Front. Nutr. Frontiers in Nutrition Front. Nutr. 2296-861X Frontiers Media S.A. 10.3389/fnut.2021.790387 Nutrition Correction Corrigendum: Inflammatory and Microbiota-Related Regulation of the Intestinal Epithelial Barrier Barbara Giovanni 1 2 * Barbaro Maria Raffaella 1 2 Fuschi Daniele 1 2 Palombo Marta 1 2 Falangone Francesca 3 Cremon Cesare 1 2 Marasco Giovanni 1 2 Stanghellini Vincenzo 1 2 1IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy 2Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy 3Medical-Surgical Department of Clinical Sciences and Translational Medicine, University Sapienza, Rome, Italy

Approved by: Frontiers Editorial Office, Frontiers Media SA, Switzerland

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

This article was submitted to Nutritional Immunology, a section of the journal Frontiers in Nutrition

 01 11 2021 2021 8 790387 06 10 2021 07 10 2021 Copyright © 2021 Barbara, Barbaro, Fuschi, Palombo, Falangone, Cremon, Marasco and Stanghellini. 2021 Barbara, Barbaro, Fuschi, Palombo, Falangone, Cremon, Marasco and Stanghellini

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

 A Corrigendum on Inflammatory and Microbiota-Related Regulation of the Intestinal Epithelial Barrier by Barbara, G., Barbaro, M. R., Fuschi, D., Palombo, M., Falangone, F., Cremon, C., Marasco, G., and Stanghellini, V. (2021). Front. Nutr. 8:718356. doi: 10.3389/fnut.2021.718356 intestinal epithelial barrier mucosal immune system gut microbiota IBS IBD celiac disease non-celiac gluten sensitivity

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 Turner JR. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol. (2009) 9:799–809. 10.1038/nri265319855405 Helander HF Fändriks L. Surface area of the digestive tract-revisited. Scand J Gastroenterol. (2014) 49:681–9. 10.3109/00365521.2014.89832624694282 Camilleri M. Leaky gut: mechanisms, measurement and clinical implications in humans. Gut. (2019) 68:1516–26. 10.1136/gutjnl-2019-31842731076401 Yen TH Wright NA. The gastrointestinal tract stem cell niche. Stem Cell Rev. (2006) 2:203–12. 10.1007/s12015-006-0048-117625256 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/nature1616126675736 Bischoff SC Barbara G Buurman W Ockhuizen T Schulzke JD Serino M . Intestinal permeability - a new target for disease prevention and therapy. BMC Gastroenterol. (2014) 14:189. 10.1186/s12876-014-0189-725407511 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.2015.3846/201526541659 Meddings J. The significance of the gut barrier in disease. Gut. (2008) 57:438–40. 10.1136/gut.2007.14317218334657 Hansson GC. Mucus and mucins in diseases of the intestinal and respiratory tracts. J Intern Med. (2019) 285:479–90. 10.1111/joim.1291030963635 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/microorganisms602005329914144 Johansson MEV Hansson GC. Immunological aspects of intestinal mucus and mucins. Nat Rev Immunol. (2016) 16:639–49. 10.1038/nri.2016.8827498766 Cone RA. Barrier properties of mucus. Adv Drug Deliv Rev. (2009) 61:75–85. 10.1016/j.addr.2008.09.00819135107 König J Wells J Cani PD García-Ródenas CL MacDonald T Mercenier A . Human intestinal barrier function in health and disease. Clin Transl Gastroenterol. (2016) 7:e196. 10.1038/ctg.2016.5427763627 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/s11894-010-0131-220703838 Hansson GC. Mucins and the Microbiome. Annu Rev Biochem. (2020) 89:769–93. 10.1146/annurev-biochem-011520-10505332243763 Bansil R Turner BS. The biology of mucus: composition, synthesis and organization. Adv Drug Deliv Rev. (2018) 124:3–15. 10.1016/j.addr.2017.09.02328970050 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.x1456650 Kim JJ Khan WI. Goblet cells and mucins: role in innate defense in enteric infections. Pathogens. (2013) 2:55–70. 10.3390/pathogens201005525436881 Strugnell RA Wijburg OLC. The role of secretory antibodies in infection immunity. Nat Rev Microbiol. (2010) 8:656–67. 10.1038/nrmicro238420694027 Huus KE Petersen C Finlay BB. Diversity and dynamism of IgA–microbiota interactions. Nat Rev Immunol. (2021) 21:514–25. 10.1038/s41577-021-00506-133568782 Pelaseyed T Hansson GC. Membrane mucins of the intestine at a glance. J Cell Sci. (2020) 133:jcs240929. 10.1242/JCS.24092932169835 Etienne-Mesmin L Chassaing B Desvaux M De Paepe K Gresse R Sauvaitre T . Experimental models to study intestinal microbes–mucus interactions in health and disease. FEMS Microbiol Rev. (2019) 43:457–89. 10.1093/femsre/fuz01331162610 Pelaseyed T Bergström JH Gustafsson JK Ermund A Birchenough GMH Schütte A . 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.1218224942678 Pabst O Mowat AM. Oral tolerance to food protein. Mucosal Immunol. (2012) 5:232–9. 10.1038/mi.2012.422318493 Shan M Gentile M Yeiser JR Walland AC Bornstein VU Chen K . Mucus enhances gut homeostasis and oral tolerance by delivering immunoregulatory signals. Science. (2013) 342:447–53. 10.1126/science.123791024072822 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.008368824358305 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.100645110720615996 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.g92211292601 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.00046.201323832518 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.2015.3225872481 Ouellette AJ. Paneth cells and innate mucosal immunity. Curr Opin Gastroenterol. (2010) 26:547–53. 10.1097/MOG.0b013e32833dccde20693892 Heazlewood CK Cook MC Eri R Price GR Tauro SB Taupin D . Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis. PLoS Med. (2008) 5:54. 10.1371/journal.pmed.005005418318598 Renner M Bergmann G Krebs I End C Lyer S Hilberg F . 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.2007.08.00717983803 Hooper LV MacPherson AJ. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat Rev Immunol. (2010) 10:159–69. 10.1038/nri271020182457 Meyer-Hoffert U Hornef MW Henriques-Normark B Axelsson LG Midtvedt T Pütsep K . Secreted enteric antimicrobial activity localises to the mucus surface layer. Gut. (2008) 57:764–71. 10.1136/gut.2007.14148118250125 Van Der Waaij LA Harmsen HJM Madjipour M Kroese FGM Zwiers M Van Dullemen HM . 