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CORRECTION article

Front. Nutr., 01 November 2021
Sec. Nutritional Immunology
Volume 8 - 2021 | https://doi.org/10.3389/fnut.2021.790387

Corrigendum: Inflammatory and Microbiota-Related Regulation of the Intestinal Epithelial Barrier

  • 1IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
  • 2Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
  • 3Medical-Surgical Department of Clinical Sciences and Translational Medicine, University Sapienza, Rome, Italy

A Corrigendum on
Inflammatory and Microbiota-Related Regulation of the Intestinal Epithelial Barrier

by Barbara, G., Barbaro, M. R., Fuschi, D., Palombo, M., Falangone, F., Cremon, C., Marasco, G., and Stanghellini, V. (2021). Front. Nutr. 8:718356. doi: 10.3389/fnut.2021.718356

Incorrect Reference

In the original article, there is a mistake in the references cited in the text. From reference 105 onwards, the number does not correspond to the correct citation. The corrected references appear below.

The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.

Publisher's Note

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References

1. Turner JR. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol. (2009) 9:799–809. doi: 10.1038/nri2653

PubMed Abstract | CrossRef Full Text | Google Scholar

2. Helander HF, Fändriks L. Surface area of the digestive tract-revisited. Scand J Gastroenterol. (2014) 49:681–9. doi: 10.3109/00365521.2014.898326

PubMed Abstract | CrossRef Full Text | Google Scholar

3. Camilleri M. Leaky gut: mechanisms, measurement and clinical implications in humans. Gut. (2019) 68:1516–26. doi: 10.1136/gutjnl-2019-318427

PubMed Abstract | CrossRef Full Text | Google Scholar

4. Yen TH, Wright NA. The gastrointestinal tract stem cell niche. Stem Cell Rev. (2006) 2:203–12. doi: 10.1007/s12015-006-0048-1

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Von Moltke J, Ji M, Liang HE, Locksley RM. Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature. (2016) 529:221–5. doi: 10.1038/nature16161

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Bischoff SC, Barbara G, Buurman W, Ockhuizen T, Schulzke JD, Serino M, et al. Intestinal permeability - a new target for disease prevention and therapy. BMC Gastroenterol. (2014) 14:189. doi: 10.1186/s12876-014-0189-7

PubMed Abstract | CrossRef Full Text

7. Salvo-Romero E, Alonso-Cotoner C, Pardo-Camacho C, Casado-Bedmar M, Vicario M. The intestinal barrier function and its involvement in digestive disease. Rev Esp Enfermedades Dig. (2015) 107:686–96. doi: 10.17235/reed.2015.3846/2015

PubMed Abstract | CrossRef Full Text | Google Scholar

8. Meddings J. The significance of the gut barrier in disease. Gut. (2008) 57:438–40. doi: 10.1136/gut.2007.143172

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Hansson GC. Mucus and mucins in diseases of the intestinal and respiratory tracts. J Intern Med. (2019) 285:479–90. doi: 10.1111/joim.12910

PubMed Abstract | CrossRef Full Text | Google Scholar

10. Gillois K, Lévêque M, Théodorou V, Robert H, Mercier-Bonin M. Mucus: an underestimated gut target for environmental pollutants and food additives. Microorganisms. (2018) 6:53. doi: 10.3390/microorganisms6020053

PubMed Abstract | CrossRef Full Text | Google Scholar

11. Johansson MEV, Hansson GC. Immunological aspects of intestinal mucus and mucins. Nat Rev Immunol. (2016) 16:639–49. doi: 10.1038/nri.2016.88

PubMed Abstract | CrossRef Full Text | Google Scholar

12. Cone RA. Barrier properties of mucus. Adv Drug Deliv Rev. (2009) 61:75–85. doi: 10.1016/j.addr.2008.09.008

PubMed Abstract | CrossRef Full Text | Google Scholar

13. König J, Wells J, Cani PD, García-Ródenas CL, MacDonald T, Mercenier A, et al. Human intestinal barrier function in health and disease. Clin Transl Gastroenterol. (2016) 7:e196. doi: 10.1038/ctg.2016.54

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Kim YS, Ho SB. Intestinal goblet cells and mucins in health and disease: recent insights and progress. Curr Gastroenterol Rep. (2010) 12:319–30. doi: 10.1007/s11894-010-0131-2

PubMed Abstract | CrossRef Full Text | Google Scholar

15. Hansson GC. Mucins and the Microbiome. Annu Rev Biochem. (2020) 89:769–93. doi: 10.1146/annurev-biochem-011520-105053

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Bansil R, Turner BS. The biology of mucus: composition, synthesis and organization. Adv Drug Deliv Rev. (2018) 124:3–15. doi: 10.1016/j.addr.2017.09.023

PubMed Abstract | CrossRef Full Text | Google Scholar

17. LAMONT JT. Mucus: the front line of intestinal mucosal defense. Ann N Y Acad Sci. (1992) 664:190–201. doi: 10.1111/j.1749-6632.1992.tb39760.x

PubMed Abstract | CrossRef Full Text | Google Scholar

18. Kim JJ, Khan WI. Goblet cells and mucins: role in innate defense in enteric infections. Pathogens. (2013) 2:55–70. doi: 10.3390/pathogens2010055

PubMed Abstract | CrossRef Full Text | Google Scholar

19. Strugnell RA, Wijburg OLC. The role of secretory antibodies in infection immunity. Nat Rev Microbiol. (2010) 8:656–67. doi: 10.1038/nrmicro2384

PubMed Abstract | CrossRef Full Text | Google Scholar

20. Huus KE, Petersen C, Finlay BB. Diversity and dynamism of IgA–microbiota interactions. Nat Rev Immunol. (2021) 21:514–25. doi: 10.1038/s41577-021-00506-1

PubMed Abstract | CrossRef Full Text | Google Scholar

21. Pelaseyed T, Hansson GC. Membrane mucins of the intestine at a glance. J Cell Sci. (2020) 133:jcs240929. doi: 10.1242/JCS.240929

PubMed Abstract | CrossRef Full Text | Google Scholar

22. Etienne-Mesmin L, Chassaing B, Desvaux M, De Paepe K, Gresse R, Sauvaitre T, et al. Experimental models to study intestinal microbes–mucus interactions in health and disease. FEMS Microbiol Rev. (2019) 43:457–89. doi: 10.1093/femsre/fuz013

PubMed Abstract | CrossRef Full Text | Google Scholar

23. Pelaseyed T, Bergström JH, Gustafsson JK, Ermund A, Birchenough GMH, Schütte A, et al. The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system. Immunol Rev. (2014) 260:8–20. doi: 10.1111/imr.12182

PubMed Abstract | CrossRef Full Text | Google Scholar

24. Pabst O, Mowat AM. Oral tolerance to food protein. Mucosal Immunol. (2012) 5:232–9. doi: 10.1038/mi.2012.4

PubMed Abstract | CrossRef Full Text | Google Scholar

25. Shan M, Gentile M, Yeiser JR, Walland AC, Bornstein VU, Chen K, et al. Mucus enhances gut homeostasis and oral tolerance by delivering immunoregulatory signals. Science. (2013) 342:447–53. doi: 10.1126/science.1237910

PubMed Abstract | CrossRef Full Text | Google Scholar

26. Ermund A, Gustafsson JK, Hansson GC, Keita Å V. Mucus properties and goblet cell quantification in mouse, rat and human ileal Peyer's patches. PLoS ONE. (2013) 8:e83688. doi: 10.1371/journal.pone.0083688

PubMed Abstract | CrossRef Full Text | Google Scholar

27. Johansson MEV, Holmén Larsson JM, Hansson GC. The two mucus layers of colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host-microbial interactions. Proc Natl Acad Sci USA. (2011) 108:4659–65. doi: 10.1073/pnas.1006451107

PubMed Abstract | CrossRef Full Text | Google Scholar

28. Atuma C, Strugala V, Allen A, Holm L. The adherent gastrointestinal mucus gel layer: thickness and physical state in vivo. Am J Physiol Gastrointest Liver Physiol. (2001) 280:G922–9. doi: 10.1152/ajpgi.2001.280.5.g922

PubMed Abstract | CrossRef Full Text | Google Scholar

29. Ermund A, Schütte A, Johansson MEV, Gustafsson JK, Hansson GC. Studies of mucus in mouse stomach, small intestine, and colon. I. Gastrointestinal mucus layers have different properties depending on location as well as over the Peyer's patches. Am J Physiol Gastrointest Liver Physiol. (2013) 305:G341–7. doi: 10.1152/ajpgi.00046.2013

PubMed Abstract | CrossRef Full Text | Google Scholar

30. Birchenough GMH, Johansson MEV, Gustafsson JK, Bergström JH, Hansson GC. New developments in goblet cell mucus secretion and function. Mucosal Immunol. (2015) 8:712–9. doi: 10.1038/mi.2015.32

PubMed Abstract | CrossRef Full Text | Google Scholar

31. Ouellette AJ. Paneth cells and innate mucosal immunity. Curr Opin Gastroenterol. (2010) 26:547–53. doi: 10.1097/MOG.0b013e32833dccde

PubMed Abstract | CrossRef Full Text | Google Scholar

32. Heazlewood CK, Cook MC, Eri R, Price GR, Tauro SB, Taupin D, et al. Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis. PLoS Med. (2008) 5:54. doi: 10.1371/journal.pmed.0050054

PubMed Abstract | CrossRef Full Text | Google Scholar

33. Renner M, Bergmann G, Krebs I, End C, Lyer S, Hilberg F, et al. DMBT1 confers mucosal protection in vivo and a deletion variant is associated with Crohn's disease. Gastroenterology. (2007) 133:1499–509. doi: 10.1053/j.gastro.2007.08.007

PubMed Abstract | CrossRef Full Text | Google Scholar

34. Hooper LV, MacPherson AJ. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat Rev Immunol. (2010) 10:159–69. doi: 10.1038/nri2710

PubMed Abstract | CrossRef Full Text | Google Scholar

35. Meyer-Hoffert U, Hornef MW, Henriques-Normark B, Axelsson LG, Midtvedt T, Pütsep K, et al. Secreted enteric antimicrobial activity localises to the mucus surface layer. Gut. (2008) 57:764–71. doi: 10.1136/gut.2007.141481

PubMed Abstract | CrossRef Full Text | Google Scholar

36. Van Der Waaij LA, Harmsen HJM, Madjipour M, Kroese FGM, Zwiers M, Van Dullemen HM, et al. Bacterial population analysis of human colon and terminal ileum biopsies with 16S rRNA-based fluorescent probes: commensal bacteria live in suspension and have no direct contact with epithelial cells. Inflamm Bowel Dis. (2005) 11:865–71. doi: 10.1097/01.mib.0000179212.80778.d3

PubMed Abstract | CrossRef Full Text | Google Scholar

37. Johansson MEV, Phillipson M, Petersson J, Velcich A, Holm L, Hansson GC. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc Natl Acad Sci USA. (2008) 105:15064–9. doi: 10.1073/pnas.0803124105

PubMed Abstract | CrossRef Full Text | Google Scholar

38. Johansson MEV, Sjövall H, Hansson GC. The gastrointestinal mucus system in health and disease. Nat Rev Gastroenterol Hepatol. (2013) 10:352–61. doi: 10.1038/nrgastro.2013.35

PubMed Abstract | CrossRef Full Text | Google Scholar

39. Li H, Limenitakis JP, Fuhrer T, Geuking MB, Lawson MA, Wyss M, et al. The outer mucus layer hosts a distinct intestinal microbial niche. Nat Commun. (2015) 6:8292. doi: 10.1038/ncomms9292

PubMed Abstract | CrossRef Full Text

40. Kamphuis JBJ, Mercier-Bonin M, Eutamène H, Theodorou V. Mucus organisation is shaped by colonic content; a new view. Sci Rep. (2017) 7:8527. doi: 10.1038/s41598-017-08938-3

PubMed Abstract | CrossRef Full Text

41. Hoskins LC, Boulding ET. Mucin degradation in human colon ecosystems. J Clin Invest. (1981) 67:163–72. doi: 10.1172/jci110009

PubMed Abstract | CrossRef Full Text | Google Scholar

42. Png CW, Lindén SK, Gilshenan KS, Zoetendal EG, McSweeney CS, Sly LI, et al. Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria. Am J Gastroenterol. (2010) 105:2420–8. doi: 10.1038/ajg.2010.281

PubMed Abstract | CrossRef Full Text | Google Scholar

43. Desai MS, Seekatz AM, Koropatkin NM, Kamada N, Hickey CA, Wolter M, et al. A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cell. (2016) 167:1339–53.e21. doi: 10.1016/j.cell.2016.10.043

PubMed Abstract | CrossRef Full Text | Google Scholar

44. Johansson MEV, Jakobsson HE, Holmén-Larsson J, Schütte A, Ermund A, Rodríguez-Piñeiro AM, et al. Normalization of host intestinal mucus layers requires long-term microbial colonization. Cell Host Microbe. (2015) 18:582–92. doi: 10.1016/j.chom.2015.10.007

PubMed Abstract | CrossRef Full Text | Google Scholar

45. Schroeder BO. Fight them or feed them: how the intestinal mucus layer manages the gut microbiota. Gastroenterol Rep. (2019) 7:3–12. doi: 10.1093/gastro/goy052

PubMed Abstract | CrossRef Full Text | Google Scholar

46. Fu J, Wei B, Wen T, Johansson MEV, Liu X, Bradford E, et al. Loss of intestinal core 1-derived O-glycans causes spontaneous colitis in mice. J Clin Invest. (2011) 121:1657–66. doi: 10.1172/JCI45538

PubMed Abstract | CrossRef Full Text | Google Scholar

47. Larsson JMH, Karlsson H, Crespo JG, Johansson MEV, Eklund L, Sjövall H, et al. Altered O-glycosylation profile of MUC2 mucin occurs in active ulcerative colitis and is associated with increased inflammation. Inflamm Bowel Dis. (2011) 17:2299–307. doi: 10.1002/ibd.21625

PubMed Abstract | CrossRef Full Text | Google Scholar

48. Johansson MEV, Gustafsson JK, Holmen-Larsson J, Jabbar KS, Xia L, Xu H, et al. Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis. Gut. (2014) 63:281–91. doi: 10.1136/gutjnl-2012-303207

PubMed Abstract | CrossRef Full Text | Google Scholar

49. Strugala V, Dettmar PW, Pearson JP. Thickness and continuity of the adherent colonic mucus barrier in active and quiescent ulcerative colitis and Crohn's disease. Int J Clin Pract. (2008) 62:762–9. doi: 10.1111/j.1742-1241.2007.01665.x

