Zonulin Upregulation Is Associated With Increased Gut Permeability in Subjects With Type 1 Diabetes and Their Relatives

  1. Anna Sapone12,
  2. Laura de Magistris2,
  3. Michelle Pietzak3,
  4. Maria G. Clemente1,
  5. Amit Tripathi1,
  6. Francesco Cucca4,
  7. Rosanna Lampis4,
  8. Deborah Kryszak1,
  9. Maria Cartenì2,
  10. Maddalena Generoso2,
  11. Dario Iafusco2,
  12. Francesco Prisco2,
  13. Francesca Laghi2,
  14. Gabriele Riegler2,
  15. Romano Carratu2,
  16. Debra Counts5 and
  17. Alessio Fasano1
  1. 1Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore, Maryland
  2. 2Department Magrassi-Lanzara, Gastroenterology Unit, II University of Naples, Naples, Italy
  3. 3University of Southern California Keck School of Medicine and the Division of Gastroenterology and Nutrition, Children’s Hospital Los Angeles, Los Angeles, California
  4. 4Department of Biomedical Science and Biotechnology, University of Cagliari, Cagliari, Italy
  5. 5Division of Pediatric Endocrinology, Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland
  1. Address correspondence and reprint requests to Alessio Fasano, MD, Mucosal Biology Research Center, University of Maryland School of Medicine, 20 Penn St., Room 345, Baltimore, MD 21201. E-mail: afasano{at}


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.


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    • Accepted February 13, 2006.
    • Received December 8, 2005.
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