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.d316189415 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.080312410521327117 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.2013.3523478383 Li H Limenitakis JP Fuhrer T Geuking MB Lawson MA Wyss M . The outer mucus layer hosts a distinct intestinal microbial niche. Nat Commun. (2015) 6:8292. 10.1038/ncomms929226392213 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/s41598-017-08938-328819121 Hoskins LC Boulding ET. Mucin degradation in human colon ecosystems. J Clin Invest. (1981) 67:163–72. 10.1172/jci1100096161136 Png CW Lindén SK Gilshenan KS Zoetendal EG McSweeney CS Sly LI . 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.2010.28120648002 Desai MS Seekatz AM Koropatkin NM Kamada N Hickey CA Wolter M . 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.2016.10.04327863247 Johansson MEV Jakobsson HE Holmén-Larsson J Schütte A Ermund A Rodríguez-Piñeiro AM . Normalization of host intestinal mucus layers requires long-term microbial colonization. Cell Host Microbe. (2015) 18:582–92. 10.1016/j.chom.2015.10.00726526499 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/goy05230792861 Fu J Wei B Wen T Johansson MEV Liu X Bradford E . Loss of intestinal core 1-derived O-glycans causes spontaneous colitis in mice. J Clin Invest. (2011) 121:1657–66. 10.1172/JCI4553821383503 Larsson JMH Karlsson H Crespo JG Johansson MEV Eklund L Sjövall H . 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.2162521290483 Johansson MEV Gustafsson JK Holmen-Larsson J Jabbar KS Xia L Xu H . 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-2012-30320723426893 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.x18194279 Pullan RD Thomas GAO Rhodes M Newcombe RG Williams GT Allen A . Thickness of adherent mucus gel on colonic mucosa in humans and its relevance to colitis. Gut. (1994) 35:353–9. 10.1136/gut.35.3.3538150346 Buisine MP Desreumaux P Leteurtre E Copin MC Colombel JF Porchet N . Mucin gene expression in intestinal epithelial cells in Crohn's disease. Gut. (2001) 49:544–51. 10.1136/gut.49.4.54411559653 Buisine MP Desreumaux P Debailleul V Gambiez L Geboes K Ectors N . Abnormalities in mucin gene expression in Crohn's disease. Inflamm Bowel Dis. (1999) 5:24–32. 10.1097/00054725-199902000-0000410028446 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)90592-47905449 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.49.7.5608813954 McGuckin MA Lindén SK Sutton P Florin TH. Mucin dynamics and enteric pathogens. Nat Rev Microbiol. (2011) 9:265–78. 10.1038/nrmicro253821407243 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. 10.1159/00016303720375571 Hayashi F Smith KD Ozinsky A Hawn TR Yi EC Goodlett DR . The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature. (2001) 410:1099–103. 10.1038/3507410611323673 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.aaf741927339979 Wang S Ahmadi S Nagpal R Jain S Mishra SP Kavanagh K . 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/s11357-019-00137-431814084 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-2195.119737027 Kamdar K Johnson AMF Chac D Myers K Kulur V Truevillian K . Innate recognition of the microbiota by TLR1 promotes epithelial homeostasis and prevents chronic inflammation. J Immunol. (2018) 201:230–42. 10.4049/jimmunol.170121629794015 Anderson JM Van Itallie CM. Physiology and function of the tight junction. Cold Spring Harb Perspect Biol. (2009) 1:a002584. 10.1101/cshperspect.a00258420066090 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.141.7.15399647647 Furuse M Hirase T Itoh M Nagafuchi A Yonemura S Tsukita S . Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol. (1993) 123:1777–88. 10.1083/jcb.123.6.17778276896 Martìn-Padura I Lostaglio S Schneemann M Williams L Romano M Fruscella P . 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.142.1.1179660867 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.20061208017353356 Günzel D Fromm M. Claudins and other tight junction proteins. Compr Physiol. (2012) 2:1819–52. 10.1002/cphy.c11004523723025 Günzel D Yu ASL. Claudins and the modulation of tight junction permeability. Physiol Rev. (2013) 93:525–69. 10.1152/physrev.00019.201223589827 Suzuki T. Regulation of the intestinal barrier by nutrients: the role of tight junctions. Anim Sci J. (2020) 91:e13357. 10.1111/asj.1335732219956 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.2019.10948531770579 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-012110-14215020936941 Van Itallie CM Anderson JM. Claudins and epithelial paracellular transport. Annu Rev Physiol. (2006) 68:403–29. 10.1146/annurev.physiol.68.040104.13140416460278 Heller F Florian P Bojarski C Richter J Christ M Hillenbrand B . 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.2005.05.00216083712 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.ch915669638 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)63051-911733350 Pizzuti D Senzolo M Buda A Chiarelli S Giacomelli L Mazzon E . In vitro model for IgE mediated food allergy. Scand J Gastroenterol. (2011) 46:177–87. 10.3109/00365521.2010.52571621028948 Assimakopoulos SF Tsamandas AC Tsiaoussis GI Karatza E Triantos C Vagianos CE . 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.x22023490 Bertiaux-Vandaële N Youmba SB Belmonte L Lecleire S Antonietti M Gourcerol G . 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.2011.25722008894 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.2001.2173611159882 Reyes JL Lamas M Martin D Namorado MDC Islas S Luna J . The renal segmental distribution of claudins changes with development. Kidney Int. (2002) 62:476–87. 10.1046/j.1523-1755.2002.00479.x12110008 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)01927-911427304 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.2150616287068 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.x19120888 Nagy Szakál D Gyorffy H Arató A Cseh Á Molnár K Papp M . 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/s00428-009-0879-720143085 Martínez C Lobo B Pigrau M Ramos L González-Castro AM Alonso C . Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier. Gut. (2013) 62:1160–8. 10.1136/gutjnl-2012-30209322637702 Zeissig S Bürgel N Günzel D Richter J Mankertz J Wahnschaffe U . 