Establishing the cut-offs of leaky gut syndrome diagnostic: where are we now?

Bansil, R., Turner, B. S. (2018). The biology of mucus: Composition, synthesis and organization. Adv. Drug Deliv. Rev., 124, 3–15.10.1016/j.addr.2017.09.02328970050 Search in Google Scholar

Berg, G., Rybakova, D., Fischer, D., Cernava, T., Vergès, M. C. C., Charles, T., Chen, X., Cocolin, L., Eversole, K., et al. (2020). Microbiome definition re-visited: Old concepts and new challenges. Microbiome, 8, 103. https://doi.org/10.1186/s40168-020-00875-0.10.1186/s40168-020-00875-0732952332605663 Search in Google Scholar

Bergmann, K. R., Lie, S. X. L., Tian, R., Kushnir, A., Turner, J. R., Li, H.-L., Chou, P. M., Weber, C. R., Plaen, I. G. (2013). Bifidobacteria stabilize claudins at tight junctions and prevent intestinal barrier dysfunction in mouse necrotizing fnterocolitis. Amer. J. Pathol., 182 (5), 2013; https://dx.doi.org/10.1016/j.ajpath.2013.01.01310.1016/j.ajpath.2013.01.013364472523470164 Search in Google Scholar

Binienda, A., Twardowska, A., Makaro, A., Salkaga, M. (2020). Dietary carbohydrates and lipids in the pathogenesis of leaky gut syndrome: An overview. Int. J. Mol. Sci., 21, 8368; DOI: 10.3390/ijms21218368.10.3390/ijms21218368766463833171587 Search in Google Scholar

Bischoff, S. C., Barbara, G., Buurman, W., Ockhuizen, T., Schulzke, J. D., Serino, M., Tilg, H., Watson, A., Wells, J. M. (2014). Intestinal permeability — a new target for disease prevention and therapy. BMC Gastroenterology, 14, 189. http://www.biomedcentral.com/1471-230X/14/18910.1186/s12876-014-0189-7425399125407511 Search in Google Scholar

Blackwood, B. P., Wood, D. R., Yuan, C. Y., Nicolas, J. D., Griffiths, A., Mestan, K., Hunter, C. J. (2015). Urinary claudin-2 measurements as a predictor of necrotizing enterocolitis: A pilot study. J. Neonatal Surg., 4 (4), 43.10.47338/jns.v4.457 Search in Google Scholar

Campbell, J. A., Corrigall, A. V., Guy, A., Kirsch, R. E. (1991). Immunhistologic localisation of alpha, mu, and pi class gluthathione S-transferase in human tissues. Cancer (Phila), 61, 1608–1613.10.1002/1097-0142(19910315)67:6<1608::AID-CNCR2820670623>3.0.CO;2-S Search in Google Scholar

Cardoso-Silva, D., Delbue, D., Itzlinger, A., Moerkens, R., Withoff, S., Branchi, F., Schumann, M. (2019). Intestinal barrier function in gluten-related disorders. Nutrients, 11 (10), 2325. DOI: 10.3390/nu11102325.10.3390/nu11102325 Search in Google Scholar

Chakaroun, R. M., Massier, L. Kovacs, P. (2020). Gut microbiome, intestinal permeability, and tissue bacteria in metabolic disease: Perpetrators or bystanders? Nutrients, 12, 1082; DOI:10.3390/nu1204108210.3390/nu12041082 Search in Google Scholar

Clarke, L. L. (2009). A guide to Ussing chamber studies of mouse intestine. Amer. J. Physiol. Gastrointest. Liver Physiol., 296, G1151–G1166.10.1152/ajpgi.90649.2008 Search in Google Scholar

Crenn, P., Coudray-Lucas, C., Thuillier, F., Cynober, L., Messing, B. (2000). Postabsorptive plasma citrulline concentration is a marker of absorptive enterocyte mass and intestinal failure in humans. Gastroenterology, 119, 1496–1505.10.1053/gast.2000.2022711113071 Search in Google Scholar

Crenn, P., Vahedi, K., Lavergne-Slove, A., Cynober, L., Matuchansky, C., Messing, B. (2003). Plasma citrulline: A marker of enterocyte mass in villous atrophy-associated small bowel disease. Gastroenterology, 124, 1210–1219.10.1016/S0016-5085(03)00170-712730862 Search in Google Scholar