PubMed Abstract | CrossRef Full Text | Google Scholar

50. Pullan RD, Thomas GAO, Rhodes M, Newcombe RG, Williams GT, Allen A, et al. Thickness of adherent mucus gel on colonic mucosa in humans and its relevance to colitis. Gut. (1994) 35:353–9. doi: 10.1136/gut.35.3.353

PubMed Abstract | CrossRef Full Text | Google Scholar

51. Buisine MP, Desreumaux P, Leteurtre E, Copin MC, Colombel JF, Porchet N, et al. Mucin gene expression in intestinal epithelial cells in Crohn's disease. Gut. (2001) 49:544–51. doi: 10.1136/gut.49.4.544

PubMed Abstract | CrossRef Full Text | Google Scholar

52. Buisine MP, Desreumaux P, Debailleul V, Gambiez L, Geboes K, Ectors N, et al. Abnormalities in mucin gene expression in Crohn's disease. Inflamm Bowel Dis. (1999) 5:24–32. doi: 10.1097/00054725-199902000-00004

PubMed Abstract | CrossRef Full Text | Google Scholar

53. Nakamori S, Ota DM, Cleary KR, Shirotani K, Irimura T. MUC1 mucin expression as a marker of progression and metastasis of human colorectal carcinoma. Gastroenterology. (1994) 106:353–61. doi: 10.1016/0016-5085(94)90592-4

PubMed Abstract | CrossRef Full Text | Google Scholar

54. Ajioka Y, Allison LJ, Jass JR. Significance of MUC1 and MUC2 mucin expression in colorectal cancer. J Clin Pathol. (1996) 49:560–4. doi: 10.1136/jcp.49.7.560

PubMed Abstract | CrossRef Full Text | Google Scholar

55. McGuckin MA, Lindén SK, Sutton P, Florin TH. Mucin dynamics and enteric pathogens. Nat Rev Microbiol. (2011) 9:265–78. doi: 10.1038/nrmicro2538

PubMed Abstract | CrossRef Full Text | Google Scholar

56. Dharmani P, Srivastava V, Kissoon-Singh V, Chadee K. Role of intestinal mucins in innate host defense mechanisms against pathogens. J Innate Immun. (2009) 1:123–35. doi: 10.1159/000163037

PubMed Abstract | CrossRef Full Text | Google Scholar

57. Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature. (2001) 410:1099–103. doi: 10.1038/35074106

PubMed Abstract | CrossRef Full Text | Google Scholar

58. Birchenough GMH, Nystrom EEL, Johansson MEV, Hansson GC. A sentinel goblet cell guards the colonic crypt by triggering Nlrp6-dependent Muc2 secretion. Science. (2016) 352:1535–42. doi: 10.1126/science.aaf7419

PubMed Abstract | CrossRef Full Text | Google Scholar

59. Wang S, Ahmadi S, Nagpal R, Jain S, Mishra SP, Kavanagh K, et al. Lipoteichoic acid from the cell wall of a heat killed Lactobacillus paracasei D3-5 ameliorates aging-related leaky gut, inflammation and improves physical and cognitive functions: from C. elegans to mice. GeroScience. (2020) 42:333–52. doi: 10.1007/s11357-019-00137-4

PubMed Abstract | CrossRef Full Text | Google Scholar

60. Lee KD, Guk SM, Chai JY. Toll-like receptor 2 and Muc2 expression on human intestinal epithelial cells by gymnophalloides seoi adult antigen. J Parasitol. (2010) 96:58–66. doi: 10.1645/GE-2195.1

PubMed Abstract | CrossRef Full Text | Google Scholar

61. Kamdar K, Johnson AMF, Chac D, Myers K, Kulur V, Truevillian K, et al. Innate recognition of the microbiota by TLR1 promotes epithelial homeostasis and prevents chronic inflammation. J Immunol. (2018) 201:230–42. doi: 10.4049/jimmunol.1701216

PubMed Abstract | CrossRef Full Text | Google Scholar

62. Anderson JM, Van Itallie CM. Physiology and function of the tight junction. Cold Spring Harb Perspect Biol. (2009) 1:a002584. doi: 10.1101/cshperspect.a002584

PubMed Abstract | CrossRef Full Text | Google Scholar

63. Furuse M, Fujita K, Hiiragi T, Fujimoto K, Tsukita S. Claudin-1 and−2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J Cell Biol. (1998) 141:1539–50. doi: 10.1083/jcb.141.7.1539

PubMed Abstract | CrossRef Full Text | Google Scholar

64. Furuse M, Hirase T, Itoh M, Nagafuchi A, Yonemura S, Tsukita S, et al. Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol. (1993) 123:1777–88. doi: 10.1083/jcb.123.6.1777

PubMed Abstract | CrossRef Full Text | Google Scholar

65. Martìn-Padura I, Lostaglio S, Schneemann M, Williams L, Romano M, Fruscella P, et al. Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration. J Cell Biol. (1998) 142:117–27. doi: 10.1083/jcb.142.1.117

PubMed Abstract | CrossRef Full Text | Google Scholar

66. Ikenouchi J, Umeda K, Tsukita S, Furuse M, Tsukita S. Requirement of ZO-1 for the formation of belt-like adherens junctions during epithelial cell polarization. J Cell Biol. (2007) 176:779–86. doi: 10.1083/jcb.200612080

PubMed Abstract | CrossRef Full Text | Google Scholar

67. Günzel D, Fromm M. Claudins and other tight junction proteins. Compr Physiol. (2012) 2:1819–52. doi: 10.1002/cphy.c110045

PubMed Abstract | CrossRef Full Text | Google Scholar

68. Günzel D, Yu ASL. Claudins and the modulation of tight junction permeability. Physiol Rev. (2013) 93:525–69. doi: 10.1152/physrev.00019.2012

PubMed Abstract | CrossRef Full Text | Google Scholar

69. Suzuki T. Regulation of the intestinal barrier by nutrients: the role of tight junctions. Anim Sci J. (2020) 91:e13357. doi: 10.1111/asj.13357

PubMed Abstract | CrossRef Full Text | Google Scholar

70. Cong X, Kong W. Endothelial tight junctions and their regulatory signaling pathways in vascular homeostasis and disease. Cell Signal. (2020) 66:109485. doi: 10.1016/j.cellsig.2019.109485

PubMed Abstract | CrossRef Full Text | Google Scholar

71. Shen L, Weber CR, Raleigh DR, Yu D, Turner JR. Tight junction pore and leak pathways: a dynamic duo. Annu Rev Physiol. (2011) 73:283–309. doi: 10.1146/annurev-physiol-012110-142150

PubMed Abstract | CrossRef Full Text | Google Scholar

72. Van Itallie CM, Anderson JM. Claudins and epithelial paracellular transport. Annu Rev Physiol. (2006) 68:403–29. doi: 10.1146/annurev.physiol.68.040104.131404

PubMed Abstract | CrossRef Full Text | Google Scholar

73. Heller F, Florian P, Bojarski C, Richter J, Christ M, Hillenbrand B, et al. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology. (2005) 129:550–64. doi: 10.1016/j.gastro.2005.05.002

PubMed Abstract | CrossRef Full Text | Google Scholar

74. Ivanov AI, Nusrat A, Parkos CA. The epithelium in inflammatory bowel disease: potential role of endocytosis of junctional proteins in barrier disruption. Novartis Found Symp. (2004) 263:115–24. doi: 10.1002/0470090480.ch9

PubMed Abstract | CrossRef Full Text | Google Scholar

75. Kucharzik T, Walsh S V., Chen J, Parkos CA, Nusrat A. Neutrophil transmigration in inflammatory bowel disease is associated with differential expression of epithelial intercellular junction proteins. Am J Pathol. (2001) 159:2001–9. doi: 10.1016/S0002-9440(10)63051-9

PubMed Abstract | CrossRef Full Text | Google Scholar

76. Pizzuti D, Senzolo M, Buda A, Chiarelli S, Giacomelli L, Mazzon E, et al. In vitro model for IgE mediated food allergy. Scand J Gastroenterol. (2011) 46:177–87. doi: 10.3109/00365521.2010.525716

PubMed Abstract | CrossRef Full Text | Google Scholar

77. Assimakopoulos SF, Tsamandas AC, Tsiaoussis GI, Karatza E, Triantos C, Vagianos CE, et al. Altered intestinal tight junctions' expression in patients with liver cirrhosis: a pathogenetic mechanism of intestinal hyperpermeability. Eur J Clin Invest. (2012) 42:439–46. doi: 10.1111/j.1365-2362.2011.02609.x

PubMed Abstract | CrossRef Full Text | Google Scholar

78. Bertiaux-Vandaële N, Youmba SB, Belmonte L, Lecleire S, Antonietti M, Gourcerol G, et al. The expression and the cellular distribution of the tight junction proteins are altered in irritable bowel syndrome patients with differences according to the disease subtype. Am J Gastroenterol. (2011) 106:2165–73. doi: 10.1038/ajg.2011.257

PubMed Abstract | CrossRef Full Text | Google Scholar

79. Rahner C, Mitic LL, Anderson JM. Heterogeneity in expression and subcellular localization of claudins 2, 3, 4, and 5 in the rat liver, pancreas, and gut. Gastroenterology. (2001) 120:411–22. doi: 10.1053/gast.2001.21736

PubMed Abstract | CrossRef Full Text | Google Scholar

80. Reyes JL, Lamas M, Martin D, Namorado MDC, Islas S, Luna J, et al. The renal segmental distribution of claudins changes with development. Kidney Int. (2002) 62:476–87. doi: 10.1046/j.1523-1755.2002.00479.x

PubMed Abstract | CrossRef Full Text | Google Scholar

81. Wolburg H, Wolburg-Buchholz K, Liebner S, Engelhardt B. Claudin-1, claudin-2 and claudin-11 are present in tight junctions of choroid plexus epithelium of the mouse. Neurosci Lett. (2001) 307:77–80. doi: 10.1016/S0304-3940(01)01927-9

PubMed Abstract | CrossRef Full Text | Google Scholar

82. Zhu Y, Brännström M, Janson PO, Sundfeldt K. Differences in expression patterns of the tight junction proteins, claudin 1, 3, 4 and 5, in human ovarian surface epithelium as compared to epithelia in inclusion cysts and epithelial ovarian tumours. Int J Cancer. (2006) 118:1884–91. doi: 10.1002/ijc.21506

PubMed Abstract | CrossRef Full Text | Google Scholar

83. Oshima T, Miwa H, Joh T. Changes in the expression of claudins in active ulcerative colitis. J Gastroenterol Hepatol. (2008) 23:3–7. doi: 10.1111/j.1440-1746.2008.05405.x

PubMed Abstract | CrossRef Full Text | Google Scholar

84. Nagy Szakál D, Gyorffy H, Arató A, Cseh Á, Molnár K, Papp M, et al. Mucosal expression of claudins 2, 3 and 4 in proximal and distal part of duodenum in children with coeliac disease. Virchows Arch. (2010) 456:245–50. doi: 10.1007/s00428-009-0879-7

PubMed Abstract | CrossRef Full Text | Google Scholar

85. Martínez C, Lobo B, Pigrau M, Ramos L, González-Castro AM, Alonso C, et al. Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier. Gut. (2013) 62:1160–8. doi: 10.1136/gutjnl-2012-302093

PubMed Abstract | CrossRef Full Text | Google Scholar

86. Zeissig S, Bürgel N, Günzel D, Richter J, Mankertz J, Wahnschaffe U, 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. (2007) 56:61–72. doi: 10.1136/gut.2006.094375

PubMed Abstract | CrossRef Full Text | Google Scholar

87. Laurila JJ, Karttunen T, Koivukangas V, Laurila PA, Syrjälä H, Saarnio J, et al. Tight junction proteins in gallbladder epithelium: different expression in acute acalculous and calculous cholecystitis. J Histochem Cytochem. (2007) 55:567–73. doi: 10.1369/jhc.6A7155.2007

PubMed Abstract | CrossRef Full Text | Google Scholar

88. Wolburg H, Wolburg-Buchholz K, Kraus J, Rascher-Eggstein G, Liebner S, Hamm S, et al. Localization of claudin-3 in tight junctions of the blood-brain barrier is selectively lost during experimental autoimmune encephalomyelitis and human glioblastoma multiforme. Acta Neuropathol. (2003) 105:586–92. doi: 10.1007/s00401-003-0688-z

PubMed Abstract | CrossRef Full Text | Google Scholar

89. Kiuchi-Saishin Y, Gotoh S, Furuse M, Takasuga A, Tano Y, Tsukita S. Differential expression patterns of claudins, tight junction membrane proteins, in mouse nephron segments. J Am Soc Nephrol. (2002) 13:875–86. doi: 10.1681/asn.v134875

PubMed Abstract | CrossRef Full Text | Google Scholar

90. Mennigen R, Nolte K, Rijcken E, Utech M, Loeffler B, Senninger N, 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. (2009) 296:G1140–9. doi: 10.1152/ajpgi.90534.2008

PubMed Abstract | CrossRef Full Text | Google Scholar

91. Oshima T, Miwa H. Gastrointestinal mucosal barrier function and diseases. J Gastroenterol. (2016) 51:768–78. doi: 10.1007/s00535-016-1207-z

PubMed Abstract | CrossRef Full Text | Google Scholar

92. Sapone A, Lammers KM, Casolaro V, Cammarota M, Giuliano MT, De Rosa M, et al. Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: Celiac disease and gluten sensitivity. BMC Med. (2011) 9:23. doi: 10.1186/1741-7015-9-23

PubMed Abstract | CrossRef Full Text | Google Scholar

93. Morita K, Sasaki H, Furuse M, Tsukita S. Endothelial claudin: Claudin-5/TMVCF constitutes tight junction strands in endothelial cells. J Cell Biol. (1999) 147:185–94. doi: 10.1083/jcb.147.1.185

PubMed Abstract | CrossRef Full Text | Google Scholar

94. Nitta T, Hata M, Gotoh S, Seo Y, Sasaki H, Hashimoto N, et al. Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice. J Cell Biol. (2003) 161:653–60. doi: 10.1083/jcb.200302070

PubMed Abstract | CrossRef Full Text | Google Scholar

95. Amasheh S, Schmidt T, Mahn M, Florian P, Mankertz J, Tavalali S, et al. Contribution of claudin-5 to barrier properties in tight junctions of epithelial cells. Cell Tissue Res. (2005) 321:89–96. doi: 10.1007/s00441-005-1101-0

PubMed Abstract | CrossRef Full Text | Google Scholar

96. Schumann M, Günzel D, Buergel N, Richter JF, Troeger H, May C, et al. Cell polarity-determining proteins Par-3 and PP-1 are involved in epithelial tight junction defects in coeliac disease. Gut. (2012) 61:220–8. doi: 10.1136/gutjnl-2011-300123