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.2006.09437516822808 Laurila JJ Karttunen T Koivukangas V Laurila PA Syrjälä H Saarnio J . Tight junction proteins in gallbladder epithelium: different expression in acute acalculous and calculous cholecystitis. J Histochem Cytochem. (2007) 55:567–73. 10.1369/jhc.6A7155.200717283368 Wolburg H Wolburg-Buchholz K Kraus J Rascher-Eggstein G Liebner S Hamm S . 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-z12734665 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.v13487511912246 Mennigen R Nolte K Rijcken E Utech M Loeffler B Senninger N . 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.90534.200819221015 Oshima T Miwa H. Gastrointestinal mucosal barrier function and diseases. J Gastroenterol. (2016) 51:768–78. 10.1007/s00535-016-1207-z27048502 Sapone A Lammers KM Casolaro V Cammarota M Giuliano MT De Rosa M . Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: Celiac disease and gluten sensitivity. BMC Med. (2011) 9:23. 10.1186/1741-7015-9-2321392369 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.147.1.18510508865 Nitta T Hata M Gotoh S Seo Y Sasaki H Hashimoto N . Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice. J Cell Biol. (2003) 161:653–60. 10.1083/jcb.20030207012743111 Amasheh S Schmidt T Mahn M Florian P Mankertz J Tavalali S . Contribution of claudin-5 to barrier properties in tight junctions of epithelial cells. Cell Tissue Res. (2005) 321:89–96. 10.1007/s00441-005-1101-016158492 Schumann M Günzel D Buergel N Richter JF Troeger H May C . 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-2011-30012321865402 Fujita H Chiba H Yokozaki H Sakai N Sugimoto K Wada T . 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.6A6944.200616651389 Go M Kojima T Takano KI Murata M Ichimiya S Tsubota H . Expression and function of tight junctions in the crypt epithelium of human palatine tonsils. J Histochem Cytochem. (2004) 52:1627–38. 10.1369/jhc.4A6339.200415557217 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.00384.200314722018 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.117411668606 Lameris AL Huybers S Kaukinen K Mäkelä TH Bindels RJ Hoenderop JG . Expression profiling of claudins in the human gastrointestinal tract in health and during inflammatory bowel disease. Scand J Gastroenterol. (2013) 48:58–69. 10.3109/00365521.2012.74161623205909 Niimi T Nagashima K Ward JM Minoo P Zimonjic DB Popescu NC . 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.21.21.7380-7390.200111585919 Linares GR Brommage R Powell DR Xing W Chen ST Alshbool FZ . Claudin 18 is a novel negative regulator of bone resorption and osteoclast differentiation. J Bone Miner Res. (2012) 27:1553–65. 10.1002/jbmr.160022437732 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.192216435283 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.c18599435490 Umeda K Ikenouchi J Katahira-Tayama S Furuse K Sasaki H Nakayama M . 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.2006.06.04316923393 González-Mariscal L Quirós M Díaz-Coránguez M. ZO proteins and redox-dependent processes. Antioxidants Redox Signal. (2011) 15:1235–53. 10.1089/ars.2011.391321294657 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.124.6.9498132716 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.273.45.297459792688 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.274.9.598110026224 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.02-0121fje12354695 Mandell KJ Parkos CA. The JAM family of proteins. Adv Drug Deliv Rev. (2005) 57:857–67. 10.1016/j.addr.2005.01.00515820556 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.00004.201728931565 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.2014.08.01125171873 Laukoetter MG Nava P Lee WY Severson EA Capaldo CT Babbin BA . JAM-A regulates permeability and inflammation in the intestine in vivo. J Exp Med. (2007) 204:3067–76. 10.1084/jem.2007141618039951 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.E08-10-101419176753 Nava P Capaldo CT Koch S Kolegraff K Rankin CR Farkas AE . JAM-A regulates epithelial proliferation through Akt/β-catenin signalling. EMBO Rep. (2011) 12:314–20. 10.1038/embor.2011.1621372850 Monteiro AC Sumagin R Rankin CR Leoni G Mina MJ Reiter DM . 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.E13-06-029823885123 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. 10.7326/0003-4819-105-6-8833777713 Martínez C Vicario M Ramos L Lobo B Mosquera JL Alonso C . 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.2011.47225091249 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.1226224286617 Drago S El Asmar R Di Pierro M Clemente MG Tripathi A Sapone A . Gliadin, zonulin and gut permeability: effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scand J Gastroenterol. (2006) 41:408–19. 10.1080/0036552050023533416635908 Vetrano S Rescigno M Rosaria Cera M Correale C Rumio C Doni A . Unique role of junctional adhesion molecule-a in maintaining mucosal homeostasis in inflammatory Bowel disease. Gastroenterology. (2008) 135:173–84. 10.1053/j.gastro.2008.04.00218514073 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.2013.9223588236 Cordenonsi M D'Atri F Hammar E Parry DAD Kendrick-Jones J Shore D . 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.147.7.156910613913 Citi S Paschoud S Pulimeno P Timolati F De Robertis F Jond L . 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.x19538293 Suarez C Kovar DR. Internetwork competition for monomers governs actin cytoskeleton organization. Nat Rev Mol Cell Biol. (2016) 17:799–810. 10.1038/nrm.2016.10627625321 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/nrm281820027187 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.178.7.464117372023 Schwayer C Shamipour S Pranjic-Ferscha K Schauer A Balda M Tada M . Mechanosensation of tight junctions depends on ZO-1 phase separation and flow. Cell. (2019) 179:937–52.e18. 10.1016/j.cell.2019.10.00631675500 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)64003-017964922 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.2007.07.01217854762 Shapiro L Weis WI. Structure and biochemistry of cadherins and catenins. Cold Spring Harb Perspect Biol. (2009) 1:a003053. 