title: Crohn disease-associated Escherichia coli promote gastrointestinal inflammatory disorders by activation of HIF-dependent responses.
abstract: Crohn disease (CD) ileal lesions are colonized by adherent-invasive E. coli (AIEC) that locally induce inflammation. Hypoxia inducible factor (HIF)-1alpha protein is expressed in acute and chronically inflamed site; however the molecular basis of this expression is not fully understood. The aim of the study was to access whether AIEC induce HIF-1α expression and to study the consequence of HIF-1α expression on the onset of Crohn disease pathogenesis. We show that HIF-1α is maximally expressed in inflamed ileal epithelium of CD-patients. CEACAM6, a protein that acts as a receptor of AIEC, is expressed in this particular condition. Using CEABAC 10 transgenic mice that express CEACAM6, we show that AIEC bacteria, but not non-pathogenic E. coli K12, induce the production of HIF-1alpha protein and the activation of VEGF/VEGFR signaling. Downstream analyses on human intestinal epithelial cells silenced for hif- 1α, highlight the crucial role of this protein in production of pro-angiogenic factors. This study highlights the crucial role of AIEC bacteria as promoter of inflammatory disorders of the gastrointestinal tract and provides clear evidence that HIF-1α protein plays a major role in mediating this effect.
authors.affiliation: The Institute of Research on Cancer and Aging, Nice, France.
authors.forename: Sanda
authors.initials: S
authors.lastname: Mimouna
authors.forename: Diogo
authors.initials: D
authors.lastname: Gonçalvès
authors.forename: Nicolas
authors.initials: N
authors.lastname: Barnich
authors.forename: Arlette
authors.initials: A
authors.lastname: Darfeuille-Michaud
authors.forename: Paul
authors.initials: P
authors.lastname: Hofman
authors.forename: Valérie
authors.initials: V
authors.lastname: Vouret-Craviari
mesh_terms: D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001422:Bacterial Adhesion; D016022:Case-Control Studies; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D003424:Crohn Disease / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D004926:Escherichia coli / Q000254:growth & development / Q000472:pathogenicity*; D004927:Escherichia coli Infections / Q000378:metabolism / Q000382:microbiology; D005260:Female; D005407:Flagella / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007082:Ileum / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D015398:Signal Transduction; D051198:Toll-Like Receptor 5 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D015703:Antigens, CD; C504117:CEACAM6 protein, human; D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C495346:TLR5 protein, human; D051198:Toll-Like Receptor 5; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse