You are here: Home / Research / Upcoming Seminars / Alessio Fasano, M.D. - "The zonulin transgenic mouse model to study the role of microbiome composition and function, gut permeability, and antigen trafficking in the pathogenesis of chronic inflammatory diseases"

Alessio Fasano, M.D. - "The zonulin transgenic mouse model to study the role of microbiome composition and function, gut permeability, and antigen trafficking in the pathogenesis of chronic inflammatory diseases"

Harvard Medical School and Massachusetts General Hospital - East, Charlestown, Boston, USA
When Sep 20, 2017
from 12:00 PM to 01:30 PM
Where Tigem, Auditorium "Vesuvius"
Contact Name
Contact Phone 081-19230659
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Abstract
Increased small intestinal permeability has recently been described as an integral element, along with genetic makeup and environmental triggers, in the pathogenesis of chronic inflammatory diseases (CIDs).  The paracellular route is the dominant pathway through which solutes flow across the intestinal epithelial barrier, and its functional state is regulated through the intercellular tight junction (TJ).  TJs are dynamic and complex structures whose pathophysiological regulation remains incompletely understood.  Mounting evidence indicates that gut barrier function is impaired in several autoimmune, metabolic, tumoral, and CID. For the past 20 years, we have used a Vibrio cholerae-elaborated protein, zonula occludens toxin (Zot) as a tool to gain insights into the regulation of TJ function.  Our studies led to the discovery of zonulin, a human eukaryotic Zot homologue, and to the definition of aspects of its physiological and pathological functions. We have demonstrated that Zot and zonulin each activate the same intracellular signaling events involving proteinase-activated receptor-2 (PAR2)–mediated transactivation of epidermal growth factor receptor (EGFR) and protein kinase C (PKC)-dependent ZO-1 and myosin 1c serine/threonine phosphorylation.  These modifications provoke ZO-1 disengagement from three of its binding partners, occludin, claudin-1, and transiently from myosin 1C, and induce actin polymerization, ultimately causing TJ disassembly.  Gliadin, the trigger of celiac disease (CD), and an imbalance microbiota both cause zonulin release. Its expression is increased in immune disorders associated with gut barrier dysfunction, such as CD and type 1 diabetes (T1D). We have discovered that zonulin is pre-haptoglobin (HP) 2, i.e., the uncleaved product of HP2, an HP allele carried by ~80% of the general population. We have also shown that the HP2-2 genotype, which has a prevalence of ~30% in the general population, is more frequently encountered (~50%) in immune-mediated conditions, including CD, Crohn’s disease (CD), and T1D, and its expression is associated with more severe clinical manifestations. Finally, using an HP2-2 zonulin transgenic mouse model, we have demonstrated that these animals have increased morbidity and mortality when challenged with dextran sulphate sodium (DSS) compared to wild type mice. This clinical outcome was related to increased zonulin gene expression causing loss of small intestinal barrier function detected both in vitro and in vivo and was completely reversed using the zonulin synthetic peptide inhibitor AT1001 (now entering in phase III trial for CD treatment with the name of Larazotide acetate).

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