10.1101/cshperspect.a00305320066110 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/B978-0-12-407697-6.00002-723445808 Takeichi M. Dynamic contacts: rearranging adherens junctions to drive epithelial remodelling. Nat Rev Mol Cell Biol. (2014) 15:397–410. 10.1038/nrm380224824068 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.20110605722184201 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.a02915728096266 Tripathi A Lammers KM Goldblum S Shea-Donohue T Netzel-Arnett S Buzza MS . 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.090677310619805376 Lammers KM Lu R Brownley J Lu B Gerard C Thomas K . 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.2008.03.02318485912 Sapone A De Magistris L Pietzak M Clemente MG Tripathi A Cucca F . Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives. Diabetes. (2006) 55:1443–9. 10.2337/db05-159316644703 Barbaro MR Cremon C Wrona D Fuschi D Marasco G Stanghellini V . Non-celiac gluten sensitivity in the context of functional gastrointestinal disorders. Nutrients. (2020) 12:1–21. 10.3390/nu1212373533291590 Fasano A. Zonulin measurement conundrum: add confusion to confusion does not lead to clarity. Gut. (2020) 70:2007–8. 10.1136/gutjnl-2020-32336733177164 Misra A. Challenges in delivery of therapeutic genomics and proteomics. Amsterdam: Elsevier Inc. (2011). 10.1016/C2010-0-65663-X Sugano K Kansy M Artursson P Avdeef A Bendels S Di L . Coexistence of passive and carrier-mediated processes in drug transport. Nat Rev Drug Discov. (2010) 9:597–614. 10.1038/nrd318720671764 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 Horisberger JD Chraïbi A. Epithelial sodium channel: a ligand-gated channel? Nephron Physiol. (2004) 96:37–41. 10.1159/00007640614988660 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 Goldstein JL Anderson RGW Brown MS. Coated pits, coated vesicles, and receptor-mediated endocytosis. Nature. (1979) 279:679–85. 10.1038/279679a06818548 Garcia-Castillo MD Chinnapen DJF Lencer WI. Membrane transport across polarized epithelia. Cold Spring Harb Perspect Biol. (2017) 9:a027912. 10.1101/cshperspect.a02791228213463 Sandvig K Kavaliauskiene S Skotland T. Clathrin-independent endocytosis: an increasing degree of complexity. Histochem Cell Biol. (2018) 150:107–18. 10.1007/s00418-018-1678-529774430 Tuma PL Hubbard AL. Transcytosis: crossing cellular barriers. Physiol Rev. (2003) 83:871–932. 10.1152/physrev.00001.200312843411 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.44.1.29862815 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.179.11.775118025221 Boullier S Tanguy M Kadaoui KA Caubet C Sansonetti P Corthésy B . 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.090183819828639 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.172.5.302614978107 Matysiak-Budnik T Moura IC Arcos-Fajardo M Lebreton C Ménard S Candalh C . 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.2007120418166587 Bevilacqua C Montagnac G Benmerah A Candalh C Brousse N Cerf-Bensussan N . Food allergens are protected from degradation during CD23-mediated transepithelial transport. Int Arch Allergy Immunol. (2004) 205:143–54. 10.1159/00008065315345909 Kaiserlian D Lachaux A Grosjean I Graber P Bonnefoy JY. Intestinal epithelial cells express the CD23/FcεRII molecule: enhanced expression in enteropathies. Immunology. (1993) 80:90–5.8244467 Montagnac G Yu LCH Bevilacqua C Heyman M Conrad DH Perdue MH . 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.x15702991 Montagnac G Mollà-Herman A Bouchet J Yu LCH Conrad DH Perdue MH . 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.174.9.556215843555 Neal MD Leaphart C Levy R Prince J Billiar TR Watkins S . Enterocyte TLR4 Mediates Phagocytosis and Translocation of Bacteria Across the Intestinal Barrier. J Immunol. (2006) 176:3070–9. 10.4049/jimmunol.176.5.307016493066 Conner SD Schmid SL. Regulated portals of entry into the cell. Nature. (2003) 422:37–44. 10.1038/nature0145112621426 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/s00281-018-0701-130182191 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.x16101676 Maloy KJ Powrie F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature. (2011) 474:298–306. 10.1038/nature1020821677746 Khor B Gardet A Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature. (2011) 474:307–17. 10.1038/nature1020921677747 Suzuki T. Regulation of intestinal epithelial permeability by tight junctions. Cell Mol Life Sci. (2013) 70:631–59. 10.1007/s00018-012-1070-x33373067 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.52.3.43912584232 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.110481615790844 Hooper L V. Littman DR Macpherson AJ. Interactions between the microbiota and the immune system. Science. (2012) 336:1268–73. 10.1126/science.122349022674334 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-070119-11510432340570 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/nature1650426762459 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.2012.08.00522940212 Baümler AJ Sperandio V. Interactions between the microbiota and pathogenic bacteria in the gut. Nature. (2016) 535:85–93. 10.1038/nature1884927383983 Buffie CG Pamer EG. Microbiota-mediated colonization resistance against intestinal pathogens. Nat Rev Immunol. (2013) 13:790–801. 10.1038/nri353524096337 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.aad937827126036 Thaiss CA Zmora N Levy M Elinav E. The microbiome and innate immunity. Nature. (2016) 535:65–74. 10.1038/nature1884727383981 Stecher B Hardt WD. Mechanisms controlling pathogen colonization of the gut. Curr Opin Microbiol. (2011) 14:82–91. 10.1016/j.mib.2010.10.00321036098 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.2010.12.01221215681 Litvak Y Byndloss MX Bäumler AJ. Colonocyte metabolism shapes the gut microbiota. Science. (2018) 362:eaat9076. 10.1126/science.aat907630498100 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.00196.201932308040 Chowdhury SR King DE Willing BP Band MR Beever JE Lane AB . Transcriptome profiling of the small intestinal epithelium in germfree versus conventional piglets. BMC Genomics. (2007) 8:215. 10.1186/1471-2164-8-21517615075 Burger-van Paassen N Vincent A Puiman PJ van der Sluis M Bouma J Boehm G . The regulation of intestinal mucin MUC2 expression by short-chain fatty acids: implications for epithelial protection. Biochem J. (2009) 420:211–9. 