title: Adherent-invasive Escherichia coli induce claudin-2 expression and barrier defect in CEABAC10 mice and Crohn's disease patients.
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 10(9) 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.
authors.affiliation: Clermont Université, Université d'Auvergne, Pathogénie Bactérienne Intestinale, JE2526, Clermont-Ferrand F-63001, France.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Denizot
authors.forename: Adeline
authors.initials: A
authors.lastname: Sivignon
authors.forename: Frederick
authors.initials: F
authors.lastname: Barreau
authors.forename: Claude
authors.initials: C
authors.lastname: Darcha
authors.forename: H F Carlos
authors.initials: HF
authors.lastname: Chan
authors.forename: Clifford P
authors.initials: CP
authors.lastname: Stanners
authors.forename: Paul
authors.initials: P
authors.lastname: Hofman
authors.forename: Arlette
authors.initials: A
authors.lastname: Darfeuille-Michaud
authors.forename: Nicolas
authors.initials: N
authors.lastname: Barnich
mesh_terms: D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001422:Bacterial Adhesion; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D057167:Claudins / Q000096:biosynthesis*; D003424:Crohn Disease / Q000378:metabolism* / Q000382:microbiology; D004195:Disease Models, Animal; D004927:Escherichia coli Infections / Q000378:metabolism* / Q000382:microbiology; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007082:Ileum / Q000378:metabolism / Q000382:microbiology; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D010539:Permeability; D046888:Tissue Array Analysis / Q000379:methods
chemical_list: D015703:Antigens, CD; C504117:CEACAM6 protein, human; C491875:CLDN2 protein, human; D015815:Cell Adhesion Molecules; D057167:Claudins; C113371:Cldn2 protein, mouse; D058851:GPI-Linked Proteins