Dastych, M., Dastych, M. Jr., Novotna, H., Cihalova, J. (2008). Lactulose/mannitol test and specificity, sensitivity, and area under curve of intestinal permeability parameters in patients with liver cirrhosis and Crohn’s disease. Dig. Dis. Sci., 53, 2789–2792. DOI: 10.1007/s10620-007-0184-8.10.1007/s10620-007-0184-818320320 Search in Google Scholar

Davenport, E. R., Sanders, J. G., Song, S. J., Amato, K. R., Clark, A. G., Knight, R. (2017). The human microbiome in evolution. BMC Biology, 15, 127. DOI 10.1186/s12915-017-0454-7.10.1186/s12915-017-0454-7574439429282061 Search in Google Scholar

DiTommaso, N., Gasbarrini, A., Ponziani, F. R. (2021). Intestinal barrier in human health and disease. Int. J. Environ. Res. Public Health, 18,12836. https://doi.org/10.3390/ijerph182312836.10.3390/ijerph182312836865720534886561 Search in Google Scholar

Dominguez-Bello, M. G., Godoy-Vitorino, F., Knight, R., Blaser, M. J. (2019). Role of the microbiome in human development. Gut, 68, 1108–1114. DOI: 10.1136/gutjnl-2018-317503.10.1136/gutjnl-2018-317503658075530670574 Search in Google Scholar

Farshchi, M. K., Azad, F. J., Salari, R., Mirsadraee, M., Anushiravani, M. (2017). A viewpoint on the leaky gut syndrome to treat allergic asthma: A novel opinion. J. Evidence-Based Complem. Altern. Med., 22 (3) 378–380.10.1177/2156587216682169587116630208732 Search in Google Scholar

Fasano, A. (2020). All disease begins in the (leaky) gut: Role of zonulin-mediated gut permeability in the pathogenesis of some chronic inflammatory diseases [version 1; peer review: 3 approved]. F1000Research, 9 (F1000 Faculty Rev), 69. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996528/. Search in Google Scholar

Fasano, A. (2012a). Intestinal permeability and its regulation by zonulin: Diagnostic and therapeutic implications. Clin. Gastroenterol. Hepatol., 10 (10), 1096–1100. DOI: 10.1016/j.cgh.2012.08.012.10.1016/j.cgh.2012.08.012345851122902773 Search in Google Scholar

Fasano, A. (2012b). Zonulin, regulation of tight junctions, and autoimmune diseases. Ann. N. Y. Acad. Sci., 1258 (1), 25–33. DOI: 10.1111/j.1749-6632.2012.06538.x.10.1111/j.1749-6632.2012.06538.x338470322731712 Search in Google Scholar

Findley, M. K., Koval, M. (2009). Regulation and roles for claudin-family tight junction proteins. Life, 61 (4), 431–437. DOI: 10.1002/iub.175.10.1002/iub.175270811719319969 Search in Google Scholar

Furuhashi, M., Hotamisligil, G. S. (2008). Fatty acid-binding proteins: Role in metabolic diseases and potential as drug targets. Nat. Rev. Drug Discov., 7 (6), 489. DOI: 10.1038/nrd2589.10.1038/nrd2589282102718511927 Search in Google Scholar

Garcia-Hernandez, V., Quiros, M., Nusrat, A. (2017). Intestinal epithelial claudins: Expression and regulation in homeostasis and inflammation. Ann. N. Y. Acad. Sci., 2017 1397 (1), 66–79. DOI: 10.1111/nyas.13360.10.1111/nyas.13360554580128493289 Search in Google Scholar

Gearhart, S. L., Delaney, C. P., Senagore, A. J., Banbury, M. KJ., Remzi, F. H., Kiran, R. P., Fazio, V. W. (2003). Prospective assessment of the predictive value of alpha-glutathione S-transferase for intestinal ischemia. Amer. Surg., 69, 324–329.10.1177/000313480306900409 Search in Google Scholar

Gerova, V. A., Stoynov, S. G., Katsarov, D. S., Svinarov, D. A. (2011). Increased intestinal permeability in inflammatory bowel diseases assessed by iohexol test. World J. Gastroenterol., 17 (17), 2211–2215.10.3748/wjg.v17.i17.2211 Search in Google Scholar

