PERMEABILITY OF THE INTESTINAL EPITHELIAL BARRIER: EVALUATION CRITERIA, ROLE IN THE PATHOGENESIS OF CELIAC DISEASE
Abstract
The main structures responsible for maintaining the integrity of the intestinal barrier are tight junctions. Evidence of their role was obtained using electron microscopy and electrophysiology. A new and promising direct method for assessing the intestinal barrier function is confocal laser endomicroscopy. There is a growing interest in indirect assessment of the integrity of the mucosa using potential biomarkers. The levels of β-zonulin in stool and serum, and claudin levels in the blood are studied in various diseases. The article reflects the literature data on studies examining the possibilities of non-invasive methods for assessing the state of the epithelial barrier in the diagnosis of celiac disease and monitoring compliance with a gluten-free diet by the patient. Despite a large number of studies demonstrating increased intestinal permeability in celiac disease, the question of the place of dysfunction of the epithelial barrier of the small intestine in the pathogenesis of celiac disease remains relevant. The question of whether the barrier dysfunction is primary or a consequence of celiac disease itself has not yet been resolved.
References
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.
Buchner A.M. Confocal laser endomicroscopy in the evaluation of inflammatory Bowel disease. Inflamm Bowel Dis. 2019;25:1302–1312. DOI: 10.1093/ibd/izz021.
Chang J., Ip M., Yang M., Wong B., Power T., Lin L. et al. The learning curve, interobserver, and intraobserver agreement of endoscopic confocal laser endomicroscopy in the assessment of mucosal barrier defects. Gastrointest Endosc. 2016;83:785–791. DOI: 10.1016/j.gie.2015.08.045.
Chang J., Leong R.W., Wasinger V.C., Ip M., Yang M., Phan T.G. Impaired intestinal permeability contributes to ongoing bowel symptoms in patients with inflammatory bowel disease and mucosal healing. Gastroenterology. 2017;153:723–731. DOI: 10.1053/j.gastro.2017.05.056.
Queneherve L., David G., Bourreille A., Hardouin J.B., Rahmi G., Neunlist M. et al. Quantitative assessment of mucosal architecture using computer-based analysis of confocal laser endomicroscopy in inflammatory bowel diseases. Gastrointest Endosc. 2019;89:626–636. DOI: 10.1016/j.gie.2018.08.006.
Farre R., Vicario M. Abnormal barrier function in gastrointestinal disorders. Handb Exp Pharmacol. 2017;239:193–217. DOI: 10.1007/164.2016.107.
Хавкин А.И., Богданова Н.М., Новикова В.П., Юдина Д.В. Зонулин: физиологическое и клиническое значение в перинатальном периоде. Вопросы гинекологии, акушерства и перинатологии. 2020;19(5):132–139. DOI: 10.20953/1726-1678-2020-5-132-139.
Łoniewska B., Węgrzyn D., Adamek K., Kaczmarczyk M., Skonieczna-Żydecka K., Adler G. et al. The Influence of Maternal-Foetal Parameters on Concentrations of Zonulin and Calprotectin in the Blood and Stool of Healthy Newborns during the First Seven Days of Life. An Observational Prospective Cohort Study. J Clin Med. 2019;8(4):473. DOI: 10.3390/jcm8040473.
Хавкин А.И. Богданова Н.М., Новикова В.П. Биологическая роль зонулина и эффективность его использования в качестве биомаркера синдрома повышенной кишечной проницаемости. Российский вестник перинатологии и педиатрии. 2021;66(1):31–38. DOI: 10.21508/1027-4065-2021-66-1-31-38.
Linsalata M., Riezzo G., D’Attoma B., Clemente C., Orlando A., Russo F. Noninvasive biomarkers of gut barrier function identify two subtypes of patients suffering from diarrhoea predominant-IBS: a case-control study. BMC Gastroenterol. 2018;18(1):167. DOI: 10.1186/s12876-018-0888-6.
Wegh C.A.M., de Roos N.M., Hovenier R., Meijerink J., Besseling-van der Vaart I. et al. Intestinal Permeability Measured by Urinary Sucrose Excretion Correlates with Serum Zonulin and Faecal Calprotectin Concentrations in UC Patients in Remission. J Nutr Metab. 2019;2019:2472754. DOI: 10.1155/2019/2472754.
DaFonte T.M., Valitutti F., Kenyon V., Locascio J.J., Montuori M., Francavilla R., Passaro T., Crocco M., Norsa L., Piemontese P., Baldassarre M., Fasano A., Leonard M.M. CD-GEMM Study Group. Zonulin as a Biomarker for the Development of Celiac Disease. Pediatrics. 2024;153(1):e2023063050. DOI: 10.1542/peds.2023-063050.