PubMed Abstract | CrossRef Full Text | Google Scholar

97. Fujita H, Chiba H, Yokozaki H, Sakai N, Sugimoto K, Wada T, et al. Differential expression and subcellular localization of claudin-7,−8,−12,−13, and−15 along the mouse intestine. J Histochem Cytochem. (2006) 54:933–44. doi: 10.1369/jhc.6A6944.2006

PubMed Abstract | CrossRef Full Text | Google Scholar

98. Go M, Kojima T, Takano KI, Murata M, Ichimiya S, Tsubota H, et al. Expression and function of tight junctions in the crypt epithelium of human palatine tonsils. J Histochem Cytochem. (2004) 52:1627–38. doi: 10.1369/jhc.4A6339.2004

PubMed Abstract | CrossRef Full Text | Google Scholar

99. Li WY, Huey CL, Yu AS. Expression of claudin-7 and−8 along the mouse nephron. Am J Physiol Renal Physiol. (2004) 286:F1063–71.doi: 10.1152/ajprenal.00384.2003

PubMed Abstract | CrossRef Full Text | Google Scholar

100. Turksen K, Troy TC. Claudin-6: a novel tight junction molecule is developmentally regulated in mouse embryonic epithelium. Dev Dyn. (2001) 222:292–300. doi: 10.1002/dvdy.1174

PubMed Abstract | CrossRef Full Text | Google Scholar

101. Lameris AL, Huybers S, Kaukinen K, Mäkelä TH, Bindels RJ, Hoenderop JG, et al. Expression profiling of claudins in the human gastrointestinal tract in health and during inflammatory bowel disease. Scand J Gastroenterol. (2013) 48:58–69. doi: 10.3109/00365521.2012.741616

PubMed Abstract | CrossRef Full Text | Google Scholar

102. Niimi T, Nagashima K, Ward JM, Minoo P, Zimonjic DB, Popescu NC, et al. claudin-18, a novel downstream target gene for the T/EBP/NKX2.1 homeodomain transcription factor, encodes lung- and stomach-specific isoforms through alternative splicing. Mol Cell Biol. (2001) 21:7380–90. doi: 10.1128/mcb.21.21.7380-7390.2001

PubMed Abstract | CrossRef Full Text | Google Scholar

103. Linares GR, Brommage R, Powell DR, Xing W, Chen ST, Alshbool FZ, et al. Claudin 18 is a novel negative regulator of bone resorption and osteoclast differentiation. J Bone Miner Res. (2012) 27:1553–65. doi: 10.1002/jbmr.1600

PubMed Abstract | CrossRef Full Text | Google Scholar

104. Sanada Y, Oue N, Mitani Y, Yoshida K, Nakayama H, Yasui W. Down-regulation of the claudin-18 gene, identified through serial analysis of gene expression data analysis, in gastric cancer with an intestinal phenotype. J Pathol. (2006) 208:633–42. doi: 10.1002/path.1922

PubMed Abstract | CrossRef Full Text | Google Scholar

105. Wong V. Phosphorylation of occludin correlates with occludin localization and function at the tight junction. Am J Physiol Cell Physiol. (1997) 273:C1859–67. doi: 10.1152/ajpcell.1997.273.6.c1859

PubMed Abstract | CrossRef Full Text | Google Scholar

106. Umeda K, Ikenouchi J, Katahira-Tayama S, Furuse K, Sasaki H, Nakayama M, et al. ZO-1 and ZO-2 independently determine where claudins are polymerized in tight-junction strand formation. Cell. (2006) 126:741–54. doi: 10.1016/j.cell.2006.06.043

PubMed Abstract | CrossRef Full Text | Google Scholar

107. González-Mariscal L, Quirós M, Díaz-Coránguez M. ZO proteins and redox-dependent processes. Antioxidants Redox Signal. (2011) 15:1235–53. doi: 10.1089/ars.2011.3913

PubMed Abstract | CrossRef Full Text | Google Scholar

108. Jesaitis LA, Goodenough DA. Molecular characterization and tissue distribution of ZO-2, a tight junction protein homologous to ZO-1 and the Drosophila discs-large tumor suppressor protein. J Cell Biol. (1994) 124:949–61. doi: 10.1083/jcb.124.6.949

PubMed Abstract | CrossRef Full Text | Google Scholar

109. Fanning AS, Jameson BJ, Jesaitis LA, Anderson JM. The tight junction protein ZO-1 establishes a link between the transmembrane protein occludin and the actin cytoskeleton. J Biol Chem. (1998) 273:29745–53. doi: 10.1074/jbc.273.45.29745

PubMed Abstract | CrossRef Full Text | Google Scholar

110. Itoh M, Morita K, Tsukita S. Characterization of ZO-2 as a MAGUK family member associated with tight as well as adherens junctions with a binding affinity to occludin and α catenin. J Biol Chem. (1999) 274:5981–6. doi: 10.1074/jbc.274.9.5981

PubMed Abstract | CrossRef Full Text | Google Scholar

111. Fanning AS, Ma TY, Anderson JM. Isolation and functional characterization of the actin binding region in the tight junction protein ZO-1. FASEB J. (2002) 16:1835–7. doi: 10.1096/fj.02-0121fje

PubMed Abstract | CrossRef Full Text | Google Scholar

112. Mandell KJ, Parkos CA. The JAM family of proteins. Adv Drug Deliv Rev. (2005) 57:857–67. doi: 10.1016/j.addr.2005.01.005

PubMed Abstract | CrossRef Full Text | Google Scholar

113. Ebnet K. Junctional adhesion molecules (JAMs): cell adhesion receptors with pleiotropic functions in cell physiology and development. Physiol Rev. (2017) 97:1529–54. doi: 10.1152/physrev.00004.2017

PubMed Abstract | CrossRef Full Text | Google Scholar

114. Van Itallie CM, Anderson JM. Architecture of tight junctions and principles of molecular composition. Semin Cell Dev Biol. (2014) 36:157–65. doi: 10.1016/j.semcdb.2014.08.011

PubMed Abstract | CrossRef Full Text | Google Scholar

115. Laukoetter MG, Nava P, Lee WY, Severson EA, Capaldo CT, Babbin BA, et al. JAM-A regulates permeability and inflammation in the intestine in vivo. J Exp Med. (2007) 204:3067–76. doi: 10.1084/jem.20071416

PubMed Abstract | CrossRef Full Text | Google Scholar

116. Severson EA, Lee WY, Capaldo CT, Nusrat A, Parkos CA. Junctional adhesion molecule a interacts with afadin and PDZ-GEF2 to activate raplA, regulate j31 integrin levels, and enhance cell migration. Mol Biol Cell. (2009) 20:1916–25. doi: 10.1091/mbc.E08-10-1014

PubMed Abstract | CrossRef Full Text | Google Scholar

117. Nava P, Capaldo CT, Koch S, Kolegraff K, Rankin CR, Farkas AE, et al. JAM-A regulates epithelial proliferation through Akt/β-catenin signalling. EMBO Rep. (2011) 12:314–20. doi: 10.1038/embor.2011.16

PubMed Abstract | CrossRef Full Text | Google Scholar

118. Monteiro AC, Sumagin R, Rankin CR, Leoni G, Mina MJ, Reiter DM, et al. JAM-A associates with ZO-2, afadin, and PDZ-GEF1 to activate Rap2c and regulate epithelial barrier function. Mol Biol Cell. (2013) 24:2849–60. doi: 10.1091/mbc.E13-06-0298

PubMed Abstract | CrossRef Full Text | Google Scholar

119. Hollander D, Vadheim CM, Brettholz E, Petersen GM, Delahunty T, Rotter JI. Increased intestinal permeability in patients with Crohn's disease and their relatives: a possible etiologic factor. Ann Intern Med. (1986) 105:883–5. doi: 10.7326/0003-4819-105-6-883

PubMed Abstract | CrossRef Full Text | Google Scholar

120. Martínez C, Vicario M, Ramos L, Lobo B, Mosquera JL, Alonso C, et al. The jejunum of diarrhea-predominant irritable bowel syndrome shows molecular alterations in the tight junction signaling pathway that are associated with mucosal pathobiology and clinical manifestations. Am J Gastroenterol. (2012) 107:736–46. doi: 10.1038/ajg.2011.472

PubMed Abstract | CrossRef Full Text | Google Scholar

121. Wilcz-Villega E, Mcclean S, O'Sullivan M. Reduced E-cadherin expression is associated with abdominal pain and symptom duration in a study of alternating and diarrhea predominant IBS. Neurogastroenterol Motil. (2014) 26:316–25. doi: 10.1111/nmo.12262

PubMed Abstract | CrossRef Full Text

122. Drago S, El Asmar R, Di Pierro M, Clemente MG, Tripathi A, Sapone A, et al. Gliadin, zonulin and gut permeability: effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scand J Gastroenterol. (2006) 41:408–19. doi: 10.1080/00365520500235334

PubMed Abstract | CrossRef Full Text | Google Scholar

123. Vetrano S, Rescigno M, Rosaria Cera M, Correale C, Rumio C, Doni A, et al. Unique role of junctional adhesion molecule-a in maintaining mucosal homeostasis in inflammatory Bowel disease. Gastroenterology. (2008) 135:173–84. doi: 10.1053/j.gastro.2008.04.002

PubMed Abstract | CrossRef Full Text | Google Scholar

124. Wilcz-Villega EM, McClean S, O'Sullivan MA. Mast cell tryptase reduces junctional adhesion molecule-A (JAM-A) expression in intestinal epithelial cells: implications for the mechanisms of barrier dysfunction in irritable bowel syndrome. Am J Gastroenterol. (2013) 108:1140–51. doi: 10.1038/ajg.2013.92

PubMed Abstract | CrossRef Full Text | Google Scholar

125. Cordenonsi M, D'Atri F, Hammar E, Parry DAD, Kendrick-Jones J, Shore D, et al. Cingulin contains globular and coiled-coil domains and interacts with ZO-1, ZO-2, ZO-3, and myosin. J Cell Biol. (1999) 147:1569–81. doi: 10.1083/jcb.147.7.1569

PubMed Abstract | CrossRef Full Text | Google Scholar

126. Citi S, Paschoud S, Pulimeno P, Timolati F, De Robertis F, Jond L, et al. The tight junction protein cingulin regulates gene expression and rhoA signaling. Ann N Y Acad Sci. (2009) 1165:88–98. doi: 10.1111/j.1749-6632.2009.04053.x

PubMed Abstract | CrossRef Full Text | Google Scholar

127. Suarez C, Kovar DR. Internetwork competition for monomers governs actin cytoskeleton organization. Nat Rev Mol Cell Biol. (2016) 17:799–810. doi: 10.1038/nrm.2016.106

PubMed Abstract | CrossRef Full Text | Google Scholar

128. Kim S, Coulombe PA. Emerging role for the cytoskeleton as an organizer and regulator of translation. Nat Rev Mol Cell Biol. (2010) 11:75–81. doi: 10.1038/nrm2818

PubMed Abstract | CrossRef Full Text | Google Scholar

129. Al-Sadi RM, Ma TY. IL-1β Causes an Increase in Intestinal Epithelial Tight Junction Permeability. J Immunol. (2007) 178:4641–9. doi: 10.4049/jimmunol.178.7.4641

PubMed Abstract | CrossRef Full Text | Google Scholar

130. Schwayer C, Shamipour S, Pranjic-Ferscha K, Schauer A, Balda M, Tada M, et al. Mechanosensation of tight junctions depends on ZO-1 phase separation and flow. Cell. (2019) 179:937–52.e18. doi: 10.1016/j.cell.2019.10.006

PubMed Abstract | CrossRef Full Text | Google Scholar

131. Holthöfer B, Windoffer R, Troyanovsky S, Leube RE. Structure and function of desmosomes. Int Rev Cytol. (2007) 264:65–163. doi: 10.1016/S0074-7696(07)64003-0

PubMed Abstract | CrossRef Full Text | Google Scholar

132. Hartsock A, Nelson WJ. Adherens and tight junctions: structure, function and connections to the actin cytoskeleton. Biochim Biophys Acta Biomembr. (2008) 1778:660–9. doi: 10.1016/j.bbamem.2007.07.012

PubMed Abstract | CrossRef Full Text | Google Scholar

133. Shapiro L, Weis WI. Structure and biochemistry of cadherins and catenins. Cold Spring Harb Perspect Biol. (2009) 1:a003053. doi: 10.1101/cshperspect.a003053

PubMed Abstract | CrossRef Full Text | Google Scholar

134. Ivanov AI, Naydenov NG. Dynamics and regulation of epithelial adherens junctions. Recent discoveries and controversies. Int Rev Cell Mol Biol. (2013) 303:27–99. doi: 10.1016/B978-0-12-407697-6.00002-7

PubMed Abstract | CrossRef Full Text | Google Scholar

135. Takeichi M. Dynamic contacts: rearranging adherens junctions to drive epithelial remodelling. Nat Rev Mol Cell Biol. (2014) 15:397–410. doi: 10.1038/nrm3802

PubMed Abstract | CrossRef Full Text | Google Scholar

136. Nekrasova OE, Amargo EV, Smith WO, Chen J, Kreitzer GE, Green KJ. Desmosomal cadherins utilize distinct kinesins for assembly into desmosomes. J Cell Biol. (2011) 195:1185–203. doi: 10.1083/jcb.201106057

PubMed Abstract | CrossRef Full Text | Google Scholar

137. Hatzfeld M, Keil R, Magin TM. Desmosomes and intermediate filaments: their consequences for tissue mechanics. Cold Spring Harb Perspect Biol. (2017) 9:a029157. doi: 10.1101/cshperspect.a029157

PubMed Abstract | CrossRef Full Text | Google Scholar

138. Tripathi A, Lammers KM, Goldblum S, Shea-Donohue T, Netzel-Arnett S, Buzza MS, et al. Identification of human zonulin, a physiological modulator of tight junctions, as prehaptoglobin-2. Proc Natl Acad Sci USA. (2009) 106:16799–804. doi: 10.1073/pnas.0906773106

PubMed Abstract | CrossRef Full Text | Google Scholar

139. Lammers KM, Lu R, Brownley J, Lu B, Gerard C, Thomas K, et al. Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology. (2008) 135:194–204.e3. doi: 10.1053/j.gastro.2008.03.023

PubMed Abstract | CrossRef Full Text | Google Scholar

140. Sapone A, De Magistris L, Pietzak M, Clemente MG, Tripathi A, Cucca F, et al. Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives. Diabetes. (2006) 55:1443–9. doi: 10.2337/db05-1593

PubMed Abstract | CrossRef Full Text | Google Scholar

141. Barbaro MR, Cremon C, Wrona D, Fuschi D, Marasco G, Stanghellini V, et al. Non-celiac gluten sensitivity in the context of functional gastrointestinal disorders. Nutrients. (2020) 12:1–21. doi: 10.3390/nu12123735