Gerova, V. A., Svinarov, D. A., Nakov, R. V., Stoynov, S. G., Tankova, L. T., Nakov, V. N. (2020). Intestinal barrier dysfunction in liver cirrhosis assessed by iohexol test. Eur. Rev. Med. Pharm. Sci., 24, 315–322. Search in Google Scholar

Grootjans, J., Thuijls, G., Verdam, F., Derikx, J. P., Lenaerts, K., Buurman, W. A. (2010). Non-invasive assessment of barrier integrity and function of the human gut. World J. Gastrointest. Surg., 2 (3), 61–69.10.4240/wjgs.v2.i3.61299922121160852 Search in Google Scholar

Griffiths, V., Al Assaf, N., Khan, R. (2021). Review of claudin proteins as potential biomarkers for necrotizing enterocolitis. Irish J. Med. Sci., 190 (4),1465–1472. https://doi.org/10.1007/s11845-020-02490-2.10.1007/s11845-020-02490-2852151433492576 Search in Google Scholar

Halme, L., Turunen, U., Tuominen, J., Forsström, T., Turpeinen, U. (2000). Comparison of iohexol and lactulose-mannitol tests as markers of disease activity in patients with inflammatory bowel disease. Scand. J. Clin. Lab. Invest., 60, 695–702.10.1080/0036551005021642011218152 Search in Google Scholar

Hansson, G. C. (2020). Mucins and the microbiome. Annu. Rev. Biochem., 89, 769–793. DOI:10.1146/annurev-biochem-011520-105053.10.1146/annurev-biochem-011520-105053844234132243763 Search in Google Scholar

Herrmann, J. R., Turner, J. R. (2016). Beyond Ussing’s chambers: Contemporary thoughts on integration of transepithelial transport. Amer. J. Physiol. Cell Physiol., 310, C423–C431. DOI: 10.1152/ajpcell.00348.2015.10.1152/ajpcell.00348.2015479628626702131 Search in Google Scholar

Hollander, D., Kaunitz, J. D. (2020). The “Leaky gut”: Tight junctions but loose associations? Dig. Dis. Sci., 65 (5), 1277–1287. DOI: 10.1007/s10620-019-05777-2.10.1007/s10620-019-05777-2719372331471860 Search in Google Scholar

Horton, F., Wright, J., Smith, L., Hinton, P. J., Robertson, M. D. (2014). Increased intestinal permeability to oral chromium (51Cr) -EDTA in human Type 2 diabetes. Diabet. Med., 31, 559–563.10.1111/dme.1236024236770 Search in Google Scholar

Human Microbiome Project. https://hmpdacc.org/ihmp/overview/ (accessed 20.02.2022). Search in Google Scholar

Jaworska, K., Konop, M., Bielinska, K., Hutsch, T., Dziekiewicz, M., Banaszkiewicz, A., Ufnal, M. (2019). Inflammatory bowel disease is associated with increased gut-to-blood penetration of short-chain fatty acids: A new, non-invasive marker of a functional intestinal lesion. Exper. Physiol.,104, 1226–1236.10.1113/EP08777331243807 Search in Google Scholar

Johansson, M. E. V., Hansson, G. C. (2016). Immunological aspects of intestinal mucus and mucins. Nat. Rev. Immunol., 16, 639–649. DOI: 10.1038/nri.2016.88.10.1038/nri.2016.88643529727498766 Search in Google Scholar

Kessoku, T., Kobayashi, T., Tanaka, K., Yamamoto, A., Takahashi, K., Iwaki, M., Ozaki, A., Kasai, Y., Nogami, A., Honda, Y., et al. (2021). The role of leaky gut in nonalcoholic fatty liver disease: A novel therapeutic target. Int. J. Mol. Sci., 22, 8161. https://doi.org/10.3390/ijms22158161.10.3390/ijms22158161834747834360923 Search in Google Scholar

Khoshbin, K., Khanna, L., Maselli, D., Atieh, J., Breen-Lyles, M., Arndt, K., Rhoten, D., Dyer, R. B., Singh, R. J., Nayar, S., et al. (2021). Development and validation of test for “leaky gut” small intestinal and colonic permeability using sugars in healthy adults. Gastroenterology, 161 (2), 463–475.e13. DOI: 10.1053/j.gastro.2021.04.020.10.1053/j.gastro.2021.04.020832888533865841 Search in Google Scholar

Khurana, S., Corbally, M. T., Manning, F., Armenise, T., Kierce, B., Kilty, C. (2002). Glutathione S-transferase: A potential new marker of intestinal ischemia. J. Pediatr. Surg., 37 (11), 1543–1548.10.1053/jpsu.2002.3618112407536 Search in Google Scholar

Kinashi, Y., Hase, K (2021). Partners in leaky gut syndrome: Intestinal dysbiosis and autoimmunity. Front. Immunol., 12, 673708. DOI: 10.3389/fimmu.2021.673708.10.3389/fimmu.2021.673708810030633968085 Search in Google Scholar

Knezevic, J., Starchl, C., Berisha, A. T., Amrein, K. (2020). Thyroid-gut-axis: How does the microbiota influence thyroid function? Nutrient, 12, 1769. DOI: 10.3390/nu12061769.10.3390/nu12061769735320332545596 Search in Google Scholar

Krug, S. M., Schulzke, J. D., Fromm, M. (2014). Tight junction, selective permeability, and related diseases. Semin. Cell Dev. Biol., 36, 166–176.10.1016/j.semcdb.2014.09.00225220018 Search in Google Scholar

Larsen, R., Mertz-Nielsen, A., Hansen, M. B., Poulsen S. S., Bindslev, N. (2001). Novel modified Ussing chamber for the study of absorption and secretion in human endoscopic biopsies. Acta Physiol. Scand., 173 (2), 213–222.10.1046/j.1365-201X.2001.00865.x11683679 Search in Google Scholar

Loret, S., Nollevaux, G., Remacle, R., Klimek, M., Barakat, I., Deloyer, P., Grandfilks, C., Dandrifosse, G. (2004). Analysis of PEG 400 and 4000 in urine for gut permeability assessment using solid phase extraction and gel permeation chromatography with refractometric detection. J. Chromatogr., 805 (2), 195–202.10.1016/j.jchromb.2004.02.03315135090 Search in Google Scholar

Lutgens, L. C., Blijlevens, N. M., Deutz, N. E., Donnely, J. P., Lambin, P., de Pauw, B. E. (2005). Monitoring myeloablative therapy-induced small bowel toxicity by serum citrulline concentration: A comparison with sugar permeability tests. Cancer, 103,191–199.10.1002/cncr.2073315573372 Search in Google Scholar

March, D. S. (2017). Intestinal fatty acid-binding protein and gut permeability responses to exercise. Eur. J. Appl. Physiol., 117, 931–941. DOI: 10.1007/s00421-017-3582-4.10.1007/s00421-017-3582-4538872028290057 Search in Google Scholar

Marchesi, J. R., Ravel, J. (2015). The vocabulary of microbiome research: A proposal. Microbiome, 3, 31.10.1186/s40168-015-0094-5452006126229597 Search in Google Scholar

Michielan, A., D’Incà, R. (2015). Intestinal permeability in inflammatory bowel disease: Pathogenesis, clinical evaluation, and therapy of leaky gut. Hindawi Publ. Corp. Med. Inflamm., 2015, 628157. http://dx.doi.org/10.1155/2015/628157.10.1155/2015/628157463710426582965 Search in Google Scholar

Mohajeri, M. H., Brummer, R. J., Rastall, R. A., Weersma, R. K., Harmsen, H. J. M., Faas, M., Eggersdorfer, M. (2018). The role of the microbiome for human health: From basic science to clinical applications. Eur. J. Nut., 57 (Suppl 1), S1–S14. https://doi.org/10.1007/00394-018-1703-4. Search in Google Scholar

Oami, T., Coopersmith, C. M. (2021). Measurement of intestinal permeability during sepsis. Methods Mol. Biol., 2321, 169–175. DOI: 10.1007/978-1-0716-1488-4_15.10.1007/978-1-0716-1488-4_15830174334048016 Search in Google Scholar

Obrenovich, M. E. M. (2018). Leaky gut, leaky brain? Microorganisms, 6, 107. DOI: 10.3390/microorganisms6040107.10.3390/microorganisms6040107631344530340384 Search in Google Scholar

