Mechanisms regulating intestinal barrier integrity and its pathological implications

Experimental and Molecular Medicine

Volumn 50, Issue 8, 2018, Pages

  Chelakkot, Chaithanya ^a   Ghim, Jaewang ^b   Ryu, Sung Ho ^a  

^a Pohang University of Science and Technology (POSTECH)   (South Korea)

^b NovaCell Technology Inc   (South Korea)

Author keywords

[No Author keywords available]

Indexed keywords

CLAUDIN; CYTOKINE; GUANOSINE TRIPHOSPHATASE; OCCLUDIN; ZONULA OCCLUDENS PROTEIN; TIGHT JUNCTION PROTEIN;

CELL FUNCTION; ENDOTHELIUM CELL; HUMAN; INFLAMMATORY BOWEL DISEASE; INTESTINE CELL; INTESTINE FUNCTION; METABOLIC DISORDER; NONHUMAN; OBESITY; PATHOPHYSIOLOGY; PERMEABILITY BARRIER; PROTEIN PROCESSING; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION; ULCERATIVE COLITIS; ANIMAL; ENTEROPATHY; EPITHELIUM CELL; INTESTINE; INTESTINE MUCOSA; METABOLISM; PATHOLOGY;

ANIMALS; EPITHELIAL CELLS; HUMANS; INTESTINAL DISEASES; INTESTINAL MUCOSA; INTESTINES; TIGHT JUNCTION PROTEINS;

EID: 85060008820     PISSN: 12263613     EISSN: 20926413     Source Type: Journal    
DOI: 10.1038/s12276-018-0126-x     Document Type: Review

References (117)