PubMed Abstract | CrossRef Full Text | Google Scholar

142. Fasano A. Zonulin measurement conundrum: add confusion to confusion does not lead to clarity. Gut. (2020) 70:2007–8. doi: 10.1136/gutjnl-2020-323367

PubMed Abstract | CrossRef Full Text | Google Scholar

143. Misra A. Challenges in delivery of therapeutic genomics and proteomics. Amsterdam: Elsevier Inc. (2011). doi: 10.1016/C2010-0-65663-X

CrossRef Full Text | Google Scholar

144. Sugano K, Kansy M, Artursson P, Avdeef A, Bendels S, Di L, et al. Coexistence of passive and carrier-mediated processes in drug transport. Nat Rev Drug Discov. (2010) 9:597–614. doi: 10.1038/nrd3187

PubMed Abstract | CrossRef Full Text | Google Scholar

145. Wang Y, DeMazumder D, Hill JA. Ionic fluxes and genesis of the cardiac action potential. Muscle. (2012) 1:67–85. doi: 10.1016/B978-0-12-381510-1.00007-7

CrossRef Full Text | Google Scholar

146. Horisberger JD, Chraïbi A. Epithelial sodium channel: a ligand-gated channel? Nephron Physiol. (2004) 96:37–41. doi: 10.1159/000076406

PubMed Abstract | CrossRef Full Text | Google Scholar

147. Mukherjee B, Satapathy BS, Bhattacharya S, Chakraborty R, Mishra VP. Chapter 19 - Pharmacokinetic and pharmacodynamic modulations of therapeutically active constituents from orally administered nanocarriers along with a glimpse of their advantages and limitations. In: Grumezescu AM, editor. Nano- and Microscale Drug Delivery Systems. Elsevier. (2017). p. 357–75. doi: 10.1016/B978-0-323-52727-9.00019-4

CrossRef Full Text | Google Scholar

148. Goldstein JL, Anderson RGW, Brown MS. Coated pits, coated vesicles, and receptor-mediated endocytosis. Nature. (1979) 279:679–85. doi: 10.1038/279679a0

PubMed Abstract | CrossRef Full Text | Google Scholar

149. Garcia-Castillo MD, Chinnapen DJF, Lencer WI. Membrane transport across polarized epithelia. Cold Spring Harb Perspect Biol. (2017) 9:a027912. doi: 10.1101/cshperspect.a027912

PubMed Abstract | CrossRef Full Text | Google Scholar

150. Sandvig K, Kavaliauskiene S, Skotland T. Clathrin-independent endocytosis: an increasing degree of complexity. Histochem Cell Biol. (2018) 150:107–18. doi: 10.1007/s00418-018-1678-5

PubMed Abstract | CrossRef Full Text | Google Scholar

151. Tuma PL, Hubbard AL. Transcytosis: crossing cellular barriers. Physiol Rev. (2003) 83:871–932. doi: 10.1152/physrev.00001.2003

PubMed Abstract | CrossRef Full Text | Google Scholar

152. Mestecky J, Russell MW, Elson CO. Intestinal IgA: novel views on its function in the defence of the largest mucosal surface. Gut. (1999) 44:2–5. doi: 10.1136/gut.44.1.2

PubMed Abstract | CrossRef Full Text | Google Scholar

153. Kadaoui KA, Corthésy B. Secretory IgA mediates bacterial translocation to dendritic cells in mouse Peyer's patches with restriction to mucosal compartment. J Immunol. (2007) 179:7751–7. doi: 10.4049/jimmunol.179.11.7751

PubMed Abstract | CrossRef Full Text | Google Scholar

154. Boullier S, Tanguy M, Kadaoui KA, Caubet C, Sansonetti P, Corthésy B, et al. Secretory IgA-mediated neutralization of Shigella flexneri prevents intestinal tissue destruction by down-regulating inflammatory circuits. J Immunol. (2009) 183:5879–85. doi: 10.4049/jimmunol.0901838

PubMed Abstract | CrossRef Full Text | Google Scholar

155. Rey J, Garin N, Spertini F, Corthésy B. Targeting of secretory IgA to Peyer's patch dendritic and T cells after transport by intestinal M cells. J Immunol. (2004) 172:3026–33. doi: 10.4049/jimmunol.172.5.3026

PubMed Abstract | CrossRef Full Text | Google Scholar

156. Matysiak-Budnik T, Moura IC, Arcos-Fajardo M, Lebreton C, Ménard S, Candalh C, et al. Secretory IgA mediates retrotranscytosis of intact gliadin peptides via the transferrin receptor in celiac disease. J Exp Med. (2008) 205:143–54. doi: 10.1084/jem.20071204

PubMed Abstract | CrossRef Full Text | Google Scholar

157. Bevilacqua C, Montagnac G, Benmerah A, Candalh C, Brousse N, Cerf-Bensussan N, et al. Food allergens are protected from degradation during CD23-mediated transepithelial transport. Int Arch Allergy Immunol. (2004) 205:143–54. doi: 10.1159/000080653

PubMed Abstract | CrossRef Full Text | Google Scholar

158. Kaiserlian D, Lachaux A, Grosjean I, Graber P, Bonnefoy JY. Intestinal epithelial cells express the CD23/FcεRII molecule: enhanced expression in enteropathies. Immunology. (1993) 80:90–5.

PubMed Abstract | Google Scholar

159. Montagnac G, Yu LCH, Bevilacqua C, Heyman M, Conrad DH, Perdue MH, et al. Differential role for CD23 splice forms in apical to basolateral transcytosis of IgE/allergen complexes. Traffic. (2005) 6:230–42. doi: 10.1111/j.1600-0854.2005.00262.x

PubMed Abstract | CrossRef Full Text | Google Scholar

160. Montagnac G, Mollà-Herman A, Bouchet J, Yu LCH, Conrad DH, Perdue MH, et al. Intracellular trafficking of CD23: differential regulation in humans and mice by both extracellular and intracellular exons. J Immunol. (2005) 174:5562–72. doi: 10.4049/jimmunol.174.9.5562

PubMed Abstract | CrossRef Full Text | Google Scholar

161. Neal MD, Leaphart C, Levy R, Prince J, Billiar TR, Watkins S, et al. Enterocyte TLR4 Mediates Phagocytosis and Translocation of Bacteria Across the Intestinal Barrier. J Immunol. (2006) 176:3070–9. doi: 10.4049/jimmunol.176.5.3070

PubMed Abstract | CrossRef Full Text | Google Scholar

162. Conner SD, Schmid SL. Regulated portals of entry into the cell. Nature. (2003) 422:37–44. doi: 10.1038/nature01451

PubMed Abstract | CrossRef Full Text | Google Scholar

163. Günther J, Seyfert HM. The first line of defence: insights into mechanisms and relevance of phagocytosis in epithelial cells. Semin Immunopathol. (2018) 40:555–65. doi: 10.1007/s00281-018-0701-1

PubMed Abstract | CrossRef Full Text | Google Scholar

164. Hommelgaard AM, Roepstorff K, Vilhardt F, Torgersen ML, Sandvig K, van Deurs B. Caveolae: stable membrane domains with a potential for internalization. Traffic. (2005) 6:720–4. doi: 10.1111/j.1600-0854.2005.00314.x

PubMed Abstract | CrossRef Full Text | Google Scholar

165. Maloy KJ, Powrie F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature. (2011) 474:298–306. doi: 10.1038/nature10208

PubMed Abstract | CrossRef Full Text | Google Scholar

166. Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature. (2011) 474:307–17. doi: 10.1038/nature10209

PubMed Abstract | CrossRef Full Text | Google Scholar

167. Suzuki T. Regulation of intestinal epithelial permeability by tight junctions. Cell Mol Life Sci. (2013) 70:631–59. doi: 10.1007/s00018-012-1070-x

PubMed Abstract | CrossRef Full Text | Google Scholar

168. Berkes J, Viswanathan VK, Savkovic SD, Hecht G. Intestinal epithelial responses to enteric pathogens: effects on the tight junction barrier, ion transport, and inflammation. Gut. (2003) 52:439–51. doi: 10.1136/gut.52.3.439

PubMed Abstract | CrossRef Full Text | Google Scholar

169. Bäckhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. Host-bacterial mutualism in the human intestine. Science. (2005) 307:1915–20. doi: 10.1126/science.1104816

PubMed Abstract | CrossRef Full Text | Google Scholar

170. Hooper L V., Littman DR, Macpherson AJ. Interactions between the microbiota and the immune system. Science. (2012) 336:1268–73. doi: 10.1126/science.1223490

PubMed Abstract | CrossRef Full Text | Google Scholar

171. Kayama H, Okumura R, Takeda K. Interaction between the microbiota, epithelia, and immune cells in the intestine. Annu Rev Immunol. (2020) 38:23–48. doi: 10.1146/annurev-immunol-070119-115104

PubMed Abstract | CrossRef Full Text | Google Scholar

172. Sonnenburg ED, Smits SA, Tikhonov M, Higginbottom SK, Wingreen NS, Sonnenburg JL. Diet-induced extinctions in the gut microbiota compound over generations. Nature. (2016) 529:212–5. doi: 10.1038/nature16504

PubMed Abstract | CrossRef Full Text | Google Scholar

173. LeBlanc JG, Milani C, de Giori GS, Sesma F, van Sinderen D, Ventura M. Bacteria as vitamin suppliers to their host: a gut microbiota perspective. Curr Opin Biotechnol. (2013) 24:160–8. doi: 10.1016/j.copbio.2012.08.005

PubMed Abstract | CrossRef Full Text | Google Scholar

174. Baümler AJ, Sperandio V. Interactions between the microbiota and pathogenic bacteria in the gut. Nature. (2016) 535:85–93. doi: 10.1038/nature18849

PubMed Abstract | CrossRef Full Text | Google Scholar

175. Buffie CG, Pamer EG. Microbiota-mediated colonization resistance against intestinal pathogens. Nat Rev Immunol. (2013) 13:790–801. doi: 10.1038/nri3535

PubMed Abstract | CrossRef Full Text | Google Scholar

176. Gensollen T, Iyer SS, Kasper DL, Blumberg RS. How colonization by microbiota in early life shapes the immune system. Science. (2016) 352:539–44. doi: 10.1126/science.aad9378

PubMed Abstract | CrossRef Full Text | Google Scholar

177. Thaiss CA, Zmora N, Levy M, Elinav E. The microbiome and innate immunity. Nature. (2016) 535:65–74. doi: 10.1038/nature18847

PubMed Abstract | CrossRef Full Text | Google Scholar

178. Stecher B, Hardt WD. Mechanisms controlling pathogen colonization of the gut. Curr Opin Microbiol. (2011) 14:82–91. doi: 10.1016/j.mib.2010.10.003

PubMed Abstract | CrossRef Full Text | Google Scholar

179. Keeney KM, Finlay BB. Enteric pathogen exploitation of the microbiota-generated nutrient environment of the gut. Curr Opin Microbiol. (2011) 14:92–8. doi: 10.1016/j.mib.2010.12.012

PubMed Abstract | CrossRef Full Text | Google Scholar

180. Litvak Y, Byndloss MX, Bäumler AJ. Colonocyte metabolism shapes the gut microbiota. Science. (2018) 362:eaat9076. doi: 10.1126/science.aat9076

PubMed Abstract | CrossRef Full Text | Google Scholar

181. van Thiel IAM, de Jonge WJ, Chiu IM, van den Wijngaard RM. Microbiota-neuroimmune cross talk in stress-induced visceral hypersensitivity of the bowel. Am J Physiol Gastrointest Liver Physiol. (2020) 318:G1034–41. doi: 10.1152/ajpgi.00196.2019

PubMed Abstract | CrossRef Full Text | Google Scholar

182. Chowdhury SR, King DE, Willing BP, Band MR, Beever JE, Lane AB, et al. Transcriptome profiling of the small intestinal epithelium in germfree versus conventional piglets. BMC Genomics. (2007) 8:215. doi: 10.1186/1471-2164-8-215

PubMed Abstract | CrossRef Full Text | Google Scholar

183. Burger-van Paassen N, Vincent A, Puiman PJ, van der Sluis M, Bouma J, Boehm G, et al. The regulation of intestinal mucin MUC2 expression by short-chain fatty acids: implications for epithelial protection. Biochem J. (2009) 420:211–9. doi: 10.1042/BJ20082222

PubMed Abstract | CrossRef Full Text | Google Scholar

184. Kim MH, Kang SG, Park JH, Yanagisawa M, Kim CH. Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. Gastroenterology. (2013) 145:396–406.e1-10. doi: 10.1053/j.gastro.2013.04.056

PubMed Abstract | CrossRef Full Text | Google Scholar

185. Singh N, Gurav A, Sivaprakasam S, Brady E, Padia R, Shi H, et al. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity. (2014) 40:128–39. doi: 10.1016/j.immuni.2013.12.007

PubMed Abstract | CrossRef Full Text | Google Scholar

186. Ghosh S, Whitley CS, Haribabu B, Jala VR. Regulation of intestinal barrier function by microbial. Cell Mol Gastroenterol Hepatol. (2021) 11:1463–82. doi: 10.1016/j.jcmgh.2021.02.007

PubMed Abstract | CrossRef Full Text | Google Scholar

187. Abreu MT. Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nat Rev Immunol. (2010) 10:131–43. doi: 10.1038/nri2707

PubMed Abstract | CrossRef Full Text | Google Scholar

188. Burgueño JF, Abreu MT. Epithelial Toll-like receptors and their role in gut homeostasis and disease. Nat Rev Gastroenterol Hepatol. (2020) 17:263–78. doi: 10.1038/s41575-019-0261-4

PubMed Abstract | CrossRef Full Text | Google Scholar

189. Allam-Ndoul B, Castonguay-Paradis S, Veilleux A. Gut microbiota and intestinal trans-epithelial permeability. Int J Mol Sci. (2020) 21:1–14. doi: 10.3390/ijms21176402

PubMed Abstract | CrossRef Full Text | Google Scholar

190. Hayes CL, Dong J, Galipeau HJ, Jury J, McCarville J, Huang X, et al. Commensal microbiota induces colonic barrier structure and functions that contribute to homeostasis. Sci Rep. (2018) 8:14184. doi: 10.1038/s41598-018-32366-6

PubMed Abstract | CrossRef Full Text | Google Scholar

191. Hooper L V., Wong MH, Thelin A, Hansson L, Falk PG, Gordon JI. Molecular analysis of commensal host-microbial relationships in the intestine. Science. (2001) 291:881–4. doi: 10.1126/science.291.5505.881

PubMed Abstract | CrossRef Full Text | Google Scholar

192. Ukena SN, Singh A, Dringenberg U, Engelhardt R, Seidler U, Hansen W, et al. Probiotic Escherichia coli Nissle 1917 inhibits leaky gut by enhancing mucosal integrity. PLoS ONE. (2007) 2:e1308. doi: 10.1371/journal.pone.0001308

