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Intestinal Permeability and Its Regulation by Zonulin: Diagnostic and Therapeutic Implications
Open accessAbstract
One of the most important and overlooked functions of the gastrointestinal tract is to provide a dynamic barrier to tightly controlled antigen trafficking through both the transcellular and paracellular pathways. Intercellular tight junctions (TJ) are the key structures regulating paracellular trafficking of macromolecules. Although steady progress has been made in understanding TJ ultrastructure, relatively little is known about their pathophysiological regulation. Our discovery of zonulin, the only known physiological modulator of intercellular TJ described so far, increased understanding of the intricate mechanisms that regulate gut permeability and led us to appreciate that its up-regulation in genetically susceptible individuals may lead to immune-mediated diseases. This information has translational implications, because the zonulin pathway is currently exploited to develop both diagnostic and therapeutic applications pertinent to a variety of immune-mediated diseases.
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“Zonulin, the only physiological modulator of tight junctions described to date, was discovered as the precursor of haptoglobin-2 (pre-Hp2) [266] and is essential for the regulation of intestinal permeability [267,268,269] (Figure 3).”
From Gut-pancreas-liver Axis as a target for treatment of NAFLD/NASH (2020) · cites this paper as [266]
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“Zonulin, the only physiological modulator of tight junctions described to date, was discovered as the precursor of haptoglobin-2 (pre-Hp2) [266] and is essential for the regulation of intestinal permeability [267,268,269] (Figure 3).”
From Gut-pancreas-liver Axis as a target for treatment of NAFLD/NASH (2020) · cites this paper as [266]
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Fasano, A. (2011) · Physiological Reviews · doi:10.1152/physrev.00003.2008 · Cited by 1,063
Self-citationSapone, A., de Magistris, L., Pietzak, M. M., Clemente, M. G., Tripathi, A. K., Cucca, F., Lampis, R., Kryszak, D., Cartenı̀, M., Generoso, M., et al. (2006) · Diabetes · doi:10.2337/db05-1593 · Cited by 550
Self-citationLammers, K. M., Lu, R., Brownley, J., Lu, B., Gerard, C. J., Thomas, K., Rallabhandi, P., Shea‐Donohue, T., Tamiz, A. P., Alkan, Ş. Ş., et al. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.03.023 · Cited by 545
Self-citationFasano, A., & Shea-Donohue, T. (2005) · Nature Clinical Practice Gastroenterology & Hepatology · doi:10.1038/ncpgasthep0259 · Cited by 484
Self-citationIdentification of human zonulin, a physiological modulator of tight junctions, as prehaptoglobin-2
Tripathi, A. K., Lammers, K. M., Goldblum, S. E., Shea‐Donohue, T., Netzel–Arnett, S., Buzza, M. S., Antalis, T., Vogel, S. N., Zhao, A., Yang, S., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0906773106 · Cited by 449
Self-citationAsmar, R. E., Panigrahi, P., Bamford, P. D., Berti, I., Not, T., Coppa, G. V., Catassi, C., & Fasano, A. (2002) · Gastroenterology · doi:10.1053/gast.2002.36578 · Cited by 369
Self-citationMoreno‐Navarrete, J. M., Sabater, M., Ortega, F. J., Ricart, W., & Fernández‐Real, J. M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037160 · Cited by 317
Watts, T. L., Berti, I., Sapone, A., Gerarduzzi, T., Not, T., Zielke, R. H., & Fasano, A. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0500178102 · Cited by 313
Self-citationPaterson, B. M., Lammers, K. M., Arrieta, M., Fasano, A., & Meddings, J. B. (2007) · Alimentary Pharmacology & Therapeutics · doi:10.1111/j.1365-2036.2007.03413.x · Cited by 279
Self-citationLeaky gut and diabetes mellitus: what is the link?
de Kort, S., Keszthelyi, D., & Masclee, A. (2011) · Obesity Reviews · doi:10.1111/j.1467-789x.2010.00845.x · Cited by 235
Zonula Occludens Toxin Structure-Function Analysis
Pierro, M. D., Lu, R., Uzzau, S., Wang, W., Margaretten, K., Pazzani, C., Maimone, F., & Fasano, A. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m009674200 · Cited by 206
Self-citationLeffler, D. A., Kelly, C. P., Abdallah, H., Colatrella, A. M., Harris, L. A., León, F., Arterburn, L. A., Paterson, B. M., Lan, Z. H., & Murray, J. A. (2012) · The American Journal of Gastroenterology · doi:10.1038/ajg.2012.211 · Cited by 186
Increased gastrointestinal permeability is an early lesion in the spontaneously diabetic BB rat
Meddings, J. B., Jarand, J. M., Urbanski, S. J., Hardin, J. W., & Gall, D. (1999) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.1999.276.4.g951 · Cited by 185
Fasano, A. (2009) · Scientific American · doi:10.1038/scientificamerican0809-54 · Cited by 82
Self-citationAn exploration of Glo-3A antibody levels in children at increased risk for type 1 diabetes mellitus
Simpson, M. D., Mojibian, M., Barriga, K. J., Fw, S., Fasano, A., Rewers, M., & Norris, J. (2009) · Pediatric Diabetes · doi:10.1111/j.1399-5448.2009.00541.x · Cited by 31
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Wells, J. M., Brummer, R. J., Derrien, M., MacDonald, T. T., Troost, F. J., Cani, P. D., Théodorou, V., Dekker, J. P., Méheust, A., de Vos, W. M., et al. (2016) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00048.2015 · Cited by 638
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Metadata
- Authors
- Fasano, A.
- Affiliations
- University of Maryland, Baltimore (US)
- Corresponding author
- Fasano, Alessio
- ORCID
- Fasano, Alessio
- Venue
- Clinical Gastroenterology and Hepatology
- Publisher
- Elsevier BV
- Published
- 2012-10
- Volume
- 10
- Issue
- 10
- Pages
- 1096-1100
- ISSN
- 1542-3565 (ISSN-L)
- PMC
- PMC3458511
- OpenAlex
- W1988279036
- Cited by
- 402
- References
- 15
- Citations by year
- 2026: 32 · 2025: 37 · 2024: 49 · 2023: 37 · 2022: 50 · 2021: 37 · 2020: 47 · 2019: 36 · 2018: 14 · 2017: 16 · 2016: 21 · 2015: 12 · 2014: 10 · 2013: 3 · 2012: 1
- FWCI
- 8.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Gastroenterology and Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 48373, R01DK048373, R21DK078699, DK-078699)
- Topics
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
- Keywords
- intestinal permeability, zonulin, tight junctions, paracellular permeability, transcellular permeability, antigen trafficking, immune-mediated diseases, intestinal barrier
- MeSH terms
- Cholera Toxin, Gastrointestinal Diseases, Haptoglobins, Humans, Immune System Diseases, Intestinal Mucosa, Permeability, Protein Precursors, Tight Junctions
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