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Review

A spotlight on intestinal permeability and inflammatory bowel diseases

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Pages 893-902 | Received 08 Mar 2023, Accepted 27 Jul 2023, Published online: 22 Aug 2023

References

  • Hollander D, Vadheim CM, Brettholz E, et al. Increased intestinal permeability in patients with Crohn’s disease and their relatives. A possible etiologic factor. Ann Intern Med. 1986 Dec;105(6):883–885.
  • Camilleri M. Leaky gut: mechanisms, measurement and clinical implications in humans. Gut. 2019 Aug;68(8):1516–1526. doi: 10.1136/gutjnl-2019-318427
  • Turner JR. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol. 2009 Nov;9(11):799–809. doi: 10.1038/nri2653
  • Suriano F, Nystrom EEL, Sergi D, et al. Diet, microbiota, and the mucus layer: The guardians of our health. Front Immunol. 2022;13:953196. doi: 10.3389/fimmu.2022.953196
  • Allam-Ndoul B, Castonguay-Paradis S, Veilleux A. Gut microbiota and intestinal trans-epithelial permeability. Int J Mol Sci. 2020 Sep 3;21(17):6402.
  • Quigley EM. Leaky gut - concept or clinical entity? Curr Opin Gastroenterol. 2016 Mar;32(2):74–79. doi: 10.1097/MOG.0000000000000243
  • Pelaseyed T, Bergstrom JH, Gustafsson JK, 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 Jul;260(1):8–20.
  • Theodossi A, Spiegelhalter DJ, Jass J, et al. Observer variation and discriminatory value of biopsy features in inflammatory bowel disease. Gut. 1994 Jul;35(7):961–968.
  • Tytgat KM, van der Wal JW, Einerhand AW, et al. Quantitative analysis of MUC2 synthesis in ulcerative colitis. Biochem Biophys Res Commun. 1996 Jul 16;224(2):397–405.
  • Van Klinken BJ, der Wal JW V, Einerhand AW, et al. Sulphation and secretion of the predominant secretory human colonic mucin MUC2 in ulcerative colitis. Gut. 1999 Mar;44(3):387–393.
  • der Sluis M V, De Koning BA, De Bruijn AC, et al. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology. 2006 Jul;131(1):117–129.
  • Wehkamp J, Stange EF. An update review on the paneth cell as key to Ileal Crohn’s disease. Front Immunol. 2020;11:646. doi: 10.3389/fimmu.2020.00646
  • Gehart H, Clevers H. Tales from the crypt: new insights into intestinal stem cells. Nat Rev Gastroenterol Hepatol. 2019 Jan;16(1):19–34. doi: 10.1038/s41575-018-0081-y
  • Peterson LW, Artis D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol. 2014 Mar;14(3):141–153. doi: 10.1038/nri3608
  • Groschwitz KR, Hogan SP. Intestinal barrier function: molecular regulation and disease pathogenesis. J Allergy Clin Immunol. 2009 Jul;124(1):3-20; quiz 21–2. doi: 10.1016/j.jaci.2009.05.038
  • Usuda H, Okamoto T, Wada K. Leaky gut: effect of dietary fiber and fats on microbiome and intestinal barrier. Int J Mol Sci. 2021 Jul 16;22(14):7613.
  • Vancamelbeke M, Vermeire S. The intestinal barrier: a fundamental role in health and disease. Expert Rev Gastroenterol Hepatol. 2017 Sep;11(9):821–834. doi: 10.1080/17474124.2017.1343143
  • Horowitz A, Chanez-Paredes SD, Haest X, et al. Paracellular permeability and tight junction regulation in gut health and disease. Nat Rev Gastroenterol Hepatol. 2023 Apr 25;20(7):1–16.
  • Meng W, Takeichi M. Adherens junction: molecular architecture and regulation. Cold Spring Harb Perspect Biol. 2009 Dec;1(6):a002899. doi: 10.1101/cshperspect.a002899
  • Rubsam M, Broussard JA, Wickstrom SA, et al. Adherens junctions and desmosomes coordinate mechanics and signaling to orchestrate tissue morphogenesis and function: an evolutionary perspective. Cold Spring Harb Perspect Biol. 2018 Nov 1;10(11):a029207.
  • Harris TJ, Tepass U. Adherens junctions: from molecules to morphogenesis. Nat Rev Mol Cell Biol. 2010 Jul;11(7):502–514. doi: 10.1038/nrm2927
  • Gagnoux-Palacios L, Awina H, Audebert S, et al. Cell polarity and adherens junction formation inhibit epithelial Fas cell death receptor signaling. J Cell Bio. 2018 Nov 5;217(11):3839–3852.