PubMed Abstract | CrossRef Full Text | Google Scholar

193. Barbaro MR, Fuschi D, Cremon C, Carapelle M, Dino P, Marcellini MM, et al. Escherichia coli Nissle 1917 restores epithelial permeability alterations induced by irritable bowel syndrome mediators. Neurogastroenterol Motil. (2018) 30:e13388. doi: 10.1111/nmo.13388

PubMed Abstract | CrossRef Full Text | Google Scholar

194. Johnson-Henry KC, Donato KA, Shen-Tu G, Gordanpour M, Sherman PM. Lactobacillus rhamnosus strain GG prevents enterohemorrhagic Escherichia coli O157:H7-induced changes in epithelial barrier function. Infect Immun. (2008) 76:1340–8. doi: 10.1128/IAI.00778-07

PubMed Abstract | CrossRef Full Text | Google Scholar

195. Yu Q, Yuan L, Deng J, Yang Q. Lactobacillus protects the integrity of intestinal epithelial barrier damaged by pathogenic bacteria. Front Cell Infect Microbiol. (2015) 5:26. doi: 10.3389/fcimb.2015.00026

PubMed Abstract | CrossRef Full Text | Google Scholar

196. Zareie M, Riff J, Donato K, McKay DM, Perdue MH, Soderholm JD, et al. Novel effects of the prototype translocating Escherichia coli, strain C25 on intestinal epithelial structure and barrier function. Cell Microbiol. (2005) 7:1782–97. doi: 10.1111/j.1462-5822.2005.00595.x

PubMed Abstract | CrossRef Full Text | Google Scholar

197. Barbara G, Feinle-Bisset C, Ghoshal UC, Santos J, Vanner SJ, Vergnolle N, et al. The intestinal microenvironment and functional gastrointestinal disorders. Gastroenterology. (2016) 150:1305–18.e8. doi: 10.1053/j.gastro.2016.02.028

PubMed Abstract | CrossRef Full Text | Google Scholar

198. Lee M, Chang EB. Inflammatory Bowel Diseases (IBD) and the microbiome—searching the crime scene for clues. Gastroenterology. (2021) 160:524–37. doi: 10.1053/j.gastro.2020.09.056

PubMed Abstract | CrossRef Full Text | Google Scholar

199. Machiels K, Joossens M, Sabino J, De Preter V, Arijs I, Eeckhaut V, et al. A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut. (2014) 63:1275–83. doi: 10.1136/gutjnl-2013-304833

PubMed Abstract | CrossRef Full Text | Google Scholar

200. Zhou L, Zhang M, Wang Y, Dorfman RG, Liu H, Yu T, et al. Faecalibacterium prausnitzii produces butyrate to maintain Th17/treg balance and to ameliorate colorectal colitis by inhibiting histone deacetylase 1. Inflamm Bowel Dis. (2018) 24:1926–40. doi: 10.1093/ibd/izy182

PubMed Abstract | CrossRef Full Text | Google Scholar

201. Cremon C, Guglielmetti S, Gargari G, Taverniti V, Castellazzi AM, Valsecchi C, et al. Effect of Lactobacillus paracasei CNCM I-1572 on symptoms, gut microbiota, short chain fatty acids, and immune activation in patients with irritable bowel syndrome: a pilot randomized clinical trial. United Eur Gastroenterol J. (2018) 6:604–13. doi: 10.1177/2050640617736478

PubMed Abstract | CrossRef Full Text | Google Scholar

202. Friedrich M, Pohin M, Powrie F. Cytokine networks in the pathophysiology of inflammatory Bowel disease. Immunity. (2019) 50:992–1006. doi: 10.1016/j.immuni.2019.03.017

PubMed Abstract | CrossRef Full Text | Google Scholar

203. Coccia M, Harrison OJ, Schiering C, Asquith MJ, Becher B, Powrie F, et al. IL-1β mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4 + Th17 cells. J Exp Med. (2012) 209:1595–609. doi: 10.1084/jem.20111453

PubMed Abstract | CrossRef Full Text | Google Scholar

204. Lee YS, Yang H, Yang JY, Kim Y, Lee SH, Kim JH, et al. Interleukin-1 (IL-1) signaling in intestinal stromal cells controls KC/ CXCL1 secretion, which correlates with recruitment of IL-22- secreting neutrophils at early stages of Citrobacter rodentium infection. Infect Immun. (2015) 83:3257–67. doi: 10.1128/IAI.00670-15

PubMed Abstract | CrossRef Full Text | Google Scholar

205. Song A, Zhu L, Gorantla G, Berdysz O, Amici SA, Guerau-De-Arellano M, et al. Salient type 1 interleukin 1 receptor expression in peripheral non-immune cells. Sci Rep. (2018) 8:723. doi: 10.1038/s41598-018-19248-7

PubMed Abstract | CrossRef Full Text | Google Scholar

206. Cox CB, Storm EE, Kapoor VN, Chavarria-Smith J, Lin DL, Wang L, et al. IL-1R1-dependent signaling coordinates epithelial regeneration in response to intestinal damage. Sci Immunol. (2021) 6:eabe8856. doi: 10.1126/sciimmunol.abe8856

PubMed Abstract | CrossRef Full Text | Google Scholar

207. Madara JL, Stafford J. Interferon-γ directly affects barrier function of cultured intestinal epithelial monolayers. J Clin Invest. (1989) 83:724–7. doi: 10.1172/JCI113938

PubMed Abstract | CrossRef Full Text | Google Scholar

208. Adams RB, Planchon SM, Roche JK. IFN-gamma modulation of epithelial barrier function. Time course, reversibility, and site of cytokine binding. J Immunol. (1993) 150:2356–63.

PubMed Abstract | Google Scholar

209. Schmitz H, Fromm M, Bentzel CJ, Scholz P, Detjen K, Mankertz J, et al. Tumor necrosis factor-alpha (TNFalpha) regulates the epithelial barrier in the human intestinal cell line HT-29/B6. J Cell Sci. (1999) 112(Pt 1):137–46.

PubMed Abstract | Google Scholar

210. Bruewer M, Luegering A, Kucharzik T, Parkos CA, Madara JL, Hopkins AM, et al. Proinflammatory cytokines disrupt epithelial barrier function by apoptosis-independent mechanisms. J Immunol. (2003) 171:6164–72. doi: 10.4049/jimmunol.171.11.6164

PubMed Abstract | CrossRef Full Text | Google Scholar

211. Barbaro MR, Di Sabatino A, Cremon C, Giuffrida P, Fiorentino M, Altimari A, et al. Interferon-γ is increased in the gut of patients with irritable bowel syndrome and modulates serotonin metabolism. Am J Physiol Gastrointest Liver Physiol. (2016) 310:G439–47. doi: 10.1152/ajpgi.00368.2015

PubMed Abstract | CrossRef Full Text | Google Scholar

212. Zolotarevsky Y, Hecht G, Koutsouris A, Gonzalez DE, Quan C, Tom J, et al. A membrane-permeant peptide that inhibits MLC kinase restores barrier function in in vitro models of intestinal disease. Gastroenterology. (2002) 123:163–72. doi: 10.1053/gast.2002.34235

PubMed Abstract | CrossRef Full Text | Google Scholar

213. Bhat AA, Uppada S, Achkar IW, Hashem S, Yadav SK, Shanmugakonar M, et al. Tight junction proteins and signaling pathways in cancer and inflammation: a functional crosstalk. Front Physiol. (2019) 10:1942. doi: 10.3389/fphys.2018.01942

PubMed Abstract | CrossRef Full Text | Google Scholar

214. Pham CTN. Neutrophil serine proteases: specific regulators of inflammation. Nat Rev Immunol. (2006) 6:541–50. doi: 10.1038/nri1841

PubMed Abstract | CrossRef Full Text | Google Scholar

215. Dale C, Vergnolle N. Protease signaling to G protein-coupled receptors: implications for inflammation and pain. J Recept Signal Transduct. (2008) 28:29–37. doi: 10.1080/10799890801941913

PubMed Abstract | CrossRef Full Text | Google Scholar

216. Chin AC, Lee WY, Nusrat A, Vergnolle N, Parkos CA. Neutrophil-mediated activation of epithelial protease-activated receptors-1 and−2 regulates barrier function and transepithelial migration. J Immunol. (2008) 181:5702–10. doi: 10.4049/jimmunol.181.8.5702

PubMed Abstract | CrossRef Full Text | Google Scholar

217. Barbara G, Stanghellini V, De Giorgio R, Corinaldesi R. Functional gastrointestinal disorders and mast cells: implications for therapy. Neurogastroenterol Motil. (2006) 18:6–17. doi: 10.1111/j.1365-2982.2005.00685.x

PubMed Abstract | CrossRef Full Text | Google Scholar

218. Bashashati M, Moossavi S, Cremon C, Barbaro MR, Moraveji S, Talmon G, et al. Colonic immune cells in irritable bowel syndrome: a systematic review and meta-analysis. Neurogastroenterol Motil. (2018) 30:10. doi: 10.1111/nmo.13192

PubMed Abstract | CrossRef Full Text | Google Scholar

219. Bashashati M, Rezaei N, Shafieyoun A, Mckernan DP, Chang L, Öhman L, Quigley EM, et al. Cytokine imbalance in irritable bowel syndrome: a systematic review and meta-analysis. Neurogastroenterol Motil. (2014) 26:1036–48. doi: 10.1111/nmo.12358

PubMed Abstract | CrossRef Full Text | Google Scholar

220. Chang L, Adeyemo M, Karagiannidis I, Videlock EJ, Bowe C, Shih W, et al. Serum and colonic mucosal immune markers in irritable bowel syndrome. Am J Gastroenterol. (2012) 107:262–72. doi: 10.1038/ajg.2011.423

PubMed Abstract | CrossRef Full Text | Google Scholar

221. McKernan DP, Gaszner G, Quigley EM, Cryan JF, Dinan TG. Altered peripheral toll-like receptor responses in the irritable bowel syndrome. Aliment Pharmacol Ther. (2011) 33:1045–52. doi: 10.1111/j.1365-2036.2011.04624.x

PubMed Abstract | CrossRef Full Text | Google Scholar

222. Darkoh C, Comer L, Zewdie G, Harold S, Snyder N, DuPont HL. Chemotactic chemokines are important in the pathogenesis of irritable bowel syndrome. PLoS ONE. (2014) 9:e93144. doi: 10.1371/journal.pone.0093144

PubMed Abstract | CrossRef Full Text | Google Scholar

223. Wang F, Graham WV, Wang Y, Witkowski ED, Schwarz BT, Turner JR. 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. (2005) 166:409–19. doi: 10.1016/S0002-9440(10)62264-X

PubMed Abstract | CrossRef Full Text | Google Scholar

224. Hanning N, Edwinson AL, Ceuleers H, Peters SA, De Man JG, Hassett LC, et al. Intestinal barrier dysfunction in irritable bowel syndrome: a systematic review. Therap Adv Gastroenterol. (2021) 14:1756284821993586. doi: 10.1177/1756284821993586

PubMed Abstract | CrossRef Full Text | Google Scholar

225. Renga G, Moretti S, Oikonomou V, Borghi M, Zelante T, Paolicelli G, et al. IL-9 and mast cells are key players of Candida albicans commensalism and pathogenesis in the gut. Cell Rep. (2018) 23:1767–78. doi: 10.1016/j.celrep.2018.04.034

PubMed Abstract | CrossRef Full Text | Google Scholar

226. Gerlach K, Hwang Y, Nikolaev A, Atreya R, Dornhoff H, Steiner S, et al. T H 9 cells that express the transcription factor PU.1 drive T cell-mediated colitis via IL-9 receptor signaling in intestinal epithelial cells. Nat Immunol. (2014) 15:676–86. doi: 10.1038/ni.2920

PubMed Abstract | CrossRef Full Text | Google Scholar

227. Gerlach K, McKenzie AN, Neurath MF, Weigmann B. IL-9 regulates intestinal barrier function in experimental T cell-mediated colitis. Tissue Barriers. (2015) 3:e983777. doi: 10.4161/21688370.2014.983777

PubMed Abstract | CrossRef Full Text | Google Scholar

228. Piche T, Barbara G, Aubert P, Des Varannes SB, Dainese R, Nano JL, et al. Impaired Intestinal barrier integrity in the colon of patients with irritable bowel syndrome: involvement of soluble mediators. Gut. (2009) 58:196–201. doi: 10.1136/gut.2007.140806

PubMed Abstract | CrossRef Full Text | Google Scholar

229. Barbara G, Stanghellini V, De Giorgio R, Cremon C, Cottrell GS, Santini D, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable Bowel syndrome. Gastroenterology. (2004) 126:693–702. doi: 10.1053/j.gastro.2003.11.055

PubMed Abstract | CrossRef Full Text | Google Scholar

230. Barbara G, Wang B, Stanghellini V, de Giorgio R, Cremon C, Di Nardo G, et al. Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable Bowel syndrome. Gastroenterology. (2007) 132:26–37. doi: 10.1053/j.gastro.2006.11.039

PubMed Abstract | CrossRef Full Text | Google Scholar

231. Gecse K, Róka R, Ferrier L, Leveque M, Eutamene H, Cartier C, et al. Increased faecal serine protease activity in diarrhoeic IBS patients: a colonic lumenal factor impairing colonic permeability and sensitivity. Gut. (2008) 57:591–8. doi: 10.1136/gut.2007.140210

PubMed Abstract | CrossRef Full Text | Google Scholar

232. Pontarollo G, Mann A, Brandão I, Malinarich F, Schöpf M, Reinhardt C. Protease-activated receptor signaling in intestinal permeability regulation. FEBS J. (2020) 287:645–58. doi: 10.1111/febs.15055

PubMed Abstract | CrossRef Full Text | Google Scholar

233. Barbara G, Grover M, Bercik P, Corsetti M, Ghoshal UC, Ohman L, et al. Rome foundation working team report on post-infection irritable Bowel syndrome. Gastroenterology. (2019) 156:46–58.e7. doi: 10.1053/j.gastro.2018.07.011

PubMed Abstract | CrossRef Full Text | Google Scholar

234. Edogawa S, Edwinson AL, Peters SA, Chikkamenahalli LL, Sundt W, Graves S, Breen-Lyles M, Johnson S, Dyer R, et al. Serine proteases as luminal mediators of intestinal barrier dysfunction and symptom severity in IBS. Gut. (2020) 69:62–73. doi: 10.1136/gutjnl-2018-317416