10.1042/BJ2008222219228118 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.2013.04.05623665276 Singh N Gurav A Sivaprakasam S Brady E Padia R Shi H . 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.2013.12.00724412617 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.2021.02.00733610769 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/nri270720098461 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/s41575-019-0261-432103203 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/ijms2117640232899147 Hayes CL Dong J Galipeau HJ Jury J McCarville J Huang X . Commensal microbiota induces colonic barrier structure and functions that contribute to homeostasis. Sci Rep. (2018) 8:14184. 10.1038/s41598-018-32366-630242285 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.291.5505.88111157169 Ukena SN Singh A Dringenberg U Engelhardt R Seidler U Hansen W . Probiotic Escherichia coli Nissle 1917 inhibits leaky gut by enhancing mucosal integrity. PLoS ONE. (2007) 2:e1308. 10.1371/journal.pone.000130818074031 Barbaro MR Fuschi D Cremon C Carapelle M Dino P Marcellini MM . Escherichia coli Nissle 1917 restores epithelial permeability alterations induced by irritable bowel syndrome mediators. Neurogastroenterol Motil. (2018) 30:e13388. 10.1111/nmo.1338829956419 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.00778-0718227169 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.2015.0002633194823 Zareie M Riff J Donato K McKay DM Perdue MH Soderholm JD . 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.x16309464 Barbara G Feinle-Bisset C Ghoshal UC Santos J Vanner SJ Vergnolle N . The intestinal microenvironment and functional gastrointestinal disorders. Gastroenterology. (2016) 150:1305–18.e8. 10.1053/j.gastro.2016.02.02827144620 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.2020.09.05633253681 Machiels K Joossens M Sabino J De Preter V Arijs I Eeckhaut V . 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-2013-30483324021287 Zhou L Zhang M Wang Y Dorfman RG Liu H Yu T . 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/izy18229796620 Cremon C Guglielmetti S Gargari G Taverniti V Castellazzi AM Valsecchi C . 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. 10.1177/205064061773647829881616 Friedrich M Pohin M Powrie F. Cytokine networks in the pathophysiology of inflammatory Bowel disease. Immunity. (2019) 50:992–1006. 10.1016/j.immuni.2019.03.01730995511 Coccia M Harrison OJ Schiering C Asquith MJ Becher B Powrie F . 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.2011145322891275 Lee YS Yang H Yang JY Kim Y Lee SH Kim JH . 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.00670-1526034212 Song A Zhu L Gorantla G Berdysz O Amici SA Guerau-De-Arellano M . Salient type 1 interleukin 1 receptor expression in peripheral non-immune cells. Sci Rep. (2018) 8:723. 10.1038/s41598-018-19248-729335509 Cox CB Storm EE Kapoor VN Chavarria-Smith J Lin DL Wang L . IL-1R1-dependent signaling coordinates epithelial regeneration in response to intestinal damage. Sci Immunol. (2021) 6:eabe8856. 10.1126/sciimmunol.abe885633963061 Madara JL Stafford J. Interferon-γ directly affects barrier function of cultured intestinal epithelial monolayers. J Clin Invest. (1989) 83:724–7. 10.1172/JCI1139382492310 Adams RB Planchon SM Roche JK. IFN-gamma modulation of epithelial barrier function. Time course, reversibility, and site of cytokine binding. J Immunol. (1993) 150:2356–63.8450217 Schmitz H Fromm M Bentzel CJ Scholz P Detjen K Mankertz J . 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):137–46.9841910 Bruewer M Luegering A Kucharzik T Parkos CA Madara JL Hopkins AM . Proinflammatory cytokines disrupt epithelial barrier function by apoptosis-independent mechanisms. J Immunol. (2003) 171:6164–72. 10.4049/jimmunol.171.11.616414634132 Barbaro MR Di Sabatino A Cremon C Giuffrida P Fiorentino M Altimari A . 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.00368.201526744473 Zolotarevsky Y Hecht G Koutsouris A Gonzalez DE Quan C Tom J . 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.2002.3423512105845 Bhat AA Uppada S Achkar IW Hashem S Yadav SK Shanmugakonar M . Tight junction proteins and signaling pathways in cancer and inflammation: a functional crosstalk. Front Physiol. (2019) 10:1942. 10.3389/fphys.2018.0194230728783 Pham CTN. Neutrophil serine proteases: specific regulators of inflammation. Nat Rev Immunol. (2006) 6:541–50. 10.1038/nri184116799473 Dale C Vergnolle N. Protease signaling to G protein-coupled receptors: implications for inflammation and pain. J Recept Signal Transduct. (2008) 28:29–37. 10.1080/1079989080194191318437628 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.181.8.570218832729 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.x16371078 Bashashati M Moossavi S Cremon C Barbaro MR Moraveji S Talmon G . Colonic immune cells in irritable bowel syndrome: a systematic review and meta-analysis. Neurogastroenterol Motil. (2018) 30:10. 10.1111/nmo.1319228851005 Bashashati M Rezaei N Shafieyoun A Mckernan DP Chang L Öhman L Quigley EM . Cytokine imbalance in irritable bowel syndrome: a systematic review and meta-analysis. Neurogastroenterol Motil. (2014) 26:1036–48. 10.1111/nmo.1235824796536 Chang L Adeyemo M Karagiannidis I Videlock EJ Bowe C Shih W . Serum and colonic mucosal immune markers in irritable bowel syndrome. Am J Gastroenterol. (2012) 107:262–72. 10.1038/ajg.2011.42322158028 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.x21453321 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.009314424667736 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-X15681825 Hanning N Edwinson AL Ceuleers H Peters SA De Man JG Hassett LC . Intestinal barrier dysfunction in irritable bowel syndrome: a systematic review. Therap Adv Gastroenterol. (2021) 14:1756284821993586. 10.1177/175628482199358633717210 Renga G Moretti S Oikonomou V Borghi M Zelante T Paolicelli G . 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.2018.04.03429742432 Gerlach K Hwang Y Nikolaev A Atreya R Dornhoff H Steiner S . 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.292024908389 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. 