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Zonulin (haptoglobin 2 precursor) [1] is a protein that increases the permeability of tight junctions between cells of the wall of the digestive tract. [2] It was discovered in 2000 by Alessio Fasano and his team at the University of Maryland School of Medicine. As the mammalian analogue of zonula occludens toxin, secreted by cholera pathogen Vibrio cholerae, zonulin has been implicated in the pathogenesis of coeliac disease and diabetes mellitus type 1. [3] Type 2 diabetic patients have shown increased zonulin. [4]
Gliadin (a glycoprotein present in gluten) activates zonulin signaling irrespective of the genetic expression of autoimmunity, leading to increased intestinal permeability of macromolecules. [3] [5]
Zonula occludens toxin is being studied as an adjuvant to improve absorption of drugs and vaccines. [6] In 2014 a zonulin receptor antagonist, larazotide acetate (formerly known as AT-1001), completed a phase 2b clinical trial. [7] [8]
See also
References
- ^ UniProtKB - P00738 (HPT_HUMAN)
- ^ Vanuytsel, T; et al. (Dec 2013). "The role of Haptoglobin and its related protein, Zonulin, in inflammatory bowel disease". Tissue Barriers. 1 (5): e27321. doi: 10.4161/tisb.27321. PMC 3943850. PMID 24868498.
- ^ a b Fasano, A (Jan 2011). "Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer". Physiol. Rev. 91 (1): 151–75. CiteSeerX 10.1.1.653.3967. doi: 10.1152/physrev.00003.2008. PMID 21248165.
- ^ Lopetuso LR, Scaldaferri F, Bruno G, Petito V, Franceschi F, Gasbarrini A (2015). "The therapeutic management of gut barrier leaking: the emerging role for mucosal barrier protectors". European Review for Medical and Pharmacological Sciences. 19 (6): 1068–1076. PMID 25855934.
- ^ Visser, Jeroen; Rozing, Jan; Sapone, Anna; Lammers, Karen; Fasano, Alessio (2009-05-01). "Tight Junctions, Intestinal Permeability, and Autoimmunity Celiac Disease and Type 1 Diabetes Paradigms". Annals of the New York Academy of Sciences. 1165: 195–205. doi: 10.1111/j.1749-6632.2009.04037.x. ISSN 0077-8923. PMC 2886850. PMID 19538307.
- ^ Lemmer, HJ; Hamman, JH (Jan 2013). "Paracellular drug absorption enhancement through tight junction modulation". Expert Opin Drug Deliv. 10 (1): 103–14. doi: 10.1517/17425247.2013.745509. PMID 23163247.
- ^ "Alba Therapeutics announces positive results of phase IIb trial in celiac disease" (Press release). Alba Therapeutics. February 11, 2014.
- ^ Leffler, DA; Kelly, CP; Green, PH; Fedorak, RN; DiMarino, A; Perrow, W; Rasmussen, H; Wang, C; Bercik, P; Bachir, NM; Murray, JA (June 2015). "Larazotide acetate for persistent symptoms of celiac disease despite a gluten-free diet: a randomized controlled trial". Gastroenterology. 148 (7): 1311-9.e6. doi: 10.1053/j.gastro.2015.02.008. PMC 4446229. PMID 25683116.