PubMed Abstract | CrossRef Full Text | Google Scholar

235. Cenac N, Bautzova T, Le Faouder P, Veldhuis NA, Poole DP, Rolland C, et al. Quantification and potential functions of endogenous agonists of transient receptor potential channels in patients with irritable bowel syndrome. Gastroenterology. (2015) 149:433–4.e7. doi: 10.1053/j.gastro.2015.04.011

PubMed Abstract | CrossRef Full Text | Google Scholar

236. Bautzova T, Hockley JRF, Perez-Berezo T, Pujo J, Tranter MM, Desormeaux C, et al. 5-oxoETE triggers nociception in constipation-predominant irritable bowel syndrome through MAS-related G protein–coupled receptor D. Sci Signal. (2018) 11:eaal2171. doi: 10.1126/scisignal.aal2171

PubMed Abstract | CrossRef Full Text | Google Scholar

237. Trifan A, Burta O, Tiuca N, Petrisor DC, Lenghel A, Santos J. Efficacy and safety of Gelsectan for diarrhoea-predominant irritable bowel syndrome: a randomised, crossover clinical trial. United Eur Gastroenterol J. (2019) 7:1093–101. doi: 10.1177/2050640619862721

PubMed Abstract | CrossRef Full Text | Google Scholar

238. Rubio-Tapia A, Murray JA. Updated guidelines by the European Society for the Study of Coeliac Disease. United Eur Gastroenterol J. (2019) 7:581–2. doi: 10.1177/2050640619849370

PubMed Abstract | CrossRef Full Text | Google Scholar

239. Schuppan D, Junker Y, Barisani D. Celiac disease: from pathogenesis to novel therapies. Gastroenterology. (2009) 137:1912–33. doi: 10.1053/j.gastro.2009.09.008

PubMed Abstract | CrossRef Full Text | Google Scholar

240. Harris LA, Park JY, Voltaggio L, Lam-Himlin D. Celiac disease: clinical, endoscopic, and histopathologic review. Gastrointest Endosc. (2012) 76:625–40. doi: 10.1016/j.gie.2012.04.473

PubMed Abstract | CrossRef Full Text | Google Scholar

241. Greco L, Romino R, Coto I, Di Cosmo N, Percopo S, Maglio M, et al. The first large population based twin study of coeliac disease. Gut. (2002) 50:624–8. doi: 10.1136/gut.50.5.624

PubMed Abstract | CrossRef Full Text | Google Scholar

242. Caminero A, McCarville JL, Galipeau HJ, Deraison C, Bernier SP, Constante M, et al. Duodenal bacterial proteolytic activity determines sensitivity to dietary antigen through protease-activated receptor-2. Nat Commun. (2019) 10:1–14. doi: 10.1038/s41467-019-09037-9

PubMed Abstract | CrossRef Full Text | Google Scholar

243. Di Biase AR, Marasco G, Ravaioli F, Dajti E, Colecchia L, Righi B, et al. Gut microbiota signatures and clinical manifestations in celiac disease children at onset: a pilot study. J Gastroenterol Hepatol. (2020) 36:446–54. doi: 10.1111/jgh.15183

PubMed Abstract | CrossRef Full Text | Google Scholar

244. Marasco G, Cirota GG, Rossini B, Lungaro L, Di Biase AR, Colecchia A, et al. Probiotics, prebiotics and other dietary supplements for gut microbiota modulation in celiac disease patients. Nutrients. (2020) 12:2674. doi: 10.3390/nu12092674

PubMed Abstract | CrossRef Full Text | Google Scholar

245. Stene LC, Honeyman MC, Hoffenberg EJ, Haas JE, Sokol RJ, Emery L, et al. Rotavirus infection frequency and risk of celiac disease autoimmunity in early childhood: a longitudinal study. Am J Gastroenterol. (2006) 101:2333–40. doi: 10.1111/j.1572-0241.2006.00741.x

PubMed Abstract | CrossRef Full Text | Google Scholar

246. Zafeiropoulou K, Nichols B, Mackinder M, Biskou O, Rizou E, Karanikolou A, et al. Alterations in intestinal microbiota of children with celiac disease at time of diagnosis and on a gluten-free diet. Gastroenterology. (2020) 159:2039–51.e20. doi: 10.1053/j.gastro.2020.08.007

PubMed Abstract | CrossRef Full Text | Google Scholar

247. Marasco G, Di Biase AR, Colecchia A. Microbial signatures in celiac disease: still far from a final answer. Gastroenterology. (2020) 161:358–9. doi: 10.1053/j.gastro.2020.10.059

PubMed Abstract | CrossRef Full Text | Google Scholar

248. Marasco G, Di Biase AR, Schiumerini R, Eusebi LH, Iughetti L, Ravaioli F, et al. Gut microbiota and celiac disease. Dig Dis Sci. (2016) 61:1461–72. doi: 10.1007/s10620-015-4020-2

PubMed Abstract | CrossRef Full Text | Google Scholar

249. Jabri B, Abadie V. IL-15 functions as a danger signal to regulate tissue-resident T cells and tissue destruction. Nat Rev Immunol. (2015) 15:771–83. doi: 10.1038/nri3919

PubMed Abstract | CrossRef Full Text | Google Scholar

250. Catassi C, Elli L, Bonaz B, Bouma G, Carroccio A, Castillejo G, et al. Diagnosis of Non-Celiac Gluten Sensitivity (NCGS): the Salerno experts' criteria. Nutrients. (2015) 7:4966–77. doi: 10.3390/nu7064966

PubMed Abstract | CrossRef Full Text | Google Scholar

251. Giovannini C, Sanchez M, Straface E, Scazzocchio B, Silano M, De Vincenzi M. Induction of apoptosis in Caco-2 cells by wheat gliadin peptides. Toxicology. (2000) 145:63–71. doi: 10.1016/S0300-483X(99)00223-1

PubMed Abstract | CrossRef Full Text | Google Scholar

252. Barone MV, Gimigliano A, Castoria G, Paolella G, Maurano F, Paparo F, et al. Growth factor-like activity of gliadin, an alimentary protein: implications for coeliac disease. Gut. (2007) 56:480–8. doi: 10.1136/gut.2005.086637

PubMed Abstract | CrossRef Full Text | Google Scholar

253. Heyman M, Abed J, Lebreton C, Cerf-Bensussan N. Intestinal permeability in coeliac disease: insight into mechanisms and relevance to pathogenesis. Gut. (2012) 61:1355–64. doi: 10.1136/gutjnl-2011-300327

PubMed Abstract | CrossRef Full Text | Google Scholar

254. Clemente MG, De Virgiliis S, Kang JS, Macatagney R, Musu MP, Di Pierro MR, et al. Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function. Gut. (2003) 52:218–23. doi: 10.1136/gut.52.2.218

PubMed Abstract | CrossRef Full Text | Google Scholar

255. Alaedini A, Latov N. Transglutaminase-independent binding of gliadin to intestinal brush border membrane and GM1 ganglioside. J Neuroimmunol. (2006) 177:167–72. doi: 10.1016/j.jneuroim.2006.04.022

PubMed Abstract | CrossRef Full Text | Google Scholar

256. Bondar C, Araya RE, Guzman L, Rua EC, Chopita N, Chirdo FG. Role of CXCR3/CXCL10 axis in immune cell recruitment into the small intestine in celiac disease. PLoS ONE. (2014) 9:e0089068. doi: 10.1371/journal.pone.0089068

PubMed Abstract | CrossRef Full Text | Google Scholar

257. Careddu P, Chiumello G, Vaccari A, Bardare M, Zilocchi A. Effects of gluten on intestinal absorption and permeability during remission of celiac disease. Boll Soc Ital Biol Sper. (1963) 1963:1235–8.

PubMed Abstract

258. Cobden I, Dickinson RJ, Rothwell J, Axon ATR. Intestinal permeability assessed by excretion ratios of two molecules: results in coeliac disease. Br Med J. (1978) 2:1060. doi: 10.1136/bmj.2.6144.1060

PubMed Abstract | CrossRef Full Text | Google Scholar

259. Oberhuber G, Vogelsang H. Gastrointestinal permeability in celiac disease [1]. Gastroenterology. (1998) 114:226. doi: 10.1016/S0016-5085(98)70661-4

PubMed Abstract | CrossRef Full Text | Google Scholar

260. Van Elburg RM, Uil JJ, Mulder CJJ, Heymans HSA. Intestinal permeability in patients with coeliac disease and relatives of patients with coeliac disease. Gut. (1993) 34:354–7. doi: 10.1136/gut.34.3.354

PubMed Abstract | CrossRef Full Text | Google Scholar

261. Schulzke JD, Bentzel CJ, Schulzke I, Riecken EO, Fromm M. Epithelial tight junction structure in the jejunum of children with acute and treated celiac sprue. Pediatr Res. (1998) 43:435–41. doi: 10.1203/00006450-199804000-00001

PubMed Abstract | CrossRef Full Text | Google Scholar

262. Goswami P, Das P, Verma AK, Prakash S, Das TK, Nag TC, et al. Are alterations of tight junctions at molecular and ultrastructural level different in duodenal biopsies of patients with celiac disease and Crohn's disease? Virchows Arch. (2014) 465:521–30. doi: 10.1007/s00428-014-1651-1

PubMed Abstract | CrossRef Full Text | Google Scholar

263. Ciccocioppo R, Finamore A, Ara C, Di Sabatino A, Mengheri E, Corazza GR. Altered expression, localization, and phosphorylation of epithelial junctional proteins in celiac disease. Am J Clin Pathol. (2006) 125:502–11. doi: 10.1309/dtyr-a91g-8r0k-tm8m

PubMed Abstract | CrossRef Full Text | Google Scholar

264. Montalto M, Cuoco L, Ricci R, Maggiano N, Vecchio FM, Gasbarrini G. Immunohistochemical analysis of ZO-1 in the duodenal mucosa of patients with untreated and treated celiac disease. Digestion. (2002) 65:227–33. doi: 10.1159/000063817

PubMed Abstract | CrossRef Full Text | Google Scholar

265. Perry I, Tselepis C, Hoyland J, Iqbal TH, Scott D, Sanders A, et al. Reduced cadherin/catenin complex expression in celiac disease can be reproduced in vitro by cytokine stimulation. Lab Invest. (1999) 79:1489–99.

PubMed Abstract | Google Scholar

266. Schumann M, Siegmund B, Schulzke JD, Fromm M. Celiac disease: role of the epithelial barrier. CMGH. (2017) 3:150–62. doi: 10.1016/j.jcmgh.2016.12.006

PubMed Abstract | CrossRef Full Text | Google Scholar

267. Mishra A, Prakash S, Sreenivas V, Das TK, Ahuja V, Gupta SD, et al. Structural and functional changes in the tight junctions of asymptomatic and serology-negative first-degree relatives of patients with celiac disease. J Clin Gastroenterol. (2016) 50:551–60. doi: 10.1097/MCG.0000000000000436

PubMed Abstract | CrossRef Full Text | Google Scholar

268. Hunt KA, Zhernakova A, Turner G, Heap GAR, Franke L, Bruinenberg M, et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nat Genet. (2008) 40:395–402. doi: 10.1038/ng.102

PubMed Abstract | CrossRef Full Text | Google Scholar

269. Wapenaar MC, Monsuur AJ, Van Bodegraven AA, Weersma RK, Bevova MR, Linskens RK, 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. (2008) 57:463–7. doi: 10.1136/gut.2007.133132

PubMed Abstract | CrossRef Full Text | Google Scholar

270. Monsuur AJ, Bakker PIWD, Alizadeh BZ, Zhernakova A, Bevova MR, Strengman E, et al. Myosin IXB variant increases the risk of celiac disease and points toward a primary intestinal barrier defect. Nat Genet. (2005) 37:1341–4. doi: 10.1038/ng1680

PubMed Abstract | CrossRef Full Text | Google Scholar

271. Wolters VM, Alizadeh BZ, Weijerman ME, Zhernakova A, van Hoogstraten IMW, Mearin ML, et al. Intestinal barrier gene variants may not explain the increased levels of antigliadin antibodies, suggesting other mechanisms than altered permeability. Hum Immunol. (2010) 71:392–6. doi: 10.1016/j.humimm.2010.01.016

PubMed Abstract | CrossRef Full Text | Google Scholar

272. Kumar V, Gutierrez-Achury J, Kanduri K, Almeida R, Hrdlickova B, Zhernakova D V, et al. Systematic annotation of celiac disease loci refines pathological pathways and suggests a genetic explanation for increased interferon-gamma levels. Hum Mol Genet. (2015) 24:397–409. doi: 10.1093/hmg/ddu453

PubMed Abstract | CrossRef Full Text | Google Scholar

273. Almeida R, Ricanõ-Ponce I, Kumar V, Deelen P, Szperl A, Trynka G, et al. Fine mapping of the celiac disease-associated LPP locus reveals a potential functional variant. Hum Mol Genet. (2014) 23:2481–9. doi: 10.1093/hmg/ddt619

PubMed Abstract | CrossRef Full Text | Google Scholar

274. Ciccocioppo R, Panelli S, Bellocchi MCC, Cangemi GC, Frulloni L, Capelli E, et al. The transcriptomic analysis of circulating immune cells in a celiac family unveils further insights into disease pathogenesis. Front Med. (2018) 5:182. doi: 10.3389/fmed.2018.00182

PubMed Abstract | CrossRef Full Text | Google Scholar

275. Dolfini E, Roncoroni L, Elli L, Fumagalli C, Colombo R, Ramponi S, et al. Cytoskeleton reorganization and ultrastructural damage induced by gliadin in a three-dimensional in vitro model. World J Gastroenterol. (2005) 11:7597–601. doi: 10.3748/wjg.v11.i48.7597

PubMed Abstract | CrossRef Full Text | Google Scholar

276. Strobel S, Brydon WG, Ferguson A. Cellobiose/mannitol sugar permeability test complements biopsy histopathology in clinical investigation of the jejunum. Gut. (1984) 25:1241–6. doi: 10.1136/gut.25.11.1241

PubMed Abstract | CrossRef Full Text | Google Scholar

277. Gass J, Bethune MT, Siegel M, Spencer A, Khosla C. Combination enzyme therapy for gastric digestion of dietary gluten in patients with celiac sprue. Gastroenterology. (2007) 133:472–80. doi: 10.1053/j.gastro.2007.05.028

PubMed Abstract | CrossRef Full Text | Google Scholar

278. Pinier M, Verdu EF, Nasser-Eddine M, David CS, Vézina A, Rivard N, et al. Polymeric binders suppress gliadin-induced toxicity in the intestinal epithelium. Gastroenterology. (2009) 136:288–98. doi: 10.1053/j.gastro.2008.09.016

PubMed Abstract | CrossRef Full Text | Google Scholar

279. Paterson BM, Lammers KM, Arrieta MC, Fasano A, Meddings JB. The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT-1001 in coeliac disease subjects: a proof of concept study. Aliment Pharmacol Ther. (2007) 26:757–66. doi: 10.1111/j.1365-2036.2007.03413.x