10.4161/21688370.2014.98377725838986 Piche T Barbara G Aubert P Des Varannes SB Dainese R Nano JL . 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.2007.14080618824556 Barbara G Stanghellini V De Giorgio R Cremon C Cottrell GS Santini D . 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.2003.11.05514988823 Barbara G Wang B Stanghellini V de Giorgio R Cremon C Di Nardo G . Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable Bowel syndrome. Gastroenterology. (2007) 132:26–37. 10.1053/j.gastro.2006.11.03917241857 Gecse K Róka R Ferrier L Leveque M Eutamene H Cartier C . 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.2007.14021018194983 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.1505531495063 Barbara G Grover M Bercik P Corsetti M Ghoshal UC Ohman L . Rome foundation working team report on post-infection irritable Bowel syndrome. Gastroenterology. (2019) 156:46–58.e7. 10.1053/j.gastro.2018.07.01130009817 Edogawa S Edwinson AL Peters SA Chikkamenahalli LL Sundt W Graves S Breen-Lyles M Johnson S Dyer R . Serine proteases as luminal mediators of intestinal barrier dysfunction and symptom severity in IBS. Gut. (2020) 69:62–73. 10.1136/gutjnl-2018-31741630923071 Cenac N Bautzova T Le Faouder P Veldhuis NA Poole DP Rolland C . 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.2015.04.01125911511 Bautzova T Hockley JRF Perez-Berezo T Pujo J Tranter MM Desormeaux C . 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.aal217130563864 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. 10.1177/205064061986272131662866 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. 10.1177/205064061984937031210939 Schuppan D Junker Y Barisani D. Celiac disease: from pathogenesis to novel therapies. Gastroenterology. (2009) 137:1912–33. 10.1053/j.gastro.2009.09.00830519552 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.2012.04.47322898420 Greco L Romino R Coto I Di Cosmo N Percopo S Maglio M . The first large population based twin study of coeliac disease. Gut. (2002) 50:624–8. 10.1136/gut.50.5.62411950806 Caminero A McCarville JL Galipeau HJ Deraison C Bernier SP Constante M . Duodenal bacterial proteolytic activity determines sensitivity to dietary antigen through protease-activated receptor-2. Nat Commun. (2019) 10:1–14. 10.1038/s41467-019-09037-930867416 Di Biase AR Marasco G Ravaioli F Dajti E Colecchia L Righi B . 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.1518332666516 Marasco G Cirota GG Rossini B Lungaro L Di Biase AR Colecchia A . Probiotics, prebiotics and other dietary supplements for gut microbiota modulation in celiac disease patients. Nutrients. (2020) 12:2674. 10.3390/nu1209267432887325 Stene LC Honeyman MC Hoffenberg EJ Haas JE Sokol RJ Emery L . 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.x17032199 Zafeiropoulou K Nichols B Mackinder M Biskou O Rizou E Karanikolou A . 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.2020.08.00732791131 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.2020.10.05933385435 Marasco G Di Biase AR Schiumerini R Eusebi LH Iughetti L Ravaioli F . Gut microbiota and celiac disease. Dig Dis Sci. (2016) 61:1461–72. 10.1007/s10620-015-4020-226725064 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/nri391926567920 Catassi C Elli L Bonaz B Bouma G Carroccio A Castillejo G . Diagnosis of Non-Celiac Gluten Sensitivity (NCGS): the Salerno experts' criteria. Nutrients. (2015) 7:4966–77. 10.3390/nu706496626096570 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)00223-110771132 Barone MV Gimigliano A Castoria G Paolella G Maurano F Paparo F . Growth factor-like activity of gliadin, an alimentary protein: implications for coeliac disease. Gut. (2007) 56:480–8. 10.1136/gut.2005.08663716891357 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-2011-30032721890812 Clemente MG De Virgiliis S Kang JS Macatagney R Musu MP Di Pierro MR . Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function. Gut. (2003) 52:218–23. 10.1136/gut.52.2.21812524403 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.2006.04.02216766047 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.008906824586509 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) 1963:1235–8.14109593 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.2.6144.1060709218 Oberhuber G Vogelsang H. Gastrointestinal permeability in celiac disease [1]. Gastroenterology. (1998) 114:226. 10.1016/S0016-5085(98)70661-49428239 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.34.3.3548472983 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. 10.1203/00006450-199804000-000019544995 Goswami P Das P Verma AK Prakash S Das TK Nag TC . 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/s00428-014-1651-125240724 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-tm8m16627260 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. 10.1159/00006381712239464 Perry I Tselepis C Hoyland J Iqbal TH Scott D Sanders A . Reduced cadherin/catenin complex expression in celiac disease can be reproduced in vitro by cytokine stimulation. Lab Invest. (1999) 79:1489–99.10616200 Schumann M Siegmund B Schulzke JD Fromm M. Celiac disease: role of the epithelial barrier. CMGH. (2017) 3:150–62. 10.1016/j.jcmgh.2016.12.00628275682 Mishra A Prakash S Sreenivas V Das TK Ahuja V Gupta SD . 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.000000000000043626535478 Hunt KA Zhernakova A Turner G Heap GAR Franke L Bruinenberg M . Newly identified genetic risk variants for celiac disease related to the immune response. Nat Genet. (2008) 40:395–402. 10.1038/ng.10218311140 Wapenaar MC Monsuur AJ Van Bodegraven AA Weersma RK Bevova MR Linskens RK . 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.2007.13313217989107 Monsuur AJ Bakker PIWD Alizadeh BZ Zhernakova A Bevova MR Strengman E . 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/ng168016282976 Wolters VM Alizadeh BZ Weijerman ME Zhernakova A van Hoogstraten IMW Mearin ML . 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.2010.01.01620096742 Kumar V Gutierrez-Achury J Kanduri K Almeida R Hrdlickova B Zhernakova D V . 