Skip to main content
NCBI home page
Frontiers in Nutrition logoLink to Frontiers in Nutrition
. 2021 Nov 1;8:790387. doi: 10.3389/fnut.2021.790387

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

Giovanni Barbara 1,2,*, Maria Raffaella Barbaro 1,2, Daniele Fuschi 1,2, Marta Palombo 1,2, Francesca Falangone 3, Cesare Cremon 1,2, Giovanni Marasco 1,2, Vincenzo Stanghellini 1,2
PMCID: PMC8591313  PMID: 34790692

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

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

  • 1.Turner JR. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol. (2009) 9:799–809. 10.1038/nri2653 [DOI] [PubMed] [Google Scholar]
  • 2.Helander HF, Fändriks L. Surface area of the digestive tract-revisited. Scand J Gastroenterol. (2014) 49:681–9. 10.3109/00365521.2014.898326 [DOI] [PubMed] [Google Scholar]
  • 3.Camilleri M. Leaky gut: mechanisms, measurement and clinical implications in humans. Gut. (2019) 68:1516–26. 10.1136/gutjnl-2019-318427 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Yen TH, Wright NA. The gastrointestinal tract stem cell niche. Stem Cell Rev. (2006) 2:203–12. 10.1007/s12015-006-0048-1 [DOI] [PubMed] [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. 10.1038/nature16161 [DOI] [PMC free article] [PubMed] [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. 10.1186/s12876-014-0189-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. 10.17235/reed.2015.3846/2015 [DOI] [PubMed] [Google Scholar]
  • 8.Meddings J. The significance of the gut barrier in disease. Gut. (2008) 57:438–40. 10.1136/gut.2007.143172 [DOI] [PubMed] [Google Scholar]
  • 9.Hansson GC. Mucus and mucins in diseases of the intestinal and respiratory tracts. J Intern Med. (2019) 285:479–90. 10.1111/joim.12910 [DOI] [PMC free article] [PubMed] [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. 10.3390/microorganisms6020053 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Johansson MEV, Hansson GC. Immunological aspects of intestinal mucus and mucins. Nat Rev Immunol. (2016) 16:639–49. 10.1038/nri.2016.88 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Cone RA. Barrier properties of mucus. Adv Drug Deliv Rev. (2009) 61:75–85. 10.1016/j.addr.2008.09.008 [DOI] [PubMed] [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. 10.1038/ctg.2016.54 [DOI] [PMC free article] [PubMed] [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. 10.1007/s11894-010-0131-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Hansson GC. Mucins and the Microbiome. Annu Rev Biochem. (2020) 89:769–93. 10.1146/annurev-biochem-011520-105053 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Bansil R, Turner BS. The biology of mucus: composition, synthesis and organization. Adv Drug Deliv Rev. (2018) 124:3–15. 10.1016/j.addr.2017.09.023 [DOI] [PubMed] [Google Scholar]
  • 17.LAMONT JT. Mucus: the front line of intestinal mucosal defense. Ann N Y Acad Sci. (1992) 664:190–201. 10.1111/j.1749-6632.1992.tb39760.x [DOI] [PubMed] [Google Scholar]
  • 18.Kim JJ, Khan WI. Goblet cells and mucins: role in innate defense in enteric infections. Pathogens. (2013) 2:55–70. 10.3390/pathogens2010055 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Strugnell RA, Wijburg OLC. The role of secretory antibodies in infection immunity. Nat Rev Microbiol. (2010) 8:656–67. 10.1038/nrmicro2384 [DOI] [PubMed] [Google Scholar]
  • 20.Huus KE, Petersen C, Finlay BB. Diversity and dynamism of IgA–microbiota interactions. Nat Rev Immunol. (2021) 21:514–25. 10.1038/s41577-021-00506-1 [DOI] [PubMed] [Google Scholar]
  • 21.Pelaseyed T, Hansson GC. Membrane mucins of the intestine at a glance. J Cell Sci. (2020) 133:jcs240929. 10.1242/JCS.240929 [DOI] [PMC free article] [PubMed] [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. 10.1093/femsre/fuz013 [DOI] [PubMed] [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. 10.1111/imr.12182 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Pabst O, Mowat AM. Oral tolerance to food protein. Mucosal Immunol. (2012) 5:232–9. 10.1038/mi.2012.4 [DOI] [PMC free article] [PubMed] [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. 10.1126/science.1237910 [DOI] [PMC free article] [PubMed] [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. 10.1371/journal.pone.0083688 [DOI] [PMC free article] [PubMed] [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. 10.1073/pnas.1006451107 [DOI] [PMC free article] [PubMed] [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. 10.1152/ajpgi.2001.280.5.g922 [DOI] [PubMed] [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. 10.1152/ajpgi.00046.2013 [DOI] [PMC free article] [PubMed] [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. 10.1038/mi.2015.32 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Ouellette AJ. Paneth cells and innate mucosal immunity. Curr Opin Gastroenterol. (2010) 26:547–53. 10.1097/MOG.0b013e32833dccde [DOI] [PubMed] [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. 10.1371/journal.pmed.0050054 [DOI] [PMC free article] [PubMed] [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. 10.1053/j.gastro.2007.08.007 [DOI] [PubMed] [Google Scholar]
  • 34.Hooper LV, MacPherson AJ. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat Rev Immunol. (2010) 10:159–69. 10.1038/nri2710 [DOI] [PubMed] [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. 10.1136/gut.2007.141481 [DOI] [PubMed] [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. 10.1097/01.mib.0000179212.80778.d3 [DOI] [PubMed] [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. 10.1073/pnas.0803124105 [DOI] [PMC free article] [PubMed] [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. 10.1038/nrgastro.2013.35 [DOI] [PMC free article] [PubMed] [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. 10.1038/ncomms9292 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. 10.1038/s41598-017-08938-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Hoskins LC, Boulding ET. Mucin degradation in human colon ecosystems. J Clin Invest. (1981) 67:163–72. 10.1172/jci110009 [DOI] [PMC free article] [PubMed] [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. 10.1038/ajg.2010.281 [DOI] [PubMed] [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. 10.1016/j.cell.2016.10.043 [DOI] [PMC free article] [PubMed] [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. 10.1016/j.chom.2015.10.007 [DOI] [PMC free article] [PubMed] [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. 10.1093/gastro/goy052 [DOI] [PMC free article] [PubMed] [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. 10.1172/JCI45538 [DOI] [PMC free article] [PubMed] [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. 10.1002/ibd.21625 [DOI] [PubMed] [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. 10.1136/gutjnl-2012-303207 [DOI] [PMC free article] [PubMed] [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. 10.1111/j.1742-1241.2007.01665.x [DOI] [PubMed] [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. 10.1136/gut.35.3.353 [DOI] [PMC free article] [PubMed] [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. 10.1136/gut.49.4.544 [DOI] [PMC free article] [PubMed] [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. 10.1097/00054725-199902000-00004 [DOI] [PubMed] [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. 10.1016/0016-5085(94)90592-4 [DOI] [PubMed] [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. 10.1136/jcp.49.7.560 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.McGuckin MA, Lindén SK, Sutton P, Florin TH. Mucin dynamics and enteric pathogens. Nat Rev Microbiol. (2011) 9:265–78. 10.1038/nrmicro2538 [DOI] [PubMed] [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. 10.1159/000163037 [DOI] [PMC free article] [PubMed] [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. 10.1038/35074106 [DOI] [PubMed] [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. 10.1126/science.aaf7419 [DOI] [PMC free article] [PubMed] [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. 10.1007/s11357-019-00137-4 [DOI] [PMC free article] [PubMed] [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. 10.1645/GE-2195.1 [DOI] [PubMed] [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. 10.4049/jimmunol.1701216 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Anderson JM, Van Itallie CM. Physiology and function of the tight junction. Cold Spring Harb Perspect Biol. (2009) 1:a002584. 10.1101/cshperspect.a002584 [DOI] [PMC free article] [PubMed] [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. 10.1083/jcb.141.7.1539 [DOI] [PMC free article] [PubMed] [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. 10.1083/jcb.123.6.1777 [DOI] [PMC free article] [PubMed] [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. 10.1083/jcb.142.1.117 [DOI] [PMC free article] [PubMed] [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. 10.1083/jcb.200612080 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Günzel D, Fromm M. Claudins and other tight junction proteins. Compr Physiol. (2012) 2:1819–52. 10.1002/cphy.c110045 [DOI] [PubMed] [Google Scholar]
  • 68.Günzel D, Yu ASL. Claudins and the modulation of tight junction permeability. Physiol Rev. (2013) 93:525–69. 10.1152/physrev.00019.2012 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Suzuki T. Regulation of the intestinal barrier by nutrients: the role of tight junctions. Anim Sci J. (2020) 91:e13357. 10.1111/asj.13357 [DOI] [PMC free article] [PubMed] [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. 10.1016/j.cellsig.2019.109485 [DOI] [PubMed] [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. 10.1146/annurev-physiol-012110-142150 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72.Van Itallie CM, Anderson JM. Claudins and epithelial paracellular transport. Annu Rev Physiol. (2006) 68:403–29. 10.1146/annurev.physiol.68.040104.131404 [DOI] [PubMed] [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. 10.1016/j.gastro.2005.05.002 [DOI] [PubMed] [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. 10.1002/0470090480.ch9 [DOI] [PubMed] [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. 10.1016/S0002-9440(10)63051-9 [DOI] [PMC free article] [PubMed] [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. 10.3109/00365521.2010.525716 [DOI] [PubMed] [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. 10.1111/j.1365-2362.2011.02609.x [DOI] [PubMed] [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. 10.1038/ajg.2011.257 [DOI] [PubMed] [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. 10.1053/gast.2001.21736 [DOI] [PubMed] [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. 10.1046/j.1523-1755.2002.00479.x [DOI] [PubMed] [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. 10.1016/S0304-3940(01)01927-9 [DOI] [PubMed] [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. 10.1002/ijc.21506 [DOI] [PubMed] [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. 10.1111/j.1440-1746.2008.05405.x [DOI] [PubMed] [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. 10.1007/s00428-009-0879-7 [DOI] [PubMed] [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. 10.1136/gutjnl-2012-302093 [DOI] [PubMed] [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. 10.1136/gut.2006.094375 [DOI] [PMC free article] [PubMed] [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. 10.1369/jhc.6A7155.2007 [DOI] [PubMed] [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. 10.1007/s00401-003-0688-z [DOI] [PubMed] [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. 10.1681/asn.v134875 [DOI] [PubMed] [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. 10.1152/ajpgi.90534.2008 [DOI] [PubMed] [Google Scholar]
  • 91.Oshima T, Miwa H. Gastrointestinal mucosal barrier function and diseases. J Gastroenterol. (2016) 51:768–78. 10.1007/s00535-016-1207-z [DOI] [PubMed] [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. 10.1186/1741-7015-9-23 [DOI] [PMC free article] [PubMed] [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. 10.1083/jcb.147.1.185 [DOI] [PMC free article] [PubMed] [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. 10.1083/jcb.200302070 [DOI] [PMC free article] [PubMed] [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. 10.1007/s00441-005-1101-0 [DOI] [PubMed] [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. 10.1136/gutjnl-2011-300123 [DOI] [PubMed] [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. 10.1369/jhc.6A6944.2006 [DOI] [PubMed] [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. 10.1369/jhc.4A6339.2004 [DOI] [PubMed] [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. 10.1152/ajprenal.00384.2003 [DOI] [PubMed] [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. 10.1002/dvdy.1174 [DOI] [PubMed] [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. 10.3109/00365521.2012.741616 [DOI] [PubMed] [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. 10.1128/mcb.21.21.7380-7390.2001 [DOI] [PMC free article] [PubMed] [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. 10.1002/jbmr.1600 [DOI] [PMC free article] [PubMed] [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. 10.1002/path.1922 [DOI] [PubMed] [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. 10.1152/ajpcell.1997.273.6.c1859 [DOI] [PubMed] [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. 10.1016/j.cell.2006.06.043 [DOI] [PubMed] [Google Scholar]
  • 107.González-Mariscal L, Quirós M, Díaz-Coránguez M. ZO proteins and redox-dependent processes. Antioxidants Redox Signal. (2011) 15:1235–53. 10.1089/ars.2011.3913 [DOI] [PubMed] [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. 10.1083/jcb.124.6.949 [DOI] [PMC free article] [PubMed] [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. 10.1074/jbc.273.45.29745 [DOI] [PubMed] [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. 10.1074/jbc.274.9.5981 [DOI] [PubMed] [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. 10.1096/fj.02-0121fje [DOI] [PubMed] [Google Scholar]
  • 112.Mandell KJ, Parkos CA. The JAM family of proteins. Adv Drug Deliv Rev. (2005) 57:857–67. 10.1016/j.addr.2005.01.005 [DOI] [PubMed] [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. 10.1152/physrev.00004.2017 [DOI] [PubMed] [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. 10.1016/j.semcdb.2014.08.011 [DOI] [PMC free article] [PubMed] [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. 10.1084/jem.20071416 [DOI] [PMC free article] [PubMed] [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. 10.1091/mbc.E08-10-1014 [DOI] [PMC free article] [PubMed] [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. 10.1038/embor.2011.16 [DOI] [PMC free article] [PubMed] [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. 10.1091/mbc.E13-06-0298 [DOI] [PMC free article] [PubMed] [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. 10.7326/0003-4819-105-6-883 [DOI] [PubMed] [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. 10.1038/ajg.2011.472 [DOI] [PubMed] [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. 10.1111/nmo.12262 [DOI] [PubMed] [Google Scholar]
  • 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. 10.1080/00365520500235334 [DOI] [PubMed] [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. 10.1053/j.gastro.2008.04.002 [DOI] [PubMed] [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. 10.1038/ajg.2013.92 [DOI] [PubMed] [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. 10.1083/jcb.147.7.1569 [DOI] [PMC free article] [PubMed] [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. 10.1111/j.1749-6632.2009.04053.x [DOI] [PubMed] [Google Scholar]
  • 127.Suarez C, Kovar DR. Internetwork competition for monomers governs actin cytoskeleton organization. Nat Rev Mol Cell Biol. (2016) 17:799–810. 10.1038/nrm.2016.106 [DOI] [PMC free article] [PubMed] [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. 10.1038/nrm2818 [DOI] [PubMed] [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. 10.4049/jimmunol.178.7.4641 [DOI] [PMC free article] [PubMed] [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. 10.1016/j.cell.2019.10.006 [DOI] [PubMed] [Google Scholar]
  • 131.Holthöfer B, Windoffer R, Troyanovsky S, Leube RE. Structure and function of desmosomes. Int Rev Cytol. (2007) 264:65–163. 10.1016/S0074-7696(07)64003-0 [DOI] [PubMed] [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. 10.1016/j.bbamem.2007.07.012 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 133.Shapiro L, Weis WI. Structure and biochemistry of cadherins and catenins. Cold Spring Harb Perspect Biol. (2009) 1:a003053. 10.1101/cshperspect.a003053 [DOI] [PMC free article] [PubMed] [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. 10.1016/B978-0-12-407697-6.00002-7 [DOI] [PubMed] [Google Scholar]
  • 135.Takeichi M. Dynamic contacts: rearranging adherens junctions to drive epithelial remodelling. Nat Rev Mol Cell Biol. (2014) 15:397–410. 10.1038/nrm3802 [DOI] [PubMed] [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. 10.1083/jcb.201106057 [DOI] [PMC free article] [PubMed] [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. 10.1101/cshperspect.a029157 [DOI] [PMC free article] [PubMed] [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. 10.1073/pnas.0906773106 [DOI] [PMC free article] [PubMed] [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. 10.1053/j.gastro.2008.03.023 [DOI] [PMC free article] [PubMed] [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. 10.2337/db05-1593 [DOI] [PubMed] [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. 10.3390/nu12123735 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 142.Fasano A. Zonulin measurement conundrum: add confusion to confusion does not lead to clarity. Gut. (2020) 70:2007–8. 10.1136/gutjnl-2020-323367 [DOI] [PubMed] [Google Scholar]
  • 143.Misra A. Challenges in delivery of therapeutic genomics and proteomics. Amsterdam: Elsevier Inc. (2011). 10.1016/C2010-0-65663-X [DOI] [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. 10.1038/nrd3187 [DOI] [PubMed] [Google Scholar]
  • 145.Wang Y, DeMazumder D, Hill JA. Ionic fluxes and genesis of the cardiac action potential. Muscle. (2012) 1:67–85. 10.1016/B978-0-12-381510-1.00007-7 [DOI] [Google Scholar]
  • 146.Horisberger JD, Chraïbi A. Epithelial sodium channel: a ligand-gated channel? Nephron Physiol. (2004) 96:37–41. 10.1159/000076406 [DOI] [PubMed] [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. 10.1016/B978-0-323-52727-9.00019-4 [DOI] [Google Scholar]
  • 148.Goldstein JL, Anderson RGW, Brown MS. Coated pits, coated vesicles, and receptor-mediated endocytosis. Nature. (1979) 279:679–85. 10.1038/279679a0 [DOI] [PubMed] [Google Scholar]
  • 149.Garcia-Castillo MD, Chinnapen DJF, Lencer WI. Membrane transport across polarized epithelia. Cold Spring Harb Perspect Biol. (2017) 9:a027912. 10.1101/cshperspect.a027912 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 150.Sandvig K, Kavaliauskiene S, Skotland T. Clathrin-independent endocytosis: an increasing degree of complexity. Histochem Cell Biol. (2018) 150:107–18. 10.1007/s00418-018-1678-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 151.Tuma PL, Hubbard AL. Transcytosis: crossing cellular barriers. Physiol Rev. (2003) 83:871–932. 10.1152/physrev.00001.2003 [DOI] [PubMed] [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. 10.1136/gut.44.1.2 [DOI] [PMC free article] [PubMed] [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. 10.4049/jimmunol.179.11.7751 [DOI] [PubMed] [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. 10.4049/jimmunol.0901838 [DOI] [PubMed] [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. 10.4049/jimmunol.172.5.3026 [DOI] [PubMed] [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. 10.1084/jem.20071204 [DOI] [PMC free article] [PubMed] [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. 10.1159/000080653 [DOI] [PubMed] [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. [PMC free article] [PubMed] [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. 10.1111/j.1600-0854.2005.00262.x [DOI] [PubMed] [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. 10.4049/jimmunol.174.9.5562 [DOI] [PubMed] [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. 10.4049/jimmunol.176.5.3070 [DOI] [PubMed] [Google Scholar]
  • 162.Conner SD, Schmid SL. Regulated portals of entry into the cell. Nature. (2003) 422:37–44. 10.1038/nature01451 [DOI] [PubMed] [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. 10.1007/s00281-018-0701-1 [DOI] [PMC free article] [PubMed] [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. 10.1111/j.1600-0854.2005.00314.x [DOI] [PubMed] [Google Scholar]
  • 165.Maloy KJ, Powrie F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature. (2011) 474:298–306. 10.1038/nature10208 [DOI] [PubMed] [Google Scholar]
  • 166.Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature. (2011) 474:307–17. 10.1038/nature10209 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 167.Suzuki T. Regulation of intestinal epithelial permeability by tight junctions. Cell Mol Life Sci. (2013) 70:631–59. 10.1007/s00018-012-1070-x [DOI] [PMC free article] [PubMed] [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. 10.1136/gut.52.3.439 [DOI] [PMC free article] [PubMed] [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. 10.1126/science.1104816 [DOI] [PubMed] [Google Scholar]
  • 170.Hooper L V., Littman DR, Macpherson AJ. Interactions between the microbiota and the immune system. Science. (2012) 336:1268–73. 10.1126/science.1223490 [DOI] [PMC free article] [PubMed] [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. 10.1146/annurev-immunol-070119-115104 [DOI] [PubMed] [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. 10.1038/nature16504 [DOI] [PMC free article] [PubMed] [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. 10.1016/j.copbio.2012.08.005 [DOI] [PubMed] [Google Scholar]
  • 174.Baümler AJ, Sperandio V. Interactions between the microbiota and pathogenic bacteria in the gut. Nature. (2016) 535:85–93. 10.1038/nature18849 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 175.Buffie CG, Pamer EG. Microbiota-mediated colonization resistance against intestinal pathogens. Nat Rev Immunol. (2013) 13:790–801. 10.1038/nri3535 [DOI] [PMC free article] [PubMed] [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. 10.1126/science.aad9378 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 177.Thaiss CA, Zmora N, Levy M, Elinav E. The microbiome and innate immunity. Nature. (2016) 535:65–74. 10.1038/nature18847 [DOI] [PubMed] [Google Scholar]