1. Koch, S. & Nusrat, A. The life and death of epithelia during inflammation: lessons learned from the gut. Ann. Rev. Pathol. 7, 35–60 (2012).
2. Artis, D. Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut. Nat. Rev. Immunol. 8, 411–420 (2008).
3. Eri, R. & Chieppa, M. Messages from the inside. The dynamic environment that favors intestinal homeostasis. Front. Immunol. 4, 323 (2013).
4. De Mey, J. R. & Freund, J. N. Understanding epithelial homeostasis in the intestine: an old battlefield of ideas, recent breakthroughs and remaining controversies. Tissue Barriers 1, e24965 (2013).
5. Madara, J. L., Nash, S., Moore, R. & Atisook, K. Structure and function of the intestinal epithelial barrier in health and disease. Monogr. Pathol. 31, 306–324 (1990).
6. Catalioto, R. M., Maggi, C. A. & Giuliani, S. Intestinal epithelial barrier dysfunction in disease and possible therapeutical interventions. Curr. Med. Chem. 18, 398–426 (2011).
7. Saenz, S. A., Taylor, B. C. & Artis, D. Welcome to the neighborhood: epithelial cell-derived cytokines license innate and adaptive immune responses at mucosal sites. Immunol. Rev. 226, 172–190 (2008).
8. Guinane, C. M. & Cotter, P. D. Role of the gut microbiota in health and chronic gastrointestinal disease: understanding a hidden metabolic organ. Ther. Adv. Gastroenterol. 6, 295–308 (2013).
9. Kahrstrom, C. T., Pariente, N. & Weiss, U. Intestinal microbiota in health and disease. Nature 535, 47 (2016).
10. Clemente, J. C., Ursell, L. K., Parfrey, L. W. & Knight, R. The impact of the gut microbiota on human health: an integrative view. Cell 148, 1258–1270 (2012).
11. Yu, Y., Sitaraman, S. & Gewirtz, A. T. Intestinal epithelial cell regulation of mucosal inflammation. Immunol. Res. 29, 55–68 (2004).
12. Bjerknes, M. & Cheng, H. Gastrointestinal stem cells. II. Intest. stem Cells Am. J. Physiol. Gastrointest. Liver Physiol. 289, G381–G387 (2005).
13. Okamoto, R. & Watanabe, M. Molecular and clinical basis for the regeneration of human gastrointestinal epithelia. J. Gastroenterol. 39, 1–6 (2004).
14. Ruemmele, F. M., Seidman, E. G. & Lentze, M. J. Regulation of intestinal epithelial cell apoptosis and the pathogenesis of inflammatory bowel disorders. J. Pediatr. Gastroenterol. Nutr. 34, 254–260 (2002).
15. Williams, J. M. et al. Epithelial cell shedding and barrier function: a matter of life and death at the small intestinal villus tip. Vet. Pathol. 52, 445–455 (2015).
16. Groschwitz, K. R. & Hogan, S. P. Intestinal barrier function: molecular regulation and disease pathogenesis. J. Allergy Clin. Immunol. 124, 3–20 (2009). quiz 21-22.
17. Kagnoff, M. F. The intestinal epithelium is an integral component of a communications network. J. Clin. Invest. 124, 2841–2843 (2014).
18. Birchenough, G. M., Johansson, M. E., Gustafsson, J. K., Bergstrom, J. H. & Hansson, G. C. New developments in goblet cell mucus secretion and function. Mucosal Immunol. 8, 712–719 (2015).
19. Kim, Y. S. & Ho, S. B. Intestinal goblet cells and mucins in health and disease: recent insights and progress. Curr. Gastroenterol. Rep. 12, 319–330 (2010).
20. Specian, R. D. & Oliver, M. G. Functional biology of intestinal goblet cells Am. J. Physiol. 260, C183–C193 (1991).
21. Rescigno, M. The intestinal epithelial barrier in the control of homeostasis and immunity. Trends Immunol. 32, 256–264 (2011).
22. Suzuki, T. Regulation of intestinal epithelial permeability by tight junctions. Cell Mol. Life Sci. 70, 631–659 (2013).
23. Maloy, K. J. & Powrie, F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 474, 298–306 (2011).
24. Khor, B., Gardet, A. & Xavier, R. J. Genetics and pathogenesis of inflammatory bowel disease. Nature 474, 307–317 (2011).
25. Diamond, J. M. Twenty-first Bowditch lecture. The epithelial junction: bridge, gate, and fence. Physiologist 20, 10–18 (1977).
26. Berkes, J., Viswanathan, V. K., Savkovic, S. D. & Hecht, G. Intestinal epithelial responses to enteric pathogens: effects on the tight junction barrier, ion transport, and inflammation. Gut 52, 439–451 (2003).
27. Gunzel, D. & Yu, A. S. Claudins and the modulation of tight junction permeability. Physiol. Rev. 93, 525–569 (2013).
28. Cereijido, M. et al. New diseases derived or associated with the tight junction. Med Res Arch. 38, 465–478 (2007).
29. Farquhar, M. G. & Palade, G. E. Junctional complexes in various epithelia. J. Cell Biol. 17, 375–412 (1963).
30. Furuse, M. et al. Occludin: a novel integral membrane protein localizing at tight junctions. J. Cell Biol. 123, 1777–1788 (1993).
31. Feldman, G. J., Mullin, J. M. & Ryan, M. P. Occludin: structure, function and regulation. Adv. Drug Deliv. Rev. 57, 883–917 (2005).