Paone, P., Cani, P. D. (2020). Mucus barrier, mucins and gut microbiota: The expected slimy partners? Gut, 69, 2232–2243. DOI: 10.1136/gutjnl-2020-322260.10.1136/gutjnl-2020-322260767748732917747 Search in Google Scholar

Paray, B. A., Albeshr, M. F., Jan, A. T., Rather, I. A. (2020). Leaky gut and autoimmunity: An intricate balance in individuals health and the diseased state. Int. J. Mol. Sci., 21, 9770. DOI: 10.3390/ijms21249770.10.3390/ijms21249770776745333371435 Search in Google Scholar

Pelaseyed, T., Hansson, G. C. (2020). Membrane mucins of the intestine at a glance. J. Cell Sci., 133, jcs240929. DOI: 10.1242/jcs.240929.10.1242/jcs.240929707504832169835 Search in Google Scholar

Peled, Y., Watz, C., Gilat, T. (1985). Measurement of intestinal permeability using 51Cr-EDTA. Amer. J. Gastroenterol., 80, 770–773. Search in Google Scholar

Pietrzak, B., Tomela, K., Olejnik-Schmidt, A., Mackiewicz, A., Schmidt, M. (2020). Secretory IgA in intestinal mucosal secretions as an adaptive barrier against microbial cells. Int. J. Mol. Sci., 21, 9254. DOI: 10.3390/ijms21239254.10.3390/ijms21239254773143133291586 Search in Google Scholar

Portincasa, P., Bonfrate, L., Khalil, M., de Angelis, M., Calabrese, F. M., D’Amato, M., Wang, D. Q. H., Di Ciaula, A. (2022). Intestinal barrier and permeability in health, obesity and NAFLD. Biomedicines, 10, 83. https://doi.org/10.3390/biomedicines10010083.10.3390/biomedicines10010083877301035052763 Search in Google Scholar

Schoultz, I., Keita, A. V. (2020). The intestinal barrier and current techniques for the assessment of gut permeability. Cells, 9, 1909. DOI: 10.3390/cells9081909.10.3390/cells9081909746371732824536 Search in Google Scholar

Schurink, M., Kooi, E. M. W., Hulzebos, C. V., Kox, R. G., Groen, H., Heineman, E., Bos, A. F., Hulscher, J. B. F. (2015). Intestinal fatty acid-binding protein as a diagnostic marker for complicated and uncomplicated necrotizing enterocolitis: A prospective cohort study. PLoS ONE, 10 (3), e0121336. DOI: 10.1371/journal.pone.0121336.10.1371/journal.pone.0121336436810025793701 Search in Google Scholar

Sequeira, I. R., Lentle, R. G., Kruger, M. C., Hurst, R. D. (2014). Standardising the lactulose mannitol test of gut permeability to minimise error and promote comparability. PLoS ONE, 9 (6), e99256. DOI: 10.1371/journal.pone.0099256.10.1371/journal.pone.0099256404711024901524 Search in Google Scholar

Shulman, R. J., Jarett, M. EW., Cain, K. C., Broussard, E. K., Heitkemper, M. M. (2014). Associations among gut permeability, inflammatory markers and symptoms in patients with irritable bowel syndrome. J. Gastroenterol., 49 (11), 1467–1476. DOI: 10.1007/s00535-013-0919-6.10.1007/s00535-013-0919-6410267424435814 Search in Google Scholar

Sicard, J.-F., Le Bihan, G., Vogeleer, P., Jacques, M., Harel, J. (2017). Interactions of intestinal bacteria with components of the intestinal mucus. Front. Cell. Infect. Microbiol., 7, 387. DOI: 10.3389/fcimb.2017.00387.10.3389/fcimb.2017.00387559195228929087 Search in Google Scholar

Smith, P. L. (1996). Methods for evaluating intestinal permeability and metabolism in vitro. Pharm. Biotechnol., 8, 13–34.10.1007/978-1-4899-1863-5_28791802 Search in Google Scholar

Sturgeon, C., Fasano, A. (2016). Zonulin, a regulator of epithelial and endothelial barrier functions, and its involvement in chronic inflammatory diseases. Tissue Barriers, 4 (4), e1251384. http://dx.doi.org/10.1080/21688370.2016.125138410.1080/21688370.2016.1251384521434728123927 Search in Google Scholar

