title: Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives.
abstract: Zonulin, a protein that modulates intestinal permeability, is upregulated in several autoimmune diseases and is involved in the pathogenesis of autoimmune diabetes in the BB/Wor animal model of the disease. To verify the association between serum zonulin levels and in vivo intestinal permeability in patients with type 1 diabetes, both parameters were investigated in different stages of the autoimmune process. Forty-two percent (141 of 339) of the patients had abnormal serum zonulin levels, as compared with age-matched control subjects. The increased zonulin levels correlated with increased intestinal permeability in vivo and changes in claudin-1, claudin-2, and myosin IXB genes expression, while no changes were detected in ZO1 and occludin genes expression. When tested in serum samples collected during the pre-type 1 diabetes phase, elevated serum zonulin was detected in 70% of subjects and preceded by 3.5 +/- 0.9 years the onset of the disease in those patients who went on to develop type 1 diabetes. Combined, these results suggest that zonulin upregulation is associated with increased intestinal permeability in a subgroup of type 1 diabetic patients. Zonulin upregulation seems to precede the onset of the disease, providing a possible link between increased intestinal permeability, environmental exposure to non-self antigens, and the development of autoimmunity in genetically susceptible individuals.
authors.affiliation: Mucosal Biology Research Center, University of Maryland School of Medicine, 20 Penn Street, Room 345, Baltimore, MD 21201, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Sapone
authors.forename: Laura
authors.initials: L
authors.lastname: de Magistris
authors.forename: Michelle
authors.initials: M
authors.lastname: Pietzak
authors.forename: Maria G
authors.initials: MG
authors.lastname: Clemente
authors.forename: Amit
authors.initials: A
authors.lastname: Tripathi
authors.forename: Francesco
authors.initials: F
authors.lastname: Cucca
authors.forename: Rosanna
authors.initials: R
authors.lastname: Lampis
authors.forename: Deborah
authors.initials: D
authors.lastname: Kryszak
authors.forename: Maria
authors.initials: M
authors.lastname: Cartenì
authors.forename: Maddalena
authors.initials: M
authors.lastname: Generoso
authors.forename: Dario
authors.initials: D
authors.lastname: Iafusco
authors.forename: Francesco
authors.initials: F
authors.lastname: Prisco
authors.forename: Francesca
authors.initials: F
authors.lastname: Laghi
authors.forename: Gabriele
authors.initials: G
authors.lastname: Riegler
authors.forename: Romano
authors.initials: R
authors.lastname: Carratu
authors.forename: Debra
authors.initials: D
authors.lastname: Counts
authors.forename: Alessio
authors.initials: A
authors.lastname: Fasano
mesh_terms: D001327:Autoimmune Diseases / Q000235:genetics / Q000503:physiopathology; D002772:Cholera Toxin / Q000235:genetics / Q000493:pharmacokinetics*; D062445:Claudin-1; D057167:Claudins; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000503:physiopathology*; D005190:Family; D020022:Genetic Predisposition to Disease; D006242:Haptoglobins; D006801:Humans; D007422:Intestines / Q000187:drug effects / Q000503:physiopathology*; D008565:Membrane Proteins / Q000235:genetics; D062793:Occludin; D010539:Permeability / Q000187:drug effects*; D011498:Protein Precursors
chemical_list: C568108:CLDN1 protein, human; C491875:CLDN2 protein, human; D062445:Claudin-1; D057167:Claudins; D006242:Haptoglobins; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; D011498:Protein Precursors; C408043:zonulin; D002772:Cholera Toxin