32. Kevil, C. G. et al. Expression of zonula occludens and adherens junctional proteins in human venous and arterial endothelial cells: role of occludin in endothelial solute barriers. Microcirculation 5, 197–210 (1998).
33. Balda, M. S. et al. Functional dissociation of paracellular permeability and transepithelial electrical resistance and disruption of the apical-basolateral intramembrane diffusion barrier by expression of a mutant tight junction membrane protein. J. Cell Biol. 134, 1031–1049 (1996).
34. Balda, M. S., Flores-Maldonado, C., Cereijido, M. & Matter, K. Multiple domains of occludin are involved in the regulation of paracellular permeability. J. Cell Biochem. 78, 85–96 (2000).
35. Chen, Y., Merzdorf, C., Paul, D. L. & Goodenough, D. A. COOH terminus of occludin is required for tight junction barrier function in early Xenopus embryos. J. Cell Biol. 138, 891–899 (1997).
36. Schulzke, J. D. et al. Epithelial transport and barrier function in occludin-deficient mice. Biochim. Biophys. Acta 1669, 34–42 (2005).
37. Saitou, M. et al. Complex phenotype of mice lacking occludin, a component of tight junction strands. Mol. Biol. Cell 11, 4131–4142 (2000).
38. Li, X. et al. Somatostatin regulates tight junction proteins expression in colitis mice. Int. J. Clin. Exp. Pathol. 7, 2153–2162 (2014).
39. Nighot, P. et al. Matrix metalloproteinase 9-induced increase in intestinal epithelial tight junction permeability contributes to the severity of experimental DSS colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 309, G988–G997 (2015).
40. Mennigen, R. et al. Probiotic mixture VSL#3 protects the epithelial barrier by maintaining tight junction protein expression and preventing apoptosis in a murine model of colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G1140–G1149 (2009).
41. Tsukita, S. & Furuse, M. Occludin and claudins in tight-junction strands: leading or supporting players? Trends Cell Biol. 9, 268–273 (1999).
42. Mrsny, R. J. et al. A key claudin extracellular loop domain is critical for epithelial barrier integrity. Am. J. Pathol. 172, 905–915 (2008).
43. 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).
44. Tsukita, S. & Furuse, M. Overcoming barriers in the study of tight junction functions: from occludin to claudin. Genes Cells 3, 569–573 (1998).
45. Findley, M. K. & Koval, M. Regulation and roles for claudin-family tight junction proteins. IUBMB Life 61, 431–437 (2009).
46. 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).
47. Ahmad, R. et al. Targeted colonic claudin-2 expression renders resistance to epithelial injury, induces immune suppression, and protects from colitis. Mucosal Immunol. 7, 1340–1353 (2014).
48. Itoh, M. et al. Direct binding of three tight junction-associated MAGUKs, ZO-1, ZO-2, and ZO-3, with the COOH termini of claudins. J. Cell Biol. 147, 1351–1363 (1999).
49. Beatch, M., Jesaitis, L. A., Gallin, W. J., Goodenough, D. A. & Stevenson, B. R. The tight junction protein ZO-2 contains three PDZ (PSD-95/Discs-Large/ZO-1) domains and an alternatively spliced region. J. Biol. Chem. 271, 25723–25726 (1996).
50. Laukoetter, M. G. et al. JAM-A regulates permeability and inflammation in the intestine in vivo. J. Exp. Med. 204, 3067–3076 (2007).
51. Khounlotham, M. et al. Compromised intestinal epithelial barrier induces adaptive immune compensation that protects from colitis. Immunity 37, 563–573 (2012).
52. Marchiando, A. M., Graham, W. V. & Turner, J. R. Epithelial barriers in homeostasis and disease. Ann. Rev. Pathol. 5, 119–144 (2010).
53. Harhaj, N. S. & Antonetti, D. A. Regulation of tight junctions and loss of barrier function in pathophysiology. Int. J. Biochem. Cell Biol. 36, 1206–1237 (2004).
54. Tsukita, S. et al. Specific proto-oncogenic tyrosine kinases of src family are enriched in cell-to-cell adherens junctions where the level of tyrosine phosphorylation is elevated. J. Cell Biol. 113, 867–879 (1991).
55. Zahraoui, A. et al. A small rab GTPase is distributed in cytoplasmic vesicles in non polarized cells but colocalizes with the tight junction marker ZO-1 in polarized epithelial cells J. Cell Biol. 124, 101–115 (1994).
56. Capaldo, C. T. & Nusrat, A. Cytokine regulation of tight junctions. Biochim. Biophys. Acta 1788, 864–871 (2009).
57. 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).
58. Wang, F. et al. Interferon-gamma and tumor necrosis factor-alpha synergize to induce intestinal epithelial barrier dysfunction by up-regulating myosin light chain kinase expression. Am. J. Pathol. 166, 409–419 (2005).
59. Zolotarevsky, Y. et al. A membrane-permeant peptide that inhibits MLC kinase restores barrier function in in vitro models of intestinal disease. Gastroenterol 123, 163–172 (2002).
