Zonulin As a Potential Therapeutic Target in Microbiota-Gut-Brain Axis Disorders: Encouraging Results and Emerging Questions

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2023 Apr 28

PMID 37108711

Authors

Apor Veres-Szekely

Csenge Szasz

Domonkos Pap

Beata Szebeni

Peter Bokrossy

Adam Vannay

Affiliations

Soon will be listed here.

Abstract

The relationship between dysbiosis and central nervous diseases has been proved in the last 10 years. Microbial alterations cause increased intestinal permeability, and the penetration of bacterial fragment and toxins induces local and systemic inflammatory processes, affecting distant organs, including the brain. Therefore, the integrity of the intestinal epithelial barrier plays a central role in the microbiota-gut-brain axis. In this review, we discuss recent findings on zonulin, an important tight junction regulator of intestinal epithelial cells, which is assumed to play a key role in maintaining of the blood-brain barrier function. In addition to focusing on the effect of microbiome on intestinal zonulin release, we also summarize potential pharmaceutical approaches to modulate zonulin-associated pathways with larazotide acetate and other zonulin receptor agonists or antagonists. The present review also addresses the emerging issues, including the use of misleading nomenclature or the unsolved questions about the exact protein sequence of zonulin.

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References

Galea I . The blood-brain barrier in systemic infection and inflammation. Cell Mol Immunol. 2021; 18(11):2489-2501. PMC: 8481764. DOI: 10.1038/s41423-021-00757-x. View

Wang W, Uzzau S, Goldblum S, Fasano A . Human zonulin, a potential modulator of intestinal tight junctions. J Cell Sci. 2000; 113 Pt 24:4435-40. DOI: 10.1242/jcs.113.24.4435. View

K Stenman L, Lehtinen M, Meland N, Christensen J, Yeung N, Saarinen M . Probiotic With or Without Fiber Controls Body Fat Mass, Associated With Serum Zonulin, in Overweight and Obese Adults-Randomized Controlled Trial. EBioMedicine. 2016; 13:190-200. PMC: 5264483. DOI: 10.1016/j.ebiom.2016.10.036. View

Chmielinska M, Olesinska M, Romanowska-Prochnicka K, Szukiewicz D . Haptoglobin and Its Related Protein, Zonulin-What Is Their Role in Spondyloarthropathy?. J Clin Med. 2021; 10(5). PMC: 7962838. DOI: 10.3390/jcm10051131. View

Vorobjova T, Raikkerus H, Kadaja L, Talja I, Uibo O, Heilman K . Circulating Zonulin Correlates with Density of Enteroviruses and Tolerogenic Dendritic Cells in the Small Bowel Mucosa of Celiac Disease Patients. Dig Dis Sci. 2016; 62(2):358-371. DOI: 10.1007/s10620-016-4403-z. View

Lammers K, 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(1):194-204.e3. PMC: 2653457. DOI: 10.1053/j.gastro.2008.03.023. View

Kuzma J, Hagman D, Cromer G, Breymeyer K, Roth C, Foster-Schubert K . Intraindividual Variation in Markers of Intestinal Permeability and Adipose Tissue Inflammation in Healthy Normal-Weight to Obese Adults. Cancer Epidemiol Biomarkers Prev. 2018; 28(3):610-615. PMC: 6401228. DOI: 10.1158/1055-9965.EPI-18-0641. View

Gopalakrishnan S, Durai M, Kitchens K, Tamiz A, Somerville R, Ginski M . Larazotide acetate regulates epithelial tight junctions in vitro and in vivo. Peptides. 2012; 35(1):86-94. DOI: 10.1016/j.peptides.2012.02.015. View

Cangemi R, Pignatelli P, Carnevale R, Bartimoccia S, Nocella C, Falcone M . Low-grade endotoxemia, gut permeability and platelet activation in community-acquired pneumonia. J Infect. 2016; 73(2):107-14. DOI: 10.1016/j.jinf.2016.05.013. View

10.

Camara-Lemarroy C, Silva C, Greenfield J, Liu W, Metz L, Yong V . Biomarkers of intestinal barrier function in multiple sclerosis are associated with disease activity. Mult Scler. 2019; 26(11):1340-1350. DOI: 10.1177/1352458519863133. View

11.

Liu W, Wang P, Shang C, Chen L, Cai H, Ma J . Endophilin-1 regulates blood-brain barrier permeability by controlling ZO-1 and occludin expression via the EGFR-ERK1/2 pathway. Brain Res. 2014; 1573:17-26. DOI: 10.1016/j.brainres.2014.05.022. View

12.

Slifer Z, Krishnan B, Madan J, Blikslager A . Larazotide acetate: a pharmacological peptide approach to tight junction regulation. Am J Physiol Gastrointest Liver Physiol. 2021; 320(6):G983-G989. PMC: 11735010. DOI: 10.1152/ajpgi.00386.2020. View

13.

Clemente M, De Virgiliis S, Kang J, Macatagney R, Musu M, Di Pierro M . Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function. Gut. 2003; 52(2):218-23. PMC: 1774976. DOI: 10.1136/gut.52.2.218. View

14.

Tarko A, Suchojad A, Michalec M, Majcherczyk M, Brzozowska A, Maruniak-Chudek I . Zonulin: A Potential Marker of Intestine Injury in Newborns. Dis Markers. 2017; 2017:2413437. PMC: 5523403. DOI: 10.1155/2017/2413437. View

15.

Laparra J, Sanz Y . Bifidobacteria inhibit the inflammatory response induced by gliadins in intestinal epithelial cells via modifications of toxic peptide generation during digestion. J Cell Biochem. 2010; 109(4):801-7. DOI: 10.1002/jcb.22459. View

16.

Di Masi A, De Simone G, Ciaccio C, DOrso S, Coletta M, Ascenzi P . Haptoglobin: From hemoglobin scavenging to human health. Mol Aspects Med. 2020; 73:100851. DOI: 10.1016/j.mam.2020.100851. View

17.

Ajamian M, Steer D, Rosella G, Gibson P . Serum zonulin as a marker of intestinal mucosal barrier function: May not be what it seems. PLoS One. 2019; 14(1):e0210728. PMC: 6331146. DOI: 10.1371/journal.pone.0210728. View

18.

Silva M, Jury J, Sanz Y, Wiepjes M, Huang X, Murray J . Increased bacterial translocation in gluten-sensitive mice is independent of small intestinal paracellular permeability defect. Dig Dis Sci. 2011; 57(1):38-47. PMC: 3507358. DOI: 10.1007/s10620-011-1847-z. View

19.

Chen Y, Zhou S, Jiang Z, Wang X, Liu Y . Chemokine receptor CXCR3 in turbot (Scophthalmus maximus): cloning, characterization and its responses to lipopolysaccharide. Fish Physiol Biochem. 2015; 42(2):659-71. DOI: 10.1007/s10695-015-0167-1. View

20.

Okuyucu M, Yalcin Kehribar D, Capraz M, Capraz A, Arslan M, Celik Z . The Relationship Between COVID-19 Disease Severity and Zonulin Levels. Cureus. 2022; 14(8):e28255. PMC: 9491012. DOI: 10.7759/cureus.28255. View