  • Schlegel N, Boerner K, Waschke J. Targeting desmosomal adhesion and signalling for intestinal barrier stabilization in inflammatory bowel diseases-Lessons from experimental models and patients. Acta Physiol (Oxf). 2021 Jan;231(1):e13492. doi: 10.1111/apha.13492
  • Sender R, Fuchs S, Milo R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol. 2016 Aug;14(8):e1002533. doi: 10.1371/journal.pbio.1002533
  • Arumugam M, Raes J, Pelletier E, et al. Enterotypes of the human gut microbiome. Nature. 2011 May 12;473(7346):174–180.
  • Vieira-Silva S, Falony G, Darzi Y, et al. Species-function relationships shape ecological properties of the human gut microbiome. Nat Microbiol. 2016 Jun 13;1(8):16088.
  • Qin J, Li R, Raes J, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010 Mar 4;464(7285):59–65.
  • Wilson AS, Koller KR, Ramaboli MC, et al. Diet and the human gut microbiome: an international review. Dig Dis Sci. 2020 Mar;65(3):723–740.
  • Macpherson AJ, Harris NL. Interactions between commensal intestinal bacteria and the immune system. Nat Rev Immunol. 2004 Jun;4(6):478–485. doi: 10.1038/nri1373
  • Mazmanian SK, Liu CH, Tzianabos AO, et al. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell. 2005 Jul 15;122(1):107–118.
  • Ussing HH, Zerahn K. Active transport of sodium as the source of electric current in the short-circuited isolated frog skin. Acta Physiol Scand. 1951 Aug 25;23(2–3):110–127.
  • Vanuytsel T, Tack J, Farre R. The role of intestinal permeability in gastrointestinal disorders and current methods of evaluation. Front Nutr. 2021;8:717925. doi: 10.3389/fnut.2021.717925
  • Keita AV, Salim SY, Jiang T, et al. Increased uptake of non-pathogenic E. coli via the follicle-associated epithelium in longstanding ileal Crohn’s disease. J Pathol. 2008 Jun;215(2):135–144.
  • Keita AV, Gullberg E, Ericson AC, et al. Characterization of antigen and bacterial transport in the follicle-associated epithelium of human ileum. Lab Invest. 2006 May;86(5):504–516.
  • Ebrahim AS, Ebrahim T, Kani H, et al. Functional optimization of electric cell-substrate impedance sensing (ECIS) using human corneal epithelial cells. Sci Rep. 2022 Aug 19;12(1):14126.
  • Kauffman AL, Gyurdieva AV, Mabus JR, et al. Alternative functional in vitro models of human intestinal epithelia. Front Pharmacol. 2013;4:79. doi: 10.3389/fphar.2013.00079
  • Boerner K, Luissint AC, Parkos CA. Functional assessment of intestinal permeability and neutrophil transepithelial migration in mice using a standardized intestinal loop model. J Vis Exp. 2021 Feb;11(168). doi: 10.3791/62093-v.
  • Wang L, Llorente C, Hartmann P, et al. Methods to determine intestinal permeability and bacterial translocation during liver disease. J Immunol Methods. 2015 Jun;421:44–53.
  • Banaszak L, Winter N, Xu Z, et al. Lipid-binding proteins: a family of fatty acid and retinoid transport proteins. Adv Protein Chem. 1994;45:89–151.
  • Flower DR. The lipocalin protein family: structure and function. Biochem J. 1996 Aug 15;318(1):1–14. (Pt 1)(Pt 1). doi: 10.1042/bj3180001
  • Pelsers MM, Hermens WT, Glatz JF. Fatty acid-binding proteins as plasma markers of tissue injury. Clin Chim Acta. 2005 Feb;352(1–2):15–35. doi: 10.1016/j.cccn.2004.09.001
  • Pelsers MM, Namiot Z, Kisielewski W, et al. Intestinal-type and liver-type fatty acid-binding protein in the intestine. Tissue distribution and clinical utility. Clin Biochem. 2003 Oct;36(7):529–535.
  • Wells JM, Brummer RJ, Derrien M, et al. Homeostasis of the gut barrier and potential biomarkers. Am J Physiol Gastrointest Liver Physiol. 2017 Mar 1;312(3):G171–G193.