  • 178.Stecher B, Hardt WD. Mechanisms controlling pathogen colonization of the gut. Curr Opin Microbiol. (2011) 14:82–91. 10.1016/j.mib.2010.10.003 [DOI] [PubMed] [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. 10.1016/j.mib.2010.12.012 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 180.Litvak Y, Byndloss MX, Bäumler AJ. Colonocyte metabolism shapes the gut microbiota. Science. (2018) 362:eaat9076. 10.1126/science.aat9076 [DOI] [PMC free article] [PubMed] [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. 10.1152/ajpgi.00196.2019 [DOI] [PMC free article] [PubMed] [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. 10.1186/1471-2164-8-215 [DOI] [PMC free article] [PubMed] [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. 10.1042/BJ20082222 [DOI] [PubMed] [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. 10.1053/j.gastro.2013.04.056 [DOI] [PubMed] [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. 10.1016/j.immuni.2013.12.007 [DOI] [PMC free article] [PubMed] [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. 10.1016/j.jcmgh.2021.02.007 [DOI] [PMC free article] [PubMed] [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. 10.1038/nri2707 [DOI] [PubMed] [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. 10.1038/s41575-019-0261-4 [DOI] [PubMed] [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. 10.3390/ijms21176402 [DOI] [PMC free article] [PubMed] [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. 10.1038/s41598-018-32366-6 [DOI] [PMC free article] [PubMed] [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. 10.1126/science.291.5505.881 [DOI] [PubMed] [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. 10.1371/journal.pone.0001308 [DOI] [PMC free article] [PubMed] [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. 10.1111/nmo.13388 [DOI] [PubMed] [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. 10.1128/IAI.00778-07 [DOI] [PMC free article] [PubMed] [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. 10.3389/fcimb.2015.00026 [DOI] [PMC free article] [PubMed] [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. 10.1111/j.1462-5822.2005.00595.x [DOI] [PubMed] [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. 10.1053/j.gastro.2016.02.028 [DOI] [PubMed] [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. 10.1053/j.gastro.2020.09.056 [DOI] [PMC free article] [PubMed] [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. 10.1136/gutjnl-2013-304833 [DOI] [PubMed] [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. 10.1093/ibd/izy182 [DOI] [PubMed] [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. 10.1177/2050640617736478 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 202.Friedrich M, Pohin M, Powrie F. Cytokine networks in the pathophysiology of inflammatory Bowel disease. Immunity. (2019) 50:992–1006. 10.1016/j.immuni.2019.03.017 [DOI] [PubMed] [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. 10.1084/jem.20111453 [DOI] [PMC free article] [PubMed] [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. 10.1128/IAI.00670-15 [DOI] [PMC free article] [PubMed] [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. 10.1038/s41598-018-19248-7 [DOI] [PMC free article] [PubMed] [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. 10.1126/sciimmunol.abe8856 [DOI] [PubMed] [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. 10.1172/JCI113938 [DOI] [PMC free article] [PubMed] [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] [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. [DOI] [PubMed] [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. 10.4049/jimmunol.171.11.6164 [DOI] [PubMed] [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. 10.1152/ajpgi.00368.2015 [DOI] [PubMed] [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. 10.1053/gast.2002.34235 [DOI] [PubMed] [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. 10.3389/fphys.2018.01942 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 214.Pham CTN. Neutrophil serine proteases: specific regulators of inflammation. Nat Rev Immunol. (2006) 6:541–50. 10.1038/nri1841 [DOI] [PubMed] [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. 10.1080/10799890801941913 [DOI] [PubMed] [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. 10.4049/jimmunol.181.8.5702 [DOI] [PMC free article] [PubMed] [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. 10.1111/j.1365-2982.2005.00685.x [DOI] [PubMed] [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. 10.1111/nmo.13192 [DOI] [PubMed] [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. 10.1111/nmo.12358 [DOI] [PubMed] [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. 10.1038/ajg.2011.423 [DOI] [PMC free article] [PubMed] [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. 10.1111/j.1365-2036.2011.04624.x [DOI] [PubMed] [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. 10.1371/journal.pone.0093144 [DOI] [PMC free article] [PubMed] [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. 10.1016/S0002-9440(10)62264-X [DOI] [PMC free article] [PubMed] [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. 10.1177/1756284821993586 [DOI] [PMC free article] [PubMed] [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. 10.1016/j.celrep.2018.04.034 [DOI] [PMC free article] [PubMed] [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. 