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/ddu45325190711 Almeida R Ricanõ-Ponce I Kumar V Deelen P Szperl A Trynka G . Fine mapping of the celiac disease-associated LPP locus reveals a potential functional variant. Hum Mol Genet. (2014) 23:2481–9. 10.1093/hmg/ddt61924334606 Ciccocioppo R Panelli S Bellocchi MCC Cangemi GC Frulloni L Capelli E . 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.2018.0018229971234 Dolfini E Roncoroni L Elli L Fumagalli C Colombo R Ramponi S . 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.i48.759716437684 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.25.11.12416437913 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.2007.05.02817681168 Pinier M Verdu EF Nasser-Eddine M David CS Vézina A Rivard N . Polymeric binders suppress gliadin-induced toxicity in the intestinal epithelium. Gastroenterology. (2009) 136:288–98. 10.1053/j.gastro.2008.09.01618992747 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.x17697209 Kelly CP Green PHR Murray JA Dimarino A Colatrella A Leffler DA . 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.1214723163616 Leffler DA Kelly CP Abdallah HZ Colatrella AM Harris LA Leon F . 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.2012.21122825365 Leffler DA Kelly CP Green PHR Fedorak RN Dimarino A Perrow W . 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.2015.02.00825683116 Hujoel IA Murray JA. Refractory celiac disease. Curr Gastroenterol Rep. (2020) 22:1–8. 10.1007/s11894-020-0756-832185560 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.2020.09.01033707052 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.285.6334.206805795 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. 10.1159/0001989326414866 Abraham C Cho JH. Mechanisms of inflammatory Bowel disease. N Engl J Med. (2009) 361:2066–78. 10.1056/NEJMra080464719923578 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/S095442241600001927087106 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.11.9422149584 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.00477.201122194420 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.00527.200920558765 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.111.04108721880829 De Medina FS Daddaoua A Requena P Capitán-Cañadas F Zarzuelo A Dolores Suárez M . 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/S002966511000178320598199 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.002640722031831 Cipriani S Mencarelli A Chini MG Distrutti E Renga B Bifulco G . 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.002563722046243 Chia-Hui Y. Microbiota dysbiosis and barrier dysfunction in inflammatory bowel disease: RSM Library Discovery Service. J Biomed Sci. (2018) 25:79. 10.1186/s12929-018-0483-830413188 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.0b013e31825ca21a23971750 Ananthakrishnan AN Bernstein CN Iliopoulos D Macpherson A Neurath MF Ali RAR . Environmental triggers in IBD: a review of progress and evidence. Nat Rev Gastroenterol Hepatol. (2018) 15:39– 49. 10.1038/nrgastro.2017.13629018271 Ho SM Lewis JD Mayer EA Plevy SE Chuang E Rappaport SM . Challenges in IBD research: environmental triggers. Inflamm Bowel Dis. (2019) 25:S13–23. 10.1093/ibd/izz07631290963 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. 10.4065/81.11.146217120402 Calkins BM. A meta-analysis of the role of smoking in inflammatory bowel disease. Dig Dis Sci. (1989) 34:1841–54. 10.1007/BF015367012598752 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.2012.19622777340 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/s10654-021-00763-334091767 Singh UP Singh NP Murphy EA Price RL Fayad R Nagarkatti M . Chemokine and cytokine levels in inflammatory bowel disease patients. Cytokine. (2016) 77:44–9. 10.1016/j.cyto.2015.10.00826520877 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.20120177324039130 Salzman NH Hung K Haribhai D Chu H Karlsson-Sjöberg J Amir E . Enteric defensins are essential regulators of intestinal microbial ecology. Nat Immunol. (2010) 11:76–83. 10.1038/ni.182519855381 Peyrin-Biroulet L Beisner J Wang G Nuding S Oommen ST Kelly D . 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.090574510720421464 Wehkamp J Harder J Weichenthal M Mueller O Herrlinger KR Fellermann K . Inducible and constitutive beta-defensins are differentially expressed in Crohn's disease and ulcerative colitis. Inflamm Bowel Dis. (2003) 9:215–23. 10.1097/00054725-200307000-0000112902844 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.2017.03.00728560287 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.151008411226512113 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.2008.4819079235 Paone P Cani PD. Mucus barrier, mucins and gut microbiota: the expected slimy partners? Gut. (2020) 69:2232–43. 10.1136/gutjnl-2020-32226032917747 Van Der Post S Jabbar KS Birchenough G Arike L Akhtar N Sjovall H . Structural weakening of the colonic mucus barrier is an early event in ulcerative colitis pathogenesis. Gut. (2019) 68:2142–51. 10.1136/gutjnl-2018-31757130914450 Johansson ME Ambort D Pelaseyed T Schütte A Gustafsson JK Ermund A . Composition and functional role of the mucus layers in the intestine. Cell Mol Life Sci. (2011) 68:3635–41. 10.1007/S00018-011-0822-321947475 Cornick S Tawiah A Chadee K. Roles and regulation of the mucus barrier in the gut. Tissue Barriers. (2015) 3:e982426. 10.4161/21688370.2014.98242625838985 Vivinus-Nébot M Frin-Mathy G Bzioueche H Dainese R Bernard G Anty R . 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-2012-30406623878165 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) 105:883–5.28286191 Arnott IDR Kingstone K Ghosh S. Abnormal intestinal permeability predicts relapse in inactive Crohn disease. Scand J Gastroenterol. (2000) 35:1163–9. 10.1080/00365520075005663711145287 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-H10338376 Arrieta MC Bistritz L Meddings JB. Alterations in intestinal permeability. Gut. (2006) 55:1512–20. 10.1136/gut.2005.08537316966705 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. 10.1097/00054725-199911000-0000410579119 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.x19538320 Su L Shen L Clayburgh DR Nalle SC Sullivan EA Jon B . Activation and contributes to development of experimental colitis. Gastroenterology. (2010) 136:551–63. 