  • Edelson MB, Sonnino RE, Bagwell CE, et al. Plasma intestinal fatty acid binding protein in neonates with necrotizing enterocolitis: a pilot study. J Pediatr Surg. 1999 Oct;34(10):1453–1457.
  • Heida FH, Hulscher JB, Schurink M, et al. Intestinal fatty acid-binding protein levels in Necrotizing Enterocolitis correlate with extent of necrotic bowel: results from a multicenter study. J Pediatr Surg. 2015 Jul;50(7):1115–1118.
  • Benoit R, Rowe S, Watkins SC, et al. Pure endotoxin does not pass across the intestinal epithelium in vitro. Shock. 1998 Jul;10(1):43–48.
  • Ge Y, Ezzell RM, Warren HS. Localization of endotoxin in the rat intestinal epithelium. J Infect Dis. 2000 Sep;182(3):873–881. doi: 10.1086/315784
  • Andreasen AS, Krabbe KS, Krogh-Madsen R, et al. Human endotoxemia as a model of systemic inflammation. Curr Med Chem. 2008;15(17):1697–1705. doi: 10.2174/092986708784872393
  • Hurley JC. Endotoxemia: methods of detection and clinical correlates. Clin Microbiol Rev. 1995 Apr;8(2):268–292. doi: 10.1128/CMR.8.2.268
  • Sharma R, Tepas JJ 3rd, Hudak ML, et al. Neonatal gut barrier and multiple organ failure: role of endotoxin and proinflammatory cytokines in sepsis and necrotizing enterocolitis. J Pediatr Surg. 2007 Mar;42(3):454–461.
  • Wellmann W, Fink PC, Benner F, et al. Endotoxaemia in active Crohn’s disease. Treatment with whole gut irrigation and 5-aminosalicylic acid. Gut. 1986 Jul;27(7):814–820.
  • Marshall JC, Walker PM, Foster DM, et al. Measurement of endotoxin activity in critically ill patients using whole blood neutrophil dependent chemiluminescence. Crit Care. 2002 Aug;6(4):342–348.
  • Schumann RR, Leong SR, Flaggs GW, et al. Structure and function of lipopolysaccharide binding protein. Science. 1990 Sep 21;249(4975):1429–1431.
  • Seethaler B, Basrai M, Neyrinck AM, et al. Biomarkers for assessment of intestinal permeability in clinical practice. Am J Physiol Gastrointest Liver Physiol. 2021 Jul 1;321(1):G11–G17.
  • Tsukita S, Tanaka H, Tamura A. The claudins: from tight junctions to biological systems. Trends Biochem Sci. 2019 Feb;44(2):141–152. doi: 10.1016/j.tibs.2018.09.008
  • Oshima T, Miwa H, Joh T. Changes in the expression of claudins in active ulcerative colitis. Journal Of Gastroenterology And Hepatology. 2008 Dec;23(Suppl 2):S146–50. doi: 10.1111/j.1440-1746.2008.05405.x
  • Prasad S, Mingrino R, Kaukinen K, et al. Inflammatory processes have differential effects on claudins 2, 3 and 4 in colonic epithelial cells. Lab Invest. 2005 Sep;85(9):1139–1162.
  • Zeissig S, Burgel N, Gunzel D, 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 Jan;56(1):61–72.
  • Venugopal S, Anwer S, Szaszi K. Claudin-2: roles beyond permeability functions. Int J Mol Sci. 2019 Nov 12;20(22):5655.
  • Ahmad R, Chaturvedi R, Olivares-Villagomez D, et al. Targeted colonic claudin-2 expression renders resistance to epithelial injury, induces immune suppression, and protects from colitis. Mucosal Immunol. 2014 Nov;7(6):1340–1353.
  • Raju P, Shashikanth N, Tsai PY, et al. Inactivation of paracellular cation-selective claudin-2 channels attenuates immune-mediated experimental colitis in mice. J Clin Invest. 2020 Oct 1;130(10):5197–5208.
  • Thuijls G, Derikx JP, de Haan JJ, et al. Urine-based detection of intestinal tight junction loss. J Clin Gastroenterol. 2010 Jan;44(1):e14–9.
  • Wang W, Uzzau S, Goldblum SE, et al. Human zonulin, a potential modulator of intestinal tight junctions. J Cell Sci. 2000 Dec;113(Pt 24):4435–4440.
  • Clemente MG, De Virgiliis S, Kang JS, et al. Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function. Gut. 2003 Feb;52(2):218–223.