Martínez Gallego M.Á., Crespo Sánchez M.G., Serrano Olmedo M.G., Buño Soto A., Álvarez Casasempere S., Nozal P., Martínez-Ojinaga E., Molina Arias M., Losantos-García I., Molero-Luis M. Trends in Faecal Zonulin Concentrations in Paediatric Patients with Celiac Disease at Baseline and on a Gluten-Free Diet: Exploring Correlations with Other Faecal Biomarkers. Nutrients. 2024;16(5):684. DOI: 10.3390/nu16050684.
Slifer Z.M., Krishnan B.R., Madan J., Blikslager A.T. Larazotide acetate: a pharmacological peptide approach to tight junction regulation. Am J Physiol Gastrointest Liver Physiol. 2021;320(6):G983–G989. DOI: 10.1152/ajpgi.00386.2020.
Paterson B.M., Lammers K.M., Arrieta M.C., Fasano A., Meddings J.B. 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;26:757–766. DOI: 10.1111/j.1365-2036.2007.03413.x.
Kivelä L., Caminero A., Leffler D.A., Pinto-Sanchez M.I., Tye-Din J.A., Lindfors K. Current and emerging therapies for coeliac disease. Nat Rev Gastroenterol Hepatol. 2021;18:181–195. DOI: 10.1038/s41575-020-00378-1.
Barrett K.E. Claudin-2 pore causes leak that breaches the dam in intestinal inflammation. J Clin Invest. 2020;130(10):5100–5101. DOI: 10.1172/JCI140528.
Garcia-Hernandez V., Quiros M., Nusrat A. Intestinal epithelial claudins: Expression and regulation in homeostasis and inflammation. Ann NY Acad Sci. 2017;1397:66–79. DOI: 10.1111/nyas.13360.
Luettig J., Rosenthal R., Barmeyer C. et al. Claudin-2 as a mediator of leaky gut barrier during intestinal inflammation. Tissue Barriers. 2015;3(1–2):e977176. DOI: 10.4161/21688370.2014.977176.
Schumann M., Gunzel D., Buergel N. et al. Cell polarity-determining proteins Par-3 and PP-1 are involved in epithelial tight junction defects in coeliac disease. Gut 2012;61(2):220–228. DOI: 10.1136/gutjnl-2011-300123.
Szakal D.N., Gyorffy H., Arato A. et al. Mucosal expression of claudins 2, 3 and 4 in proximal and distal part of duodenum in children with coeliac disease. Virchows Arch. 2010;456(3):245–250. DOI: 10.1007/s00428-009-0879-7.
Schumann M., Siegmund B., Schulzke J.D., Fromm M. Celiac Disease: Role of the Epithelial Barrier. Cell Mol. Gastroenterol. Hepatol. 2017;3:150–162. DOI: 10.1016/j.jcmgh.2016.12.006.
van Elburg R.M., Uil J.J., Mulder C.J., Heymans H.S. Intestinal permeability in patients with coeliac disease and relatives of patients with coeliac disease. Gut. 1993;34:354–357. DOI: 10.1136/gut.34.3.354.
Kumar V., Gutierrez-Achury J., Kanduri K., Almeida R., Hrdlickova B., Zhernakova D.V., Westra H.J., Karjalainen J., Ricano-Ponce I., Li Y. et al. Systematic annotation of celiac disease loci refines pathological pathways and suggests a genetic explanation for increased interferon-gamma levels. Hum Mol Genet. 2015;24:397–409. DOI: 10.1093/hmg/ddu453.
Cardoso-Silva D., Delbue D., Itzlinger A., Moerkens R., Withoff S., Branchi F., Schumann M. Intestinal Barrier Function in Gluten-Related Disorders. Nutrients. 2019;11:2325. DOI: 10.3390/nu11102325.
Matysiak-Budnik T., Moura I.C., Arcos-Fajardo M., Lebreton C., Menard S., Candalh C., Ben-Khalifa K., Dugave C., Tamouza H., van Niel G. et al. Secretory IgA mediates retrotranscytosis of intact gliadin peptides via the transferrin receptor in celiac disease. J Exp Med. 2008;205:143–154. DOI: 10.1084/jem.20071204.
Menard S., Lebreton C., Schumann M., Matysiak-Budnik T., Dugave C., Bouhnik Y., Malamut G., Cellier C., Allez M., Crenn P. et al. Paracellular versus transcellular intestinal permeability to gliadin peptides in active celiac disease. Am J Pathol. 2012;180:608–615. DOI: 10.1016/j.ajpath.2011.10.019.
Schumann M., Richter J.F., Wedell I., Moos V., Zimmermann-Kordmann M., Schneider T., Daum S., Zeitz M., Fromm M., Schulzke J.D. Mechanisms of epithelial translocation of the alpha(2)-gliadin-33mer in coeliac sprue. Gut. 2008;57:747–754. DOI: 10.1136/gut.2007.136366.
Delbue D., Cardoso-Silva D., Branchi F., Itzlinger A., Letizia M., Siegmund B., Schumann M. Celiac Disease Monocytes Induce a Barrier Defect in Intestinal Epithelial Cells. Int J Mol Sci. 2019;20(22):5597. DOI: 10.3390/ijms20225597.