10.1038/ni.2920 [DOI] [PubMed] [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. 10.4161/21688370.2014.983777 [DOI] [PMC free article] [PubMed] [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. 10.1136/gut.2007.140806 [DOI] [PubMed] [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. 10.1053/j.gastro.2003.11.055 [DOI] [PubMed] [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. 10.1053/j.gastro.2006.11.039 [DOI] [PubMed] [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. 10.1136/gut.2007.140210 [DOI] [PubMed] [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. 10.1111/febs.15055 [DOI] [PubMed] [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. 10.1053/j.gastro.2018.07.011 [DOI] [PMC free article] [PubMed] [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. 10.1136/gutjnl-2018-317416 [DOI] [PMC free article] [PubMed] [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. 10.1053/j.gastro.2015.04.011 [DOI] [PubMed] [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. 10.1126/scisignal.aal2171 [DOI] [PMC free article] [PubMed] [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. 10.1177/2050640619862721 [DOI] [PMC free article] [PubMed] [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. 10.1177/2050640619849370 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 239.Schuppan D, Junker Y, Barisani D. Celiac disease: from pathogenesis to novel therapies. Gastroenterology. (2009) 137:1912–33. 10.1053/j.gastro.2009.09.008 [DOI] [PubMed] [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. 10.1016/j.gie.2012.04.473 [DOI] [PubMed] [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. 10.1136/gut.50.5.624 [DOI] [PMC free article] [PubMed] [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. 10.1038/s41467-019-09037-9 [DOI] [PMC free article] [PubMed] [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. 10.1111/jgh.15183 [DOI] [PubMed] [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. 10.3390/nu12092674 [DOI] [PMC free article] [PubMed] [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. 10.1111/j.1572-0241.2006.00741.x [DOI] [PubMed] [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. 10.1053/j.gastro.2020.08.007 [DOI] [PMC free article] [PubMed] [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. 10.1053/j.gastro.2020.10.059 [DOI] [PubMed] [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. 10.1007/s10620-015-4020-2 [DOI] [PubMed] [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. 10.1038/nri3919 [DOI] [PMC free article] [PubMed] [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. 10.3390/nu7064966 [DOI] [PMC free article] [PubMed] [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. 10.1016/S0300-483X(99)00223-1 [DOI] [PubMed] [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. 10.1136/gut.2005.086637 [DOI] [PMC free article] [PubMed] [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. 10.1136/gutjnl-2011-300327 [DOI] [PubMed] [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. 10.1136/gut.52.2.218 [DOI] [PMC free article] [PubMed] [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. 10.1016/j.jneuroim.2006.04.022 [DOI] [PubMed] [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. 10.1371/journal.pone.0089068 [DOI] [PMC free article] [PubMed] [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] [Google Scholar]
  • 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. 10.1136/bmj.2.6144.1060 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 259.Oberhuber G, Vogelsang H. Gastrointestinal permeability in celiac disease [1]. Gastroenterology. (1998) 114:226. 10.1016/S0016-5085(98)70661-4 [DOI] [PubMed] [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. 10.1136/gut.34.3.354 [DOI] [PMC free article] [PubMed] [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. 10.1203/00006450-199804000-00001 [DOI] [PubMed] [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. 10.1007/s00428-014-1651-1 [DOI] [PubMed] [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. 10.1309/dtyr-a91g-8r0k-tm8m [DOI] [PubMed] [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. 10.1159/000063817 [DOI] [PubMed] [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] [Google Scholar]
  • 266.Schumann M, Siegmund B, Schulzke JD, Fromm M. Celiac disease: role of the epithelial barrier. CMGH. (2017) 3:150–62. 10.1016/j.jcmgh.2016.12.006 [DOI] [PMC free article] [PubMed] [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. 10.1097/MCG.0000000000000436 [DOI] [PubMed] [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. 10.1038/ng.102 [DOI] [PMC free article] [PubMed] [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. 10.1136/gut.2007.133132 [DOI] [PubMed] [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. 10.1038/ng1680 [DOI] [PubMed] [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. 10.1016/j.humimm.2010.01.016 [DOI] [PubMed] [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. 10.1093/hmg/ddu453 [DOI] [PubMed] [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. 10.1093/hmg/ddt619 [DOI] [PMC free article] [PubMed] [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. 10.3389/fmed.2018.00182 [DOI] [PMC free article] [PubMed] [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. 10.3748/wjg.v11.i48.7597 [DOI] [PMC free article] [PubMed] [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. 10.1136/gut.25.11.1241 [DOI] [PMC free article] [PubMed] [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. 10.1053/j.gastro.2007.05.028 [DOI] [PubMed] [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. 