  • Tripathi A, Lammers KM, Goldblum S, et al. Identification of human zonulin, a physiological modulator of tight junctions, as prehaptoglobin-2. Proc Natl Acad Sci U S A. 2009 Sep 29;106(39):16799–16804.
  • Massier L, Chakaroun R, Kovacs P, et al. Blurring the picture in leaky gut research: how shortcomings of zonulin as a biomarker mislead the field of intestinal permeability. Gut. 2021 Sep;70(9):1801–1802.
  • Caviglia GP, Dughera F, Ribaldone DG, et al. Serum zonulin in patients with inflammatory bowel disease: a pilot study. Minerva Med. 2019 Apr;110(2):95–100.
  • Szymanska E, Wierzbicka A, Dadalski M, et al. Fecal zonulin as a noninvasive biomarker of intestinal permeability in pediatric patients with inflammatory bowel diseases—correlation with disease activity and fecal calprotectin. JCM. 2021 Aug 30;10(17):3905.
  • Ajamian M, Steer D, Rosella G, et al. Serum zonulin as a marker of intestinal mucosal barrier function: may not be what it seems. Plos One. 2019;14(1):e0210728. doi: 10.1371/journal.pone.0210728
  • Scheffler L, Crane A, Heyne H, et al. Widely used commercial ELISA does not detect precursor of haptoglobin2, but recognizes properdin as a potential second member of the zonulin family. Front Endocrinol. 2018;9:22. doi: 10.3389/fendo.2018.00022
  • Leibovitzh H, Lee SH, Raygoza Garay JA, et al. Immune response and barrier dysfunction-related proteomic signatures in preclinical phase of Crohn’s disease highlight earliest events of pathogenesis. Gut. 2023 Feb 14;72(8):1462–1471.
  • Al-Sadi R, Khatib K, Guo S, et al. Occludin regulates macromolecule flux across the intestinal epithelial tight junction barrier. Am J Physiol Gastrointest Liver Physiol. 2011 Jun;300(6):G1054–64.
  • Grootjans J, Thuijls G, Verdam F, et al. Non-invasive assessment of barrier integrity and function of the human gut. World J Gastrointest Surg. 2010 Mar 27;2(3):61–69.
  • Odenwald MA, Turner JR. Intestinal permeability defects: is it time to treat? Clin Gastroenterol Hepatol. 2013 Sep;11(9):1075–1083. doi: 10.1016/j.cgh.2013.07.001
  • Meddings JB, Gibbons I. Discrimination of site-specific alterations in gastrointestinal permeability in the rat. Gastroenterology. 1998 Jan;114(1):83–92. doi: 10.1016/S0016-5085(98)70636-5
  • Bjarnason I, MacPherson A, Hollander D. Intestinal permeability: an overview. Gastroenterology. 1995 May;108(5):1566–1581. doi: 10.1016/0016-5085(95)90708-4
  • Kiesslich R, Burg J, Vieth M, et al. Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo. Gastroenterology. 2004 Sep;127(3):706–713.
  • Rath T, Tontini GE, Neurath MF, et al. From the surface to the single cell: Novel endoscopic approaches in inflammatory bowel disease. World J Gastroenterol. 2015 Oct 28;21(40):11260–11272.
  • Waldner MJ, Rath T, Schurmann S, et al. Imaging of mucosal inflammation: current technological developments, clinical implications, and future perspectives. Front Immunol. 2017;8:1256. doi: 10.3389/fimmu.2017.01256
  • Chang J, Leong RW, Wasinger VC, et al. Impaired intestinal permeability contributes to ongoing bowel symptoms in patients with inflammatory bowel disease and mucosal healing. Gastroenterology. 2017 Sep;153(3):723–731 e1.
  • Fritscher-Ravens A, Pflaum T, Mosinger M, et al. Many patients with irritable bowel syndrome have atypical food allergies not associated with immunoglobulin E. Gastroenterology. 2019 Jul;157(1):109–118 e5.
  • Fritscher-Ravens A, Schuppan D, Ellrichmann M, et al. Confocal endomicroscopy shows food-associated changes in the intestinal mucosa of patients with irritable bowel syndrome. Gastroenterology. 2014 Nov;147(5):1012–20 e4.
  • Karstensen JG, Saftoiu A, Brynskov J, et al. Confocal laser endomicroscopy: a novel method for prediction of relapse in Crohn’s disease. Endoscopy. 2016 Apr;48(4):364–372.
  • Kiesslich R, Duckworth CA, Moussata D, et al. Local barrier dysfunction identified by confocal laser endomicroscopy predicts relapse in inflammatory bowel disease. Gut. 2012 Aug;61(8):1146–1153.
