 909–917 (2009).
  PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• Smecuol, E. et al. Sugar tests detect celiac disease among first-degree relatives. Am. J. Gastroenterol. 94, 3547–3552 (1999).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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