10.1053/j.gastro.2008.09.016 [DOI] [PubMed] [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. 10.1111/j.1365-2036.2007.03413.x [DOI] [PubMed] [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. 10.1111/apt.12147 [DOI] [PubMed] [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. 10.1038/ajg.2012.211 [DOI] [PMC free article] [PubMed] [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. 10.1053/j.gastro.2015.02.008 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 283.Hujoel IA, Murray JA. Refractory celiac disease. Curr Gastroenterol Rep. (2020) 22:1–8. 10.1007/s11894-020-0756-8 [DOI] [PubMed] [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. 10.1016/bs.ircmb.2020.09.010 [DOI] [PubMed] [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. 10.1136/bmj.285.6334.20 [DOI] [PMC free article] [PubMed] [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. 10.1159/000198932 [DOI] [PubMed] [Google Scholar]
  • 287.Abraham C, Cho JH. Mechanisms of inflammatory Bowel disease. N Engl J Med. (2009) 361:2066–78. 10.1056/NEJMra0804647 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 288.Miner-Williams WM, Moughan PJ. Intestinal barrier dysfunction: implications for chronic inflammatory conditions of the bowel. Nutr Res Rev. (2016) 29:40–59. 10.1017/S0954422416000019 [DOI] [PubMed] [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. 10.1586/egh.11.94 [DOI] [PubMed] [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. 10.1152/ajpgi.00477.2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 291.Dalmasso G, Nguyen HTT, Charrier-Hisamuddin L, Yan Y, Laroui H, Demoulin B., 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. 10.1152/ajpgi.00527.2009 [DOI] [PMC free article] [PubMed] [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. 10.1124/dmd.111.041087 [DOI] [PMC free article] [PubMed] [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. 10.1017/S0029665110001783 [DOI] [PubMed] [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. 10.1371/journal.pone.0026407 [DOI] [PMC free article] [PubMed] [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. 10.1371/journal.pone.0025637 [DOI] [PMC free article] [PubMed] [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. 10.1186/s12929-018-0483-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 297.Gruber L, Lichti P, Rath E, Haller D. Nutrigenomics and nutrigenetics in inflammatory bowel diseases. J Clin Gastroenterol. (2012) 46:735–47. 10.1097/MCG.0b013e31825ca21a [DOI] [PubMed] [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. 10.1038/nrgastro.2017.136 [DOI] [PubMed] [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. 10.1093/ibd/izz076 [DOI] [PMC free article] [PubMed] [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. 10.4065/81.11.1462 [DOI] [PubMed] [Google Scholar]
  • 301.Calkins BM. A meta-analysis of the role of smoking in inflammatory bowel disease. Dig Dis Sci. (1989) 34:1841–54. 10.1007/BF01536701 [DOI] [PubMed] [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. 10.1038/ajg.2012.196 [DOI] [PMC free article] [PubMed] [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. 10.1007/s10654-021-00763-3 [DOI] [PubMed] [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. 10.1016/j.cyto.2015.10.008 [DOI] [PMC free article] [PubMed] [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. 10.1002/emmm.201201773 [DOI] [PMC free article] [PubMed] [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. 10.1038/ni.1825 [DOI] [PMC free article] [PubMed] [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. 10.1073/PNAS.0905745107 [DOI] [PMC free article] [PubMed] [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. 10.1097/00054725-200307000-00001 [DOI] [PubMed] [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. 10.1016/j.jcmgh.2017.03.007 [DOI] [PMC free article] [PubMed] [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. 10.1073/pnas.1510084112 [DOI] [PMC free article] [PubMed] [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. 10.1038/mi.2008.48 [DOI] [PubMed] [Google Scholar]
  • 312.Paone P, Cani PD. Mucus barrier, mucins and gut microbiota: the expected slimy partners? Gut. (2020) 69:2232–43. 10.1136/gutjnl-2020-322260 [DOI] [PMC free article] [PubMed] [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. 10.1136/gutjnl-2018-317571 [DOI] [PMC free article] [PubMed] [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. 10.1007/S00018-011-0822-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 315.Cornick S, Tawiah A, Chadee K. Roles and regulation of the mucus barrier in the gut. Tissue Barriers. (2015) 3:e982426. 10.4161/21688370.2014.982426 [DOI] [PMC free article] [PubMed] [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. 10.1136/gutjnl-2012-304066 [DOI] [PubMed] [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. [DOI] [PubMed] [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. 10.1080/003655200750056637 [DOI] [PubMed] [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. 10.1016/0140-6736(93)90882-H [DOI] [PubMed] [Google Scholar]