PubMed Abstract | CrossRef Full Text | Google Scholar

280. Kelly CP, Green PHR, Murray JA, Dimarino A, Colatrella A, Leffler DA, et al. Larazotide acetate in patients with coeliac disease undergoing a gluten challenge: a randomised placebo-controlled study. Aliment Pharmacol Ther. (2013) 37:252–62. doi: 10.1111/apt.12147

PubMed Abstract | CrossRef Full Text | Google Scholar

281. Leffler DA, Kelly CP, Abdallah HZ, Colatrella AM, Harris LA, Leon F, et al. A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge. Am J Gastroenterol. (2012) 107:1554–62. doi: 10.1038/ajg.2012.211

PubMed Abstract | CrossRef Full Text | Google Scholar

282. Leffler DA, Kelly CP, Green PHR, Fedorak RN, Dimarino A, Perrow W, et al. Larazotide acetate for persistent symptoms of celiac disease despite a gluten-free diet: a randomized controlled trial. Gastroenterology. (2015) 148:1311–9.e6. doi: 10.1053/j.gastro.2015.02.008

PubMed Abstract | CrossRef Full Text | Google Scholar

283. Hujoel IA, Murray JA. Refractory celiac disease. Curr Gastroenterol Rep. (2020) 22:1–8. doi: 10.1007/s11894-020-0756-8

PubMed Abstract | CrossRef Full Text | Google Scholar

284. Jauregi-Miguel A. The tight junction and the epithelial barrier in coeliac disease. Int Rev Cell Mol Biol. (2021) 358:105–32. doi: 10.1016/bs.ircmb.2020.09.010

PubMed Abstract | CrossRef Full Text | Google Scholar

285. Pearson ADJ, Eastham EJ, Laker MF, Craft AW, Nelson R. Intestinal permeability in children with Crohn's disease and Coeliac disease. Br Med J. (1982) 285:20–21. doi: 10.1136/bmj.285.6334.20

PubMed Abstract | CrossRef Full Text | Google Scholar

286. Ukabam SO, Clamp JR, Cooper BT. Abnormal small intestinal permeability to sugars in patients with Crohn's disease of the terminal ileum and colon. Digestion. (1983) 27:70–4. doi: 10.1159/000198932

PubMed Abstract | CrossRef Full Text | Google Scholar

287. Abraham C, Cho JH. Mechanisms of inflammatory Bowel disease. N Engl J Med. (2009) 361:2066–78. doi: 10.1056/NEJMra0804647

PubMed Abstract | CrossRef Full Text

288. Miner-Williams WM, Moughan PJ. Intestinal barrier dysfunction: implications for chronic inflammatory conditions of the bowel. Nutr Res Rev. (2016) 29:40–59. doi: 10.1017/S0954422416000019

PubMed Abstract | CrossRef Full Text | Google Scholar

289. Khan MW, Kale AA, Bere P, Vajjala S, Gounaris E, Pakanati KC. Microbes, intestinal inflammation and probiotics. Expert Rev Gastroenterol Hepatol. (2012) 6:81–94. doi: 10.1586/egh.11.94

PubMed Abstract | CrossRef Full Text | Google Scholar

290. Ingersoll SA, Ayyadurai S, Charania MA, Laroui H, Yan Y, Merlin D. The role and pathophysiological relevance of membrane transporter pept1 in intestinal inflammation and inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol. (2012) 302:G484–92. doi: 10.1152/ajpgi.00477.2011

PubMed Abstract | CrossRef Full Text | Google Scholar

291. Dalmasso G, Nguyen HTT, Charrier-Hisamuddin L, Yan Y, Laroui H, Demoulin B, et al. Merlin D. PepT1 mediates transport of the proinflammatory bacterial tripeptide L-Ala-γ-D-Glu-meso-DAP in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol. (2010) 299:687–96. doi: 10.1152/ajpgi.00527.2009

PubMed Abstract | CrossRef Full Text | Google Scholar

292. Jappar D, Hu Y, Smith DE. Effect of dose escalation on the in vivo oral absorption and disposition of glycylsarcosine in wild-type and Pept1 knockout mice. Drug Metab Dispos. (2011) 39:2250–7. doi: 10.1124/dmd.111.041087

PubMed Abstract | CrossRef Full Text | Google Scholar

293. De Medina FS, Daddaoua A, Requena P, Capitán-Cañadas F, Zarzuelo A, Dolores Suárez M, et al. New insights into the immunological effects of food bioactive peptides in animal models of intestinal inflammation. Proc Nutr Soc. (2010) 69:454–62. doi: 10.1017/S0029665110001783

PubMed Abstract | CrossRef Full Text | Google Scholar

294. Nässl AM, Rubio-Aliaga I, Sailer M, Daniel H. The intestinal peptide transporter pept1 is involved in food intake regulation in mice fed a high-protein diet. PLoS ONE. (2011) 6:e0026407. doi: 10.1371/journal.pone.0026407

PubMed Abstract | CrossRef Full Text | Google Scholar

295. Cipriani S, Mencarelli A, Chini MG, Distrutti E, Renga B, Bifulco G, et al. The bile acid receptor GPBAR-1 (TGR5) modulates integrity of intestinal barrier and immune response to experimental colitis. PLoS ONE. (2011) 6:e0025637. doi: 10.1371/journal.pone.0025637

PubMed Abstract | CrossRef Full Text | Google Scholar

296. Chia-Hui Y. Microbiota dysbiosis and barrier dysfunction in inflammatory bowel disease: RSM Library Discovery Service. J Biomed Sci. (2018) 25:79. doi: 10.1186/s12929-018-0483-8

PubMed Abstract | CrossRef Full Text

297. Gruber L, Lichti P, Rath E, Haller D. Nutrigenomics and nutrigenetics in inflammatory bowel diseases. J Clin Gastroenterol. (2012) 46:735–47. doi: 10.1097/MCG.0b013e31825ca21a

PubMed Abstract | CrossRef Full Text | Google Scholar

298. Ananthakrishnan AN, Bernstein CN, Iliopoulos D, Macpherson A, Neurath MF, Ali RAR, et al. Environmental triggers in IBD: a review of progress and evidence. Nat Rev Gastroenterol Hepatol. (2018) 15:39– 49. doi: 10.1038/nrgastro.2017.136

PubMed Abstract | CrossRef Full Text | Google Scholar

299. Ho SM, Lewis JD, Mayer EA, Plevy SE, Chuang E, Rappaport SM, et al. Challenges in IBD research: environmental triggers. Inflamm Bowel Dis. (2019) 25:S13–23. doi: 10.1093/ibd/izz076

PubMed Abstract | CrossRef Full Text | Google Scholar

300. Mahid SS, Minor KS, Soto RE, Hornung CA, Galandiuk S. Smoking and inflammatory bowel disease: a meta-analysis. Mayo Clin Proc. (2006) 81:1462–71. doi: 10.4065/81.11.1462

PubMed Abstract | CrossRef Full Text | Google Scholar

301. Calkins BM. A meta-analysis of the role of smoking in inflammatory bowel disease. Dig Dis Sci. (1989) 34:1841–54. doi: 10.1007/BF01536701

PubMed Abstract | CrossRef Full Text | Google Scholar

302. Higuchi LM, Khalili H, Chan AT, Richter JM, Bousvaros A, Fuchs CS. A prospective study of cigarette smoking and the risk of inflammatory bowel disease in women. Am J Gastroenterol. (2012) 107:1399–406. doi: 10.1038/ajg.2012.196

PubMed Abstract | CrossRef Full Text | Google Scholar

303. Pedersen KM, Çolak Y, Vedel-Krogh S, Kobylecki CJ, Bojesen SE, Nordestgaard BG. Risk of ulcerative colitis and Crohn's disease in smokers lacks causal evidence. Eur J Epidemiol. (2021) 10.1007/s10654-021-00763-3. doi: 10.1007/s10654-021-00763-3

PubMed Abstract | CrossRef Full Text | Google Scholar

304. Singh UP, Singh NP, Murphy EA, Price RL, Fayad R, Nagarkatti M, et al. Chemokine and cytokine levels in inflammatory bowel disease patients. Cytokine. (2016) 77:44–9. doi: 10.1016/j.cyto.2015.10.008

PubMed Abstract | CrossRef Full Text | Google Scholar

305. Ostaff MJ, Stange EF, Wehkamp J. Antimicrobial peptides and gut microbiota in homeostasis and pathology. EMBO Mol Med. (2013) 5:1465–83. doi: 10.1002/emmm.201201773

PubMed Abstract | CrossRef Full Text | Google Scholar

306. Salzman NH, Hung K, Haribhai D, Chu H, Karlsson-Sjöberg J, Amir E, et al. Enteric defensins are essential regulators of intestinal microbial ecology. Nat Immunol. (2010) 11:76–83. doi: 10.1038/ni.1825

PubMed Abstract | CrossRef Full Text | Google Scholar

307. Peyrin-Biroulet L, Beisner J, Wang G, Nuding S, Oommen ST, Kelly D, et al. Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon. Proc Natl Acad Sci USA. (2010) 107:8772–7. doi: 10.1073/PNAS.0905745107

PubMed Abstract | CrossRef Full Text | Google Scholar

308. Wehkamp J, Harder J, Weichenthal M, Mueller O, Herrlinger KR, Fellermann K, et al. Inducible and constitutive beta-defensins are differentially expressed in Crohn's disease and ulcerative colitis. Inflamm Bowel Dis. (2003) 9:215–23. doi: 10.1097/00054725-200307000-00001

PubMed Abstract | CrossRef Full Text | Google Scholar

309. Martini E, Krug SM, Siegmund B, Neurath MF, Becker C. Mend your fences: the epithelial barrier and its relationship with mucosal immunity in inflammatory bowel disease. Cmgh. (2017) 4:33–46. doi: 10.1016/j.jcmgh.2017.03.007

PubMed Abstract | CrossRef Full Text | Google Scholar

310. Courth LF, Ostaff MJ, Mailänder-Sánchez D, Malek NP, Stange EF, Wehkamp J. Crohn's disease-derived monocytes fail to induce Paneth cell defensins. Proc Natl Acad Sci USA. (2015) 112:14000–5. doi: 10.1073/pnas.1510084112

PubMed Abstract | CrossRef Full Text | Google Scholar

311. Wehkamp J, Koslowski M, Wang G, Stange EF. Barrier dysfunction due to distinct defensin deficiencies in small intestinal and colonic Crohn's disease. Mucosal Immunol. (2008) 1:67–74. doi: 10.1038/mi.2008.48

PubMed Abstract | CrossRef Full Text | Google Scholar

312. Paone P, Cani PD. Mucus barrier, mucins and gut microbiota: the expected slimy partners? Gut. (2020) 69:2232–43. doi: 10.1136/gutjnl-2020-322260

PubMed Abstract | CrossRef Full Text | Google Scholar

313. Van Der Post S, Jabbar KS, Birchenough G, Arike L, Akhtar N, Sjovall H, et al. Structural weakening of the colonic mucus barrier is an early event in ulcerative colitis pathogenesis. Gut. (2019) 68:2142–51. doi: 10.1136/gutjnl-2018-317571

PubMed Abstract | CrossRef Full Text | Google Scholar

314. Johansson ME, Ambort D, Pelaseyed T, Schütte A, Gustafsson JK, Ermund A, et al. Composition and functional role of the mucus layers in the intestine. Cell Mol Life Sci. (2011) 68:3635–41. doi: 10.1007/S00018-011-0822-3

PubMed Abstract | CrossRef Full Text | Google Scholar

315. Cornick S, Tawiah A, Chadee K. Roles and regulation of the mucus barrier in the gut. Tissue Barriers. (2015) 3:e982426. doi: 10.4161/21688370.2014.982426

PubMed Abstract | CrossRef Full Text | Google Scholar

316. Vivinus-Nébot M, Frin-Mathy G, Bzioueche H, Dainese R, Bernard G, Anty R, et al. Functional bowel symptoms in quiescent inflammatory bowel diseases: role of epithelial barrier disruption and low-grade inflammation. Gut. (2014) 63:744–52. doi: 10.1136/gutjnl-2012-304066

PubMed Abstract | CrossRef Full Text | Google Scholar

317. Hollander D, Vadheim CM, Brettholz E, Peterson GM, Delahunty T, Rotter J. Increased intestinal permeability in patients with Crohn's disease and their relatives. Ann Intern Med. (1986) 105:883–5.

PubMed Abstract | Google Scholar

318. Arnott IDR, Kingstone K, Ghosh S. Abnormal intestinal permeability predicts relapse in inactive Crohn disease. Scand J Gastroenterol. (2000) 35:1163–9. doi: 10.1080/003655200750056637

PubMed Abstract | CrossRef Full Text | Google Scholar

319. Wyatt J, Vogelsang H, Hübl W, Waldhoer T, Lochs H. Intestinal permeability and the prediction of relapse in Crohn's disease. Lancet. (1993) 341:1437–9. doi: 10.1016/0140-6736(93)90882-H

PubMed Abstract | CrossRef Full Text | Google Scholar

320. Arrieta MC, Bistritz L, Meddings JB. Alterations in intestinal permeability. Gut. (2006) 55:1512–20. doi: 10.1136/gut.2005.085373

PubMed Abstract | CrossRef Full Text | Google Scholar

321. Madsen KL, Malfair D, Gray D, Doyle JS, Jewell LD, Fedorak RN. Interleukin-10 gene-deficient mice develop a primary intestinal permeability defect in response to enteric microflora. Inflamm Bowel Dis. (1999) 5:262–70. doi: 10.1097/00054725-199911000-00004

PubMed Abstract | CrossRef Full Text | Google Scholar

322. Reuter BK, Pizarro TT. Mechanisms of tight junction dysregulation in the SAMP1YitFc model of Crohn's disease-like ileitis. Ann N Y Acad Sci. (2009) 1165:301–7. doi: 10.1111/j.1749-6632.2009.04035.x

PubMed Abstract | CrossRef Full Text | Google Scholar

323. Su L, Shen L, Clayburgh DR, Nalle SC, Sullivan EA, Jon B, et al. Activation and contributes to development of experimental colitis. Gastroenterology. (2010) 136:551–63. doi: 10.1053/j.gastro.2008.10.081

PubMed Abstract | CrossRef Full Text | Google Scholar

324. Blair SA, Kane S V., Clayburgh DR, Turner JR. Epithelial myosin light chain kinase expression and activity are upregulated in inflammatory bowel disease. Lab Investig. (2006) 86:191–201. doi: 10.1038/labinvest.3700373