  • Kiesslich R, Goetz M, Angus EM, et al. Identification of epithelial gaps in human small and large intestine by confocal endomicroscopy. Gastroenterology. 2007 Dec;133(6):1769–1778.
  • Lim LG, Neumann J, Hansen T, et al. Confocal endomicroscopy identifies loss of local barrier function in the duodenum of patients with Crohn’s disease and ulcerative colitis. Inflamm Bowel Dis. 2014;20(5):892–900. doi: 10.1097/MIB.0000000000000027
  • Rath T, Dieterich W, Katscher-Murad C, et al. Cross-sectional imaging of intestinal barrier dysfunction by confocal laser endomicroscopy can identify patients with food allergy in vivo with high sensitivity. Sci Rep. 2021 Jun 17;11(1):12777.
  • Andre F, Andre C, Emery Y, et al. Assessment of the lactulose-mannitol test in Crohn’s disease. Gut. 1988 Apr;29(4):511–515.
  • Wyatt J, Vogelsang H, Hubl W, et al. Intestinal permeability and the prediction of relapse in Crohn’s disease. Lancet. 1993 Jun 5;341(8858):1437–1439.
  • Turpin W, Lee SH, Raygoza Garay JA, et al. Increased intestinal permeability is associated with later development of Crohn’s disease. Gastroenterology. 2020 Dec;159(6):2092–2100 e5.
  • Kuhn R, Lohler J, Rennick D, et al. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993 Oct 22;75(2):263–274.
  • Madsen K, Cornish A, Soper P, et al. Probiotic bacteria enhance murine and human intestinal epithelial barrier function. Gastroenterology. 2001 Sep;121(3):580–591.
  • Schmitz H, Barmeyer C, Fromm M, et al. Altered tight junction structure contributes to the impaired epithelial barrier function in ulcerative colitis. Gastroenterology. 1999 Feb;116(2):301–309.
  • Gitter AH, Wullstein F, Fromm M, et al. Epithelial barrier defects in ulcerative colitis: characterization and quantification by electrophysiological imaging. Gastroenterology. 2001 Dec;121(6):1320–1328.
  • Katinios G, Casado-Bedmar M, Walter SA, et al. Increased colonic epithelial permeability and mucosal eosinophilia in ulcerative colitis in remission compared with irritable bowel syndrome and health. Inflamm Bowel Dis. 2020 Jun 18;26(7):974–984.
  • Marin ML, Geller SA, Greenstein AJ, et al. Ultrastructural pathology of Crohn’s disease: correlated transmission electron microscopy, scanning electron microscopy, and freeze fracture studies. Am J Gastroenterol. 1983 Jun;78(6):355–364.
  • Marin ML, Greenstein AJ, Geller SA, et al. A freeze fracture study of Crohn’s disease of the terminal ileum: changes in epithelial tight junction organization. Am J Gastroenterol. 1983 Sep;78(9):537–547.
  • Kucharzik T, Walsh SV, Chen J, et al. Neutrophil transmigration in inflammatory bowel disease is associated with differential expression of epithelial intercellular junction proteins. Am J Pathol. 2001 Dec;159(6):2001–2009.
  • Keita AV, Soderholm JD. Barrier dysfunction and bacterial uptake in the follicle-associated epithelium of ileal Crohn’s disease. Annals Of The New York Academy Of Sciences. 2012 Jul;1258(1):125–134. doi: 10.1111/j.1749-6632.2012.06502.x
  • Soderholm JD, Peterson KH, Olaison G, et al. Epithelial permeability to proteins in the noninflamed ileum of Crohn’s disease? Gastroenterology. 1999 Jul;117(1):65–72.
  • Soderholm JD, Streutker C, Yang PC, et al. Increased epithelial uptake of protein antigens in the ileum of Crohn’s disease mediated by tumour necrosis factor alpha. Gut. 2004 Dec;53(12):1817–1824.
  • Pastor Rojo O, Lopez San Roman A, Albeniz Arbizu E, et al. Serum lipopolysaccharide-binding protein in endotoxemic patients with inflammatory bowel disease. Inflamm Bowel Dis. 2007 Mar;13(3):269–277.
  • Rath T, Atreya R, Bodenschatz J, et al. Intestinal barrier healing is superior to endoscopic and histologic remission for predicting major adverse outcomes in inflammatory bowel disease: the prospective ERIca trial. Gastroenterology. 2023 Feb;164(2):241–255.

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