60. Utech, M. et al. Mechanism of IFN-gamma-induced endocytosis of tight junction proteins: myosin II-dependent vacuolarization of the apical plasma membrane. Mol. Biol. Cell 16, 5040–5052 (2005).
61. Bruewer, M. et al. Interferon-gamma induces internalization of epithelial tight junction proteins via a macropinocytosis-like process. FASEB J. 19, 923–933 (2005).
62. Scharl, M., Paul, G., Barrett, K. E. & McCole, D. F. AMP-activated protein kinase mediates the interferon-gamma-induced decrease in intestinal epithelial barrier function. J. Biol. Chem. 284, 27952–27963 (2009).
63. Ozaki, H. et al. Cutting edge: combined treatment of TNF-alpha and IFN-gamma causes redistribution of junctional adhesion molecule in human endothelial cells J. Immunol. 163, 553–557 (1999).
64. Ye, D., Ma, I. & Ma, T. Y. Molecular mechanism of tumor necrosis factor-alpha modulation of intestinal epithelial tight junction barrier. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G496–G504 (2006).
65. Graham, W. V. et al. Tumor necrosis factor-induced long myosin light chain kinase transcription is regulated by differentiation-dependent signaling events. Characterization of human long myosin light chain kinase promoter. J. Biol. Chem. 281, 26205–26215 (2006).
66. Su, L. et al. TNFR2 activates MLCK-dependent tight junction dysregulation to cause apoptosis-mediated barrier loss and experimental colitis. Gastroenterol 145, 407–415 (2013).
67. Yu, D. et al. MLCK-dependent exchange and actin binding region-dependent anchoring of ZO-1 regulate tight junction barrier function. Proc. Natl Acad. Sci. USA 107, 8237–8241 (2010).
68. Shen, L. et al. Myosin light chain phosphorylation regulates barrier function by remodeling tight junction structure. J. Cell Sci. 119, 2095–2106 (2006).
69. Shen, L. Tight junctions on the move: molecular mechanisms for epithelial barrier regulation. Ann. N. Y. Acad. Sci. 1258, 9–18 (2012).
70. Cunningham, K. E. & Turner, J. R. Myosin light chain kinase: pulling the strings of epithelial tight junction function. Ann. N. Y. Acad. Sci. 1258, 34–42 (2012).
71. Farshori, P. & Kachar, B. Redistribution and phosphorylation of occludin during opening and resealing of tight junctions in cultured epithelial cells J. Membr. Biol. 170, 147–156 (1999).
72. Rao, R. Occludin phosphorylation in regulation of epithelial tight junctions. Ann. N. Y. Acad. Sci. 1165, 62–68 (2009).
73. Seth, A., Sheth, P., Elias, B. C. & Rao, R. Protein phosphatases 2A and 1 interact with occludin and negatively regulate the assembly of tight junctions in the CACO-2 cell monolayer. J. Biol. Chem. 282, 11487–11498 (2007).
74. Nunbhakdi-Craig, V. et al. Protein phosphatase 2A associates with and regulates atypical PKC and the epithelial tight junction complex. J. Cell Biol. 158, 967–978 (2002).
75. Kale, G., Naren, A. P., Sheth, P. & Rao, R. K. Tyrosine phosphorylation of occludin attenuates its interactions with ZO-1, ZO-2, and ZO-3. Biochem. Biophys. Res. Commun. 302, 324–329 (2003).
76. Wong, V. Phosphorylation of occludin correlates with occludin localization and function at the tight junction. Am. J. Physiol. 273, C1859–C1867 (1997).
77. Rao, R. K., Basuroy, S., Rao, V. U., Karnaky, K. J. Jr & Gupta, A. Tyrosine phosphorylation and dissociation of occludin-ZO-1 and E-cadherin-beta-catenin complexes from the cytoskeleton by oxidative stress. Biochem. J. 368, 471–481 (2002).
78. Basuroy, S. et al. Expression of kinase-inactive c-Src delays oxidative stress-induced disassembly and accelerates calcium-mediated reassembly of tight junctions in the Caco-2 cell monolayer. J. Biol. Chem. 278, 11916–11924 (2003).
79. Coeffier, M. et al. Increased proteasome-mediated degradation of occludin in irritable bowel syndrome. Am. J. Gastroenterol. 105, 1181–1188 (2010).
80. Raikwar, N. S., Vandewalle, A. & Thomas, C. P. Nedd4-2 interacts with occludin to inhibit tight junction formation and enhance paracellular conductance in collecting duct epithelia. Am. J. Physiol. Ren. Physiol. 299, F436–F444 (2010).
81. Zhang, L., Li, J., Young, L. H. & Caplan, M. J. AMP-activated protein kinase regulates the assembly of epithelial tight junctions. Proc. Natl Acad. Sci. USA 103, 17272–17277 (2006).
82. Peng, L., Li, Z. R., Green, R. S., Holzman, I. R. & Lin, J. Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers. J. Nutr. 139, 1619–1625 (2009).
83. Ma, T. Y. Intestinal epithelial barrier dysfunction in Crohn’s disease. Proc. Soc. Exp. Biol. Med. Soc. Exp. Biol. Med. 214, 318–327 (1997).
84. Hanauer, S. B. Inflammatory bowel disease: epidemiology, pathogenesis, and therapeutic opportunities. Inflamm. Bowel Dis. 12(Suppl 1), S3–S9 (2006).
85. Schmidt, C. & Stallmach, A. Etiology and pathogenesis of inflammatory bowel disease. Minerva Gastroenterol. Dietol. 51, 127–145 (2005).