Sugimoto, M. (1995). Glutathione S-transferases (GSTs). Nihon Rinsho, 53 (5), 1253–1259. 7602788. Search in Google Scholar

Suzuki, T. (2020). Regulation of the intestinal barrier by nutrients: The role of tight junctions. Anim. Sci. J., 91, e13357. https://doi.org/10.1111/asj.13357.10.1111/asj.13357718724032219956 Search in Google Scholar

Takiishi, T., Fenero, C. I. M., Câmara, N. O. S. (2017). Intestinal barrier and gut microbiota: Shaping our immune responses throughout life. Tissue Barriers, 5 (4), e1373208. https://doi.org/10.1080/21688370.2017.1373208.10.1080/21688370.2017.1373208578842528956703 Search in Google Scholar

Thomson, A., Smart, K., Somerville, M. S., Lauder, S. N., Appanna, G., Horwood, J., Raj, L. S., Sristava, B., Durai, D., Scurr, M. J., et al. (2019). The Ussing chamber system for measuring intestinal permeability in health and disease. BMC Gastroenterol., 19, 98.10.1186/s12876-019-1002-4658511131221083 Search in Google Scholar

Thuijls, G., Derikx, J. P., de Haan, J. J., Grootajans, J., de Bruïne, A., Masclee, A. A. M., Heineman, E., Buurman, W. A. (2009). Urine-based detection of intestinal tight junction loss. J. Clin. Gastroenterol., 44 (1), e14–e19. DOI: 10.1097/MCG.0b013e31819f5652.10.1097/MCG.0b013e31819f565219525861 Search in Google Scholar

Turpin, W., Lee, S. H., Raygoza Garay, J. A., Madsen, K. L., Meddings, J. B., Bedrani, L., Power, N., Espin-Garcia, O., Xu, W., Smith, M. I., et al. (2020). Increased intestinal permeability is associated with later development of Crohn’s disease. Gastroenterology, 159, 2092–2100.e2095.10.1053/j.gastro.2020.08.00532791132 Search in Google Scholar

Vancamelbeke, M., Vermeire, S. (2017). The intestinal barrier: A fundamental role in health and disease. Expert Rev. Gastroenterol. Hepatol., 11 (9), 821–834. DOI: 10.1080/17474124.2017.1343143.10.1080/17474124.2017.1343143610480428650209 Search in Google Scholar

Vuong, C. N., Mukllenix, G. J., Kidd, M. T., Bottje, W. G., Hargis, B. M., Tellez-Isaias, G. (2021). Research note: Modified serum fluorescein isothiocyanate dextran (FITC-d) assay procedure to determine intestinal permeability in poultry fed diets high in natural or synthetic pigments. Poultry Sci., 100, 101138.10.1016/j.psj.2021.101138813173733975047 Search in Google Scholar

Watson, C. J., Rowland, M., Warhurst, G. (2001). Functional modeling of tight junctions in intestinal cell monolayers using polyethylene glycol oligomers. Amer. J. Physiol. Cell Physiol., 281, C388–C397.10.1152/ajpcell.2001.281.2.C38811443038 Search in Google Scholar

Woting, A., Blaut, M. (2018). Small intestinal permeability and gut-transit time determined with low and high molecular weight fluorescein isothiocyanate-dextrans in C3H mice. Nutrients, 10, 685. DOI: 10.3390w/nu10060685. Search in Google Scholar

Wuyts, B., Riwthorst, D., Brouwers, J., Tack, J., Annaert, P., Augustijns, P. (2015). Evaluation of fasted and fed state simulated and human intestinal fluids as solvent system in the Ussing chambers model to explore food effects on intestinal permeability. Int. J. Pharmaceut., 478, 736–744.10.1016/j.ijpharm.2014.12.02125510602 Search in Google Scholar

Zheng, D. Liao, H., Chen, S., Liu, X., Mao, C., Zhang, C., Meng, M., Wang, Zhi, Wang, Y., Jianget, Q., et al. (2021). Elevated levels of circulating biomarkers related to leaky gut syndrome and bacterial translocation are associated with Graves’ disease. Front. Endocrinol., 12, 796212. DOI: 10.3389/fendo.2021.796212.10.3389/fendo.2021.796212871683134975767 Search in Google Scholar