  • 320.Arrieta MC, Bistritz L, Meddings JB. Alterations in intestinal permeability. Gut. (2006) 55:1512–20. 10.1136/gut.2005.085373 [DOI] [PMC free article] [PubMed] [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. 10.1097/00054725-199911000-00004 [DOI] [PubMed] [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. 10.1111/j.1749-6632.2009.04035.x [DOI] [PubMed] [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. 10.1053/j.gastro.2008.10.081 [DOI] [PMC free article] [PubMed] [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. 10.1038/labinvest.3700373 [DOI] [PubMed] [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. 10.1053/gast.2002.30294 [DOI] [PubMed] [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. 10.1038/labinvest.3700316 [DOI] [PubMed] [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. 10.1038/mi.2010.5 [DOI] [PubMed] [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. 10.1006/mvre.2000.2288 [DOI] [PubMed] [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. 10.3390/cells8020135 [DOI] [PMC free article] [PubMed] [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. 10.1371/journal.pone.0085345 [DOI] [PMC free article] [PubMed] [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. 10.1152/ajpgi.2001.281.1.g216 [DOI] [PubMed] [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. 10.1007/978-1-4419-6612-4_29 [DOI] [PubMed] [Google Scholar]
  • 333.Cooney R, Jewell D. The genetic basis of inflammatory bowel disease. Dig Dis. (2009) 27:428–42. 10.1159/000234909 [DOI] [PubMed] [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. 10.1007/s00535-009-0141-8 [DOI] [PubMed] [Google Scholar]
  • 335.Mayer L. Evolving paradigms in the pathogenesis of IBD. J Gastroenterol. (2010) 45:9–16. 10.1007/s00535-009-0138-3 [DOI] [PubMed] [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. 10.1038/35079107 [DOI] [PubMed] [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. 10.1002/ibd.21223 [DOI] [PubMed] [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. 10.1007/978-1-4419-0901-5_3 [DOI] [PubMed] [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. 10.1074/jbc.C200651200 [DOI] [PubMed] [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. 10.1074/jbc.C200673200 [DOI] [PubMed] [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. 10.1053/gast.2003.50157 [DOI] [PubMed] [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. 10.1136/gut.2005.065557 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 343.Matsuoka K, Kanai T. The gut microbiota and inflammatory bowel disease. Semin Immunopathol. (2015) 37:47–55. 10.1007/s00281-014-0454-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 344.Fukata M, Arditi M. The role of pattern recognition receptors in intestinal inflammation. Mucosal Immunol. (2013) 6:451–63. 10.1038/mi.2013.13 [DOI] [PMC free article] [PubMed] [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. 10.1111/j.1365-2567.2007.02687.x [DOI] [PMC free article] [PubMed] [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. 10.1038/ni1192 [DOI] [PubMed] [Google Scholar]
  • 347.Travis S, Menzies I. Intestinal permeability: functional assessment and significance. Clin Sci. (1992) 82:471–88. 10.1042/cs0820471 [DOI] [PubMed] [Google Scholar]
  • 348.Bjarnason I, Macpherson A, Hollander D. Intestinal permeability: an overview. Gastroenterology. (1995) 108:1566–81. 10.1016/0016-5085(95)90708-4 [DOI] [PubMed] [Google Scholar]
  • 349.Wehkamp J, Stange EF. Paneth's disease. J Crohn's Colitis. (2010) 4:523–31. 10.1016/j.crohns.2010.05.010 [DOI] [PubMed] [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. 10.1152/AJPGI.00245.2020 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 351.Camilleri M. Human intestinal barrier: effects of stressors, diet, prebiotics, and probiotics. Clin Transl Gastroenterol. (2021) 12:e00308. 10.14309/ctg.0000000000000308 [DOI] [PMC free article] [PubMed] [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] [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. 10.1177/0148607103027004241 [DOI] [PubMed] [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. 10.1016/j.burns.2003.09.032 [DOI] [PubMed] [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. 10.1136/gutjnl-2017-315136 [DOI] [PMC free article] [PubMed] [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. 10.1093/ajcn/88.2.491s [DOI] [PubMed] [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. 10.1152/ajpgi.00398.2007 [DOI] [PubMed] [Google Scholar]
  • 358.Hewison M. Vitamin D and innate and adaptive immunity. Vitam Horm. (2011) 86:23–62. 10.1016/B978-0-12-386960-9.00002-2 [DOI] [PubMed] [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. 10.1186/1471-2172-8-5 [DOI] [PMC free article] [PubMed] [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. 10.1186/1471-230X-12-57 [DOI] [PMC free article] [PubMed] [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. 10.1093/ibd/izaa087 [DOI] [PubMed] [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. 10.1177/2050640615572176 [DOI] [PMC free article] [PubMed] [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. 10.1038/cti.2016.17 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. 10.3389/fmicb.2016.00185 [DOI] [PMC free article] [PubMed] [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. 10.1128/AEM.66.4.1654-1661.2000 [DOI] [PMC free article] [PubMed] [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. 10.1111/j.1462-2920.2009.02066.x [DOI] [PubMed] [Google Scholar]
  • 367.Vital M, Howe AC, Tiedje JM. Revealing the bacterial butyrate synthesis pathways by analyzing (meta)genomic data. MBio. (2014) 5:e00889. 10.1128/mBio.00889-14 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 368.Kannampalli P, Shaker R, Sengupta JN. Colonic butyrate- algesic or analgesic? Neurogastroenterol Motil. (2011) 23:975–9. 10.1111/j.1365-2982.2011.01775.x [DOI] [PMC free article] [PubMed] [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. 10.1111/j.1463-1318.2012.03152.x [DOI] [PubMed] [Google Scholar]

Articles from Frontiers in Nutrition are provided here courtesy of Frontiers Media SA

RESOURCES