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.