PubMed Abstract | CrossRef Full Text | Google Scholar

325. Swidsinski A, Ladhoff A, Pernthaler A, Swidsinski S, Loening Baucke V, Ortner M, et al. Mucosal flora in inflammatory bowel disease. Gastroenterology. (2002) 122:44–54. doi: 10.1053/gast.2002.30294

PubMed Abstract | CrossRef Full Text | Google Scholar

326. Prasad S, Mingrino R, Kaukinen K, Hayes KL, Powell RM, MacDonald TT, et al. Inflammatory processes have differential effects on claudins 2, 3 and 4 in colonic epithelial cells. Lab Investig. (2005) 85:1139–62. doi: 10.1038/labinvest.3700316

PubMed Abstract | CrossRef Full Text | Google Scholar

327. Ménard S, Cerf-Bensussan N, Heyman M. Multiple facets of intestinal permeability and epithelial handling of dietary antigens. Mucosal Immunol. (2010) 3:247–59. doi: 10.1038/mi.2010.5

PubMed Abstract | CrossRef Full Text | Google Scholar

328. Oshima T, Laroux FS, Coe LL, Morise Z, Kawachi S, Bauer P, et al. Interferon-γ and interleukin-10 reciprocally regulate endothelial junction integrity and barrier function. Microvasc Res. (2001) 61:130–43. doi: 10.1006/mvre.2000.2288

PubMed Abstract | CrossRef Full Text | Google Scholar

329. Albert-Bayo M, Paracuellos I, González-Castro AM, Rodríguez-Urrutia A, Rodríguez-Lagunas MJ, Alonso-Cotoner C, et al. Intestinal mucosal mast cells: key modulators of barrier function and homeostasis. Cells. (2019) 8:135. doi: 10.3390/cells8020135

PubMed Abstract | CrossRef Full Text | Google Scholar

330. Al-Sadi R, Ye D, Boivin M, Guo S, Hashimi M, Ereifej L, et al. Interleukin-6 modulation of intestinal epithelial tight junction permeability is mediated by JNK pathway. PLoS ONE. (2014) 9:e0085345. doi: 10.1371/journal.pone.0085345

PubMed Abstract | CrossRef Full Text | Google Scholar

331. Gassler N, Rohr C, Schneider A, Kartenbeck J, Bach A, Obermüller N, et al. Inflammatory bowel disease is associated with changes of enterocytic junctions. Am J Physiol Gastrointest Liver Physiol. (2001) 281:216–28. doi: 10.1152/ajpgi.2001.281.1.g216

PubMed Abstract | CrossRef Full Text | Google Scholar

332. Shih DQ, Michelsen KS, Barrett RJ, Biener-Ramanujan E, Gonsky R, Zhang X, et al. Insights into TL1A and IBD pathogenesis. Adv Exp Med Biol. (2011) 691:279–88. doi: 10.1007/978-1-4419-6612-4_29

PubMed Abstract | CrossRef Full Text | Google Scholar

333. Cooney R, Jewell D. The genetic basis of inflammatory bowel disease. Dig Dis. (2009) 27:428–42. doi: 10.1159/000234909

PubMed Abstract | CrossRef Full Text | Google Scholar

334. Ishihara S, Aziz MM, Yuki T, Kazumori H, Kinoshita Y. Inflammatory bowel disease: review from the aspect of genetics. J Gastroenterol. (2009) 44:1097–108. doi: 10.1007/s00535-009-0141-8

PubMed Abstract | CrossRef Full Text | Google Scholar

335. Mayer L. Evolving paradigms in the pathogenesis of IBD. J Gastroenterol. (2010) 45:9–16. doi: 10.1007/s00535-009-0138-3

PubMed Abstract | CrossRef Full Text | Google Scholar

336. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cézard JP, Belaiche J, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature. (2001) 411:599–603. doi: 10.1038/35079107

PubMed Abstract | CrossRef Full Text | Google Scholar

337. Kosovac K, Brenmoehl J, Holler E, Falk W, Schoelmerich J, Hausmann M, et al. Association of the NOD2 genotype with bacterial translocation via altered cell-cell contacts in Crohn's disease patients. Inflamm Bowel Dis. (2010) 16:1311–21. doi: 10.1002/ibd.21223

PubMed Abstract | CrossRef Full Text | Google Scholar

338. Rosenstiel P, Sebreiber S. NOD-like receptors-pivotal guardians of the immunological integrity of barrier organs. Adv Exp Med Biol. (2009) 653:35–47. doi: 10.1007/978-1-4419-0901-5_3

PubMed Abstract | CrossRef Full Text | Google Scholar

339. Girardin SE, Boneca IG, Viala J, Chamaillard M, Labigne A, Thomas G, et al. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem. (2003) 278:8869–72. doi: 10.1074/jbc.C200651200

PubMed Abstract | CrossRef Full Text | Google Scholar

340. Inohara N, Ogura Y, Fontalba A, Gutierrez O, Pons F, Crespo J, et al. Host recognition of bacterial muramyl dipeptide mediated through NOD2: implications for Crohn's disease. J Biol Chem. (2003) 278:5509–12. doi: 10.1074/jbc.C200673200

PubMed Abstract | CrossRef Full Text | Google Scholar

341. Rosenstiel P, Fantini M, Bräutigam K, Kühbacher T, Waetzig GH, Seegert D, et al. TNF-α and IFN-γ regulate the expression of the NOD2 (CARD15) gene in human intestinal epithelial cells. Gastroenterology. (2003) 124:1001–9. doi: 10.1053/gast.2003.50157

PubMed Abstract | CrossRef Full Text | Google Scholar

342. Buhner S, Buning C, Genschel J, Kling K, Herrmann D, Dignass A, et al. Genetic basis for increased intestinal permeability in families with Crohn's disease: role of CARD15 3020insC mutation? Gut. (2006) 55:342–7. doi: 10.1136/gut.2005.065557

PubMed Abstract | CrossRef Full Text | Google Scholar

343. Matsuoka K, Kanai T. The gut microbiota and inflammatory bowel disease. Semin Immunopathol. (2015) 37:47–55. doi: 10.1007/s00281-014-0454-4

PubMed Abstract | CrossRef Full Text | Google Scholar

344. Fukata M, Arditi M. The role of pattern recognition receptors in intestinal inflammation. Mucosal Immunol. (2013) 6:451–63. doi: 10.1038/mi.2013.13

PubMed Abstract | CrossRef Full Text | Google Scholar

345. Zeuthen LH, Fink LN, Frokiaer H. Epithelial cells prime the immune response to an array of gut-derived commensals towards a tolerogenic phenotype through distinct actions of thymic stromal lymphopoietin and transforming growth factor-β. Immunology. (2008) 123:197–208. doi: 10.1111/j.1365-2567.2007.02687.x

PubMed Abstract | CrossRef Full Text | Google Scholar

346. Rimoldi M, Chieppa M, Salucci V, Avogadri F, Sonzogni A, Sampietro GM, et al. Intestinal immune homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells. Nat Immunol. (2005) 6:507–14. doi: 10.1038/ni1192

PubMed Abstract | CrossRef Full Text | Google Scholar

347. Travis S, Menzies I. Intestinal permeability: functional assessment and significance. Clin Sci. (1992) 82:471–88. doi: 10.1042/cs0820471

PubMed Abstract | CrossRef Full Text | Google Scholar

348. Bjarnason I, Macpherson A, Hollander D. Intestinal permeability: an overview. Gastroenterology. (1995) 108:1566–81. doi: 10.1016/0016-5085(95)90708-4

PubMed Abstract | CrossRef Full Text | Google Scholar

349. Wehkamp J, Stange EF. Paneth's disease. J Crohn's Colitis. (2010) 4:523–31. doi: 10.1016/j.crohns.2010.05.010

PubMed Abstract | CrossRef Full Text | Google Scholar

350. Khoshbin K, Camilleri M. Effects of dietary components on intestinal permeability in health and disease. Am J Physiol Gastrointest Liver Physiol. (2020) 319:G589–608. doi: 10.1152/AJPGI.00245.2020

PubMed Abstract | CrossRef Full Text | Google Scholar

351. Camilleri M. Human intestinal barrier: effects of stressors, diet, prebiotics, and probiotics. Clin Transl Gastroenterol. (2021) 12:e00308. doi: 10.14309/ctg.0000000000000308

PubMed Abstract | CrossRef Full Text | Google Scholar

352. Klimberg VS, Souba WW. The importance of intestinal glutamine metabolism in maintaining a healthy gastrointestinal tract and supporting the body's response to injury and illness. Surg Annu. (1990) 22:61–76.

PubMed Abstract | Google Scholar

353. Zhou YP, Jiang ZM, Sun YH, Wang XR, Ma EL, Wilmore D. The effect of supplemental enteral glutamine on plasma levels, gut function, and outcome in severe burns: a randomized, double-blind, controlled clinical trial. J Parenter Enter Nutr. (2003) 27:241–5. doi: 10.1177/0148607103027004241

PubMed Abstract | CrossRef Full Text | Google Scholar

354. Peng X, Yan H, You Z, Wang P, Wang S. Effects of enteral supplementation with glutamine granules on intestinal mucosal barrier function in severe burned patients. Burns. (2004) 30:135–9. doi: 10.1016/j.burns.2003.09.032

PubMed Abstract | CrossRef Full Text | Google Scholar

355. Zhou QQ, Verne ML, Fields JZ, Lefante JJ, Basra S, Salameh H, et al. Randomised placebo-controlled trial of dietary glutamine supplements for postinfectious irritable bowel syndrome. Gut. (2019) 68:996–1002. doi: 10.1136/gutjnl-2017-315136

PubMed Abstract | CrossRef Full Text | Google Scholar

356. Norman AW. From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health. Am J Clin Nutr. (2008) 88:491–9S. doi: 10.1093/ajcn/88.2.491s

PubMed Abstract | CrossRef Full Text | Google Scholar

357. Kong J, Zhang Z, Musch MW, Ning G, Sun J, Hart J, et al. Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier. Am J Physiol Gastrointest Liver Physiol. (2007) 294:G208–16. doi: 10.1152/ajpgi.00398.2007

PubMed Abstract | CrossRef Full Text | Google Scholar

358. Hewison M. Vitamin D and innate and adaptive immunity. Vitam Horm. (2011) 86:23–62. doi: 10.1016/B978-0-12-386960-9.00002-2

PubMed Abstract | CrossRef Full Text | Google Scholar

359. Froicu M, Cantorna MT. Vitamin D and the vitamin D receptor are critical for control of the innate immune response to colonic injury. BMC Immunol. (2007) 8:5. doi: 10.1186/1471-2172-8-5

PubMed Abstract | CrossRef Full Text | Google Scholar

360. Zhao H, Zhang H, Wu H, Li H, Liu L, Guo J, et al. Protective role of 1,25(OH)2vitamin D3 in the mucosal injury and epithelial barrier disruption in DSS-induced acute colitis in mice. BMC Gastroenterol. (2012) 12:57. doi: 10.1186/1471-230X-12-57

PubMed Abstract | CrossRef Full Text | Google Scholar

361. Guzman-Prado Y, Samson O, Segal JP, Limdi JK, Hayee B. Vitamin D therapy in adults with inflammatory bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis. (2020) 26:1819–30. doi: 10.1093/ibd/izaa087

PubMed Abstract | CrossRef Full Text | Google Scholar

362. Raftery T, Martineau AR, Greiller CL, Ghosh S, McNamara D, Bennett K, et al. Effects of vitamin D supplementation on intestinal permeability, cathelicidin and disease markers in Crohn's disease: results from a randomised double-blind placebo-controlled study. United Eur Gastroenterol J. (2015) 3:294–302. doi: 10.1177/2050640615572176

PubMed Abstract | CrossRef Full Text | Google Scholar

363. Corrêa-Oliveira R, Fachi JL, Vieira A, Sato FT, Vinolo MAR. Regulation of immune cell function by short-chain fatty acids. Clin Transl Immunol. (2016) 5:e73. doi: 10.1038/cti.2016.17

PubMed Abstract | CrossRef Full Text

364. Ríos-Covián D, Ruas-Madiedo P, Margolles A, Gueimonde M, De los Reyes-Gavilán CG, Salazar N. Intestinal short chain fatty acids and their link with diet and human health. Front Microbiol. (2016) 7:185. doi: 10.3389/fmicb.2016.00185

PubMed Abstract | CrossRef Full Text | Google Scholar

365. Barcenilla A, Pryde SE, Martin JC, Duncan SH, Stewart CS, Henderson C, et al. Phylogenetic relationships of butyrate-producing bacteria from the human gut. Appl Environ Microbiol. (2000) 66:1654–61. doi: 10.1128/AEM.66.4.1654-1661.2000

PubMed Abstract | CrossRef Full Text | Google Scholar

366. Louis P, Young P, Holtrop G, Flint HJ. Diversity of human colonic butyrate-producing bacteria revealed by analysis of the butyryl-CoA:acetate CoA-transferase gene. Environ Microbiol. (2010) 12:304–14. doi: 10.1111/j.1462-2920.2009.02066.x

PubMed Abstract | CrossRef Full Text | Google Scholar

367. Vital M, Howe AC, Tiedje JM. Revealing the bacterial butyrate synthesis pathways by analyzing (meta)genomic data. MBio. (2014) 5:e00889. doi: 10.1128/mBio.00889-14

PubMed Abstract | CrossRef Full Text | Google Scholar

368. Kannampalli P, Shaker R, Sengupta JN. Colonic butyrate- algesic or analgesic? Neurogastroenterol Motil. (2011) 23:975–9. doi: 10.1111/j.1365-2982.2011.01775.x

PubMed Abstract | CrossRef Full Text | Google Scholar

369. Banasiewicz T, Krokowicz, Stojcev Z, Kaczmarek BF, Kaczmarek E, Maik J, et al. Microencapsulated sodium butyrate reduces the frequency of abdominal pain in patients with irritable bowel syndrome. Color Dis. (2013) 15:204–9. doi: 10.1111/j.1463-1318.2012.03152.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Keywords: intestinal epithelial barrier, mucosal immune system, gut microbiota, IBS, IBD, celiac disease, non-celiac gluten sensitivity

Citation: Barbara G, Barbaro MR, Fuschi D, Palombo M, Falangone F, Cremon C, Marasco G and Stanghellini V (2021) Corrigendum: Inflammatory and Microbiota-Related Regulation of the Intestinal Epithelial Barrier. Front. Nutr. 8:790387. doi: 10.3389/fnut.2021.790387

Received: 06 October 2021; Accepted: 07 October 2021;
Published: 01 November 2021.

Approved by:

Frontiers Editorial Office, Frontiers Media SA, Switzerland

Copyright © 2021 Barbara, Barbaro, Fuschi, Palombo, Falangone, Cremon, Marasco and Stanghellini. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Giovanni Barbara, giovanni.barbara@unibo.it

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