86. Leake, I. IBD: treatment for acute severe ulcerative colitis. Nat. Rev. Gastroenterol. Hepatol. 13, 436 (2016).
87. Nguyen, G. C. et al. Inflammatory bowel disease characteristics among African Americans, Hispanics, and non-Hispanic Whites: characterization of a large North American cohort. Am. J. Gastroenterol. 101, 1012–1023 (2006).
88. Karlinger, K., Gyorke, T., Mako, E., Mester, A. & Tarjan, Z. The epidemiology and the pathogenesis of inflammatory bowel disease. Eur. J. Radiol. 35, 154–167 (2000).
89. Sartor, R. B. Current concepts of the etiology and pathogenesis of ulcerative colitis and Crohn’s disease. Gastroenterol. Clin. North Am. 24, 475–507 (1995).
90. Xavier, R. J. & Podolsky, D. K. Unravelling the pathogenesis of inflammatory bowel disease. Nature 448, 427–434 (2007).
91. Stefanelli, T., Malesci, A., Repici, A., Vetrano, S. & Danese, S. New insights into inflammatory bowel disease pathophysiology: paving the way for novel therapeutic targets. Curr. Drug. Targets 9, 413–418 (2008).
92. Kucharzik, T. et al. Recent understanding of IBD pathogenesis: implications for future therapies. Inflamm. Bowel Dis. 12, 1068–1083 (2006).
93. MacDermott, R. P. Alterations of the mucosal immune system in inflammatory bowel disease. J. Gastroenterol. 31, 907–916 (1996).
94. Takeuchi, K., Maiden, L. & Bjarnason, I. Genetic aspects of intestinal permeability in inflammatory bowel disease. Novartis Found. Symp. 263, 151–158 (2004). discussion 159-163, 211-158.
95. 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).
96. Arnott, I. D., Kingstone, K. & Ghosh, S. Abnormal intestinal permeability predicts relapse in inactive Crohn disease. Scand. J. Gastroenterol. 35, 1163–1169 (2000).
97. Soderholm, J. D. et al. Different intestinal permeability patterns in relatives and spouses of patients with Crohn’s disease: an inherited defect in mucosal defence? Gut 44, 96–100 (1999).
98. Wapenaar, M. C. et al. Associations with tight junction genes PARD3 and MAGI2 in Dutch patients point to a common barrier defect for coeliac disease and ulcerative colitis. Gut 57, 463–467 (2008).
99. van Bodegraven, A. A. et al. Genetic variation in myosin IXB is associated with ulcerative colitis. Gastroenterol 131, 1768–1774 (2006).
100. 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).
101. Chelakkot, C. et al. Intestinal epithelial cell-specific deletion of PLD2 alleviates DSS-induced colitis by regulating occludin. Sci. Rep. 7, 1573 (2017).
102. Damms-Machado, A. et al. Gut permeability is related to body weight, fatty liver disease, and insulin resistance in obese individuals undergoing weight reduction. Am. J. Clin. Nutr. 105, 127–135 (2017).
103. Cox, A. J. et al. Increased intestinal permeability as a risk factor for type 2 diabetes. Diabetes Metab. 43, 163–166 (2017).
104. Fasano, A. Gut permeability, obesity, and metabolic disorders: who is the chicken and who is the egg?. Am. J. Clin. Nutr. 105, 3–4 (2017).
105. Cani, P. D. et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761–1772 (2007).
106. Cani, P. D. et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57, 1470–1481 (2008).
107. Moreira, A. P., Texeira, T. F., Ferreira, A. B., Peluzio Mdo, C. & Alfenas Rde, C. Influence of a high-fat diet on gut microbiota, intestinal permeability and metabolic endotoxaemia. Br. J. Nutr. 108, 801–809 (2012).
108. Guo, S., Al-Sadi, R., Said, H. M. & Ma, T. Y. Lipopolysaccharide causes an increase in intestinal tight junction permeability in vitro and in vivo by inducing enterocyte membrane expression and localization of TLR-4 and CD14. Am. J. Pathol. 182, 375–387 (2013).
109. Hur, K. Y. Is GDF15 a novel biomarker to predict the development of prediabetes or diabetes? Diabetes Metab. J. 38, 437–438 (2014).
110. Cani, P. D. et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 58, 1091–1103 (2009).
111. Cani, P. D., Osto, M., Geurts, L. & Everard, A. Involvement of gut microbiota in the development of low-grade inflammation and type 2 diabetes associated with obesity. Gut Microbes 3, 279–288 (2012).
112. Qin, J. et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490, 55–60 (2012).
113. Dao, M. C. et al. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut 65, 426–436 (2016).
114. Everard, A. et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc. Natl Acad. Sci. USA 110, 9066–9071 (2013).
115. Shin, N. R. et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 63, 727–735 (2014).
116. Plovier, H. et al. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat. Med. 23, 107–113 (2017).
117. Kang, C. S. et al. Extracellular vesicles derived from gut microbiota, especially Akkermansia muciniphila, protect the progression of dextran sulfate sodium-induced colitis. PLoS ONE 8, e76520 (2013).