EPIGENETIC MASTER REGULATORS HDAC1 AND HDAC5 CONTROL PATHOBIONT ENTEROBACTERIA COLONIZATION IN ILEAL MUCOSA IN CROHN’S DISEASE PATIENTS
Résumé
Adherent-invasive Escherichia coli (AIEC) pathotype abnormally colonizes the ileal mucosa of Crohn’s disease (CD) patients. AIEC bacteria contribute to the induction and/or maintenance of the intestinal inflammation characteristic of CD. The aim of this study was to investigate whether histone deacetylases (HDAC) in intestinal epithelial cells regulate Enterobacteria and AIEC encroachment to intestinal mucosa. We show that global level of acetylated histone H3 is higher in patients colonized by AIEC bacteria compared to patients non-colonized by Enterobacteria and that HDAC inhibition-mediated H3 hyperacetylation promotes the entry of AIEC bacteria within intestinal cells. Specific silencing of HDAC1 and HDAC5 resulted in opposite effects: more bacteria entered cells silenced for HDAC1, while less invasive bacteria were numbered in HDAC5-silenced cells. These data were confirmed in mouse models and in a large cohort of CD patients, where we observed that HDAC1 and HDAC5 expression levels respectively correlated negatively and positively to Enterobacteria load associated to ileal mucosa. Together, these results support the role of HDAC in the interaction between Enterobacteria and intestinal mucosa in CD patients. These data are of interest to better understand the molecular mechanisms leading to AIEC colonization in CD patients and to bring to light new therapeutic targets.