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Adherent-invasive Escherichia coli induce claudin-2 expression and barrier defect in CEABAC10 mice and Crohn's disease patients

Authors

  • Jeremy Denizot,

    1. Clermont Université, Université d'Auvergne, Pathogénie Bactérienne Intestinale, JE2526
    2. Unité Sous Contrat Institut National de la Recherche Agronomique 2018, Clermont-Ferrand F-63001, France
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  • Adeline Sivignon,

    1. Clermont Université, Université d'Auvergne, Pathogénie Bactérienne Intestinale, JE2526
    2. Unité Sous Contrat Institut National de la Recherche Agronomique 2018, Clermont-Ferrand F-63001, France
    3. Institut Universitaire de Technologie, Génie Biologique, Aubière F-63172, France
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  • Frederick Barreau PhD,

    1. Université Paris VII, INSERM U843, Paris F-75019, France
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  • Claude Darcha MD,

    1. Anatomie et Cytologie Pathologiques, CHU, Clermont-Ferrand F-63001, France
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  • H.F. Carlos Chan MD,

    1. Department of Surgery, McGill University, Montréal, Québec, Canada
    2. Goodman Cancer Research Centre and McGill University, Montréal, Québec, Canada
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  • Clifford P. Stanners MD,

    1. Goodman Cancer Research Centre and McGill University, Montréal, Québec, Canada
    2. Department of Biochemistry, McGill University, Montréal, Québec, Canada
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  • Paul Hofman MD,

    1. INSERM ERI-21/EA 4319, Laboratoire de Pathologie Clinique et Expérimentale et CRB INSERM, Hôpital Pasteur et Faculté de Médecine, Université de Nice Sophia Antipolis, Nice F-06000 France
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  • Arlette Darfeuille-Michaud PhD,

    1. Clermont Université, Université d'Auvergne, Pathogénie Bactérienne Intestinale, JE2526
    2. Unité Sous Contrat Institut National de la Recherche Agronomique 2018, Clermont-Ferrand F-63001, France
    3. Institut Universitaire de Technologie, Génie Biologique, Aubière F-63172, France
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  • Nicolas Barnich PhD

    Corresponding author
    1. Clermont Université, Université d'Auvergne, Pathogénie Bactérienne Intestinale, JE2526
    2. Unité Sous Contrat Institut National de la Recherche Agronomique 2018, Clermont-Ferrand F-63001, France
    3. Institut Universitaire de Technologie, Génie Biologique, Aubière F-63172, France
    • Pathogénie Bactérienne Intestinale, Laboratoire de Bactériologie, CBRV, 28 place Henri Dunant, 63001 Clermont-Ferrand, France
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  • Supported by the Ministère de la Recherche et de la Technologie (JE2526), INRA (USC-2018), and by grants from the Association F. Aupetit (AFA), Région Auvergne (Nouveau Chercheur), from European Commission through FP7 IBDase project, from ANR in the frame of ERA-NET PathoGenomics, and Grant 2010 from Infectiopôle Sud, Marseille, France.

Abstract

Background:

Abnormal expression of CEACAM6 observed on the ileal epithelium in Crohn's disease (CD) patients allows adherent-invasive Escherichia coli (AIEC) to colonize gut mucosa. Since intestinal permeability is significantly increased in CD patients, we aimed at investigating whether and how AIEC alter barrier function.

Methods:

Tissue microarray was performed on ileal biopsies from CD patients in quiescent and active phases. CEABAC10 or wildtype mice were orally challenged with 109 bacteria. Intestinal permeability was assessed by measuring 4 kDa dextran-FITC flux in serum, barrier integrity was analyzed using biotin tracer experiment, and claudin-2 protein immunostaining. Bacterial translocation was analyzed in Ussing chambers.

Results:

Pore-forming tight junction protein claudin-2 is strongly expressed in the ileum of 51% patients in quiescent phase and in 49% of the patients with active CD. Infection of CEABAC10 transgenic mice expressing human CEACAMs with AIEC, but not with nonpathogenic E. coli, led to a significant 3.0-fold increase in intestinal permeability and to disruption of mucosal integrity in a type 1 pili-dependent mechanism. This is consistent with the claudin-2 abnormal expression at the plasma membrane of intestinal epithelial cells observed in AIEC-infected CEABAC10 mice. AIEC bacteria were able to translocate through CEABAC10 intestinal mucosa.

Conclusions:

These findings strongly support the hypothesis that AIEC type 1 pili-mediated interaction with CEACAM6 abnormally expressed in the quiescent phase of CD may disrupt intestinal barrier integrity before the onset of inflammation. Thus, therapeutic targeting claudin-2 induced by AIEC infection could be a new clinical strategy for preserving intestinal barrier function in CD patients. (Inflamm Bowel Dis 2011;)

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