10.1053/j.gastro.2008.10.08119027740 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.370037316402035 Swidsinski A Ladhoff A Pernthaler A Swidsinski S Loening Baucke V Ortner M . Mucosal flora in inflammatory bowel disease. Gastroenterology. (2002) 122:44–54. 10.1053/gast.2002.3029411781279 Prasad S Mingrino R Kaukinen K Hayes KL Powell RM MacDonald TT . Inflammatory processes have differential effects on claudins 2, 3 and 4 in colonic epithelial cells. Lab Investig. (2005) 85:1139–62. 10.1038/labinvest.370031616007110 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.2010.520404811 Oshima T Laroux FS Coe LL Morise Z Kawachi S Bauer P . Interferon-γ and interleukin-10 reciprocally regulate endothelial junction integrity and barrier function. Microvasc Res. (2001) 61:130–43. 10.1006/mvre.2000.228811162203 Albert-Bayo M Paracuellos I González-Castro AM Rodríguez-Urrutia A Rodríguez-Lagunas MJ Alonso-Cotoner C . Intestinal mucosal mast cells: key modulators of barrier function and homeostasis. Cells. (2019) 8:135. 10.3390/cells802013530744042 Al-Sadi R Ye D Boivin M Guo S Hashimi M Ereifej L . Interleukin-6 modulation of intestinal epithelial tight junction permeability is mediated by JNK pathway. PLoS ONE. (2014) 9:e0085345. 10.1371/journal.pone.008534524662742 Gassler N Rohr C Schneider A Kartenbeck J Bach A Obermüller N . 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.g21611408275 Shih DQ Michelsen KS Barrett RJ Biener-Ramanujan E Gonsky R Zhang X . Insights into TL1A and IBD pathogenesis. Adv Exp Med Biol. (2011) 691:279–88. 10.1007/978-1-4419-6612-4_2921153332 Cooney R Jewell D. The genetic basis of inflammatory bowel disease. Dig Dis. (2009) 27:428–42. 10.1159/00023490919900309 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/s00535-009-0141-819802731 Mayer L. Evolving paradigms in the pathogenesis of IBD. J Gastroenterol. (2010) 45:9–16. 10.1007/s00535-009-0138-319960355 Hugot JP Chamaillard M Zouali H Lesage S Cézard JP Belaiche J . Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature. (2001) 411:599–603. 10.1038/3507910711385576 Kosovac K Brenmoehl J Holler E Falk W Schoelmerich J Hausmann M . 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.2122320232407 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_319799110 Girardin SE Boneca IG Viala J Chamaillard M Labigne A Thomas G . Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem. (2003) 278:8869–72. 10.1074/jbc.C20065120012527755 Inohara N Ogura Y Fontalba A Gutierrez O Pons F Crespo J . Host recognition of bacterial muramyl dipeptide mediated through NOD2: implications for Crohn's disease. J Biol Chem. (2003) 278:5509–12. 10.1074/jbc.C20067320012514169 Rosenstiel P Fantini M Bräutigam K Kühbacher T Waetzig GH Seegert D . 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.2003.5015712671897 Buhner S Buning C Genschel J Kling K Herrmann D Dignass A . 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.2005.06555716000642 Matsuoka K Kanai T. The gut microbiota and inflammatory bowel disease. Semin Immunopathol. (2015) 37:47–55. 10.1007/s00281-014-0454-425420450 Fukata M Arditi M. The role of pattern recognition receptors in intestinal inflammation. Mucosal Immunol. (2013) 6:451–63. 10.1038/mi.2013.1323515136 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.x17655740 Rimoldi M Chieppa M Salucci V Avogadri F Sonzogni A Sampietro GM . Intestinal immune homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells. Nat Immunol. (2005) 6:507–14. 10.1038/ni119225689446 Travis S Menzies I. Intestinal permeability: functional assessment and significance. Clin Sci. (1992) 82:471–88. 10.1042/cs08204711317756 Bjarnason I Macpherson A Hollander D. Intestinal permeability: an overview. Gastroenterology. (1995) 108:1566–81. 10.1016/0016-5085(95)90708-47729650 Wehkamp J Stange EF. Paneth's disease. J Crohn's Colitis. (2010) 4:523–31. 10.1016/j.crohns.2010.05.01021122555 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.00245.202032902315 Camilleri M. Human intestinal barrier: effects of stressors, diet, prebiotics, and probiotics. Clin Transl Gastroenterol. (2021) 12:e00308. 10.14309/ctg.000000000000030833492118 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) 22:61–76.2408172 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. 10.1177/014860710302700424112903886 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.2003.09.03215019120 Zhou QQ Verne ML Fields JZ Lefante JJ Basra S Salameh H . Randomised placebo-controlled trial of dietary glutamine supplements for postinfectious irritable bowel syndrome. Gut. (2019) 68:996–1002. 10.1136/gutjnl-2017-31513630108163 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/88.2.491s18689389 Kong J Zhang Z Musch MW Ning G Sun J Hart J . 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.00398.200717962355 Hewison M. Vitamin D and innate and adaptive immunity. Vitam Horm. (2011) 86:23–62. 10.1016/B978-0-12-386960-9.00002-221419266 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. 10.1186/1471-2172-8-517397543 Zhao H Zhang H Wu H Li H Liu L Guo J . 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-12-5722647055 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/izaa08732385487 Raftery T Martineau AR Greiller CL Ghosh S McNamara D Bennett K . 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. 10.1177/205064061557217626137304 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.2016.1727195116 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.2016.0018526925050 Barcenilla A Pryde SE Martin JC Duncan SH Stewart CS Henderson C . Phylogenetic relationships of butyrate-producing bacteria from the human gut. Appl Environ Microbiol. (2000) 66:1654–61. 10.1128/AEM.66.4.1654-1661.200010742256 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.x19807780 Vital M Howe AC Tiedje JM. Revealing the bacterial butyrate synthesis pathways by analyzing (meta)genomic data. MBio. (2014) 5:e00889. 10.1128/mBio.00889-1424757212 Kannampalli P Shaker R Sengupta JN. Colonic butyrate- algesic or analgesic? Neurogastroenterol Motil. (2011) 23:975–9. 10.1111/j.1365-2982.2011.01775.x21981302 Banasiewicz T Krokowicz Stojcev Z Kaczmarek BF Kaczmarek E Maik J . 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.x22738315