EPIGENETIC MASTER REGULATORS HDAC1 AND HDAC5 CONTROL PATHOBIONT ENTEROBACTERIA COLONIZATION IN ILEAL MUCOSA IN CROHN'S DISEASE PATIENTS

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Chervy, Mélissa | Sivignon, Adeline | Allez, Matthieu | Le Bourhis, Lionel | Barnich, Nicolas | Denizot, Jérémy

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International audience. Introduction: The 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. A recent focus has been carried on the part of epigenetics in the pathogenesis of CD with the observation of a global lower expression of the histones deacetylases (HDAC), the enzymes responsible for deacetylation of histones. Mechanisms leading to the abnormal AIEC colonization of the intestinal mucosa have not been fully characterized. The aim of this study was to investigate whether HDAC expression/activity in intestinal epithelial cells of CD patients regulate Enterobacteria and AIEC encroachment to intestinal mucosa.Material and Methods: Global acetylation of the histone H3 was studied on CD patients’ tissue by immunostaining. The invasive ability of AIEC strain LF82 was studied in Caco-2 cells treated with a pan-HDAC inhibitor (SAHA), or silenced for the different HDAC, with a gentamicin protection assay. Transgenic mice expressing human CEACAM6 treated with a class I HDAC inhibitor (MS-275) or HDAC5 inhibitor (LMK-235) were orally challenged with the AIEC strain LF82 and AIEC intestinal colonization was followed up by numbering AIEC bacteria in the stools and associated to colonic mucosa. CD patients samples were used to study correlation between Enterobacteria load associated to ileal mucosa and HDAC1/HDAC5 expression.Results: Global level of acetylated histone H3 was higher in patients colonized by AIEC bacteria compared to patients non-colonized by Enterobacteria suggesting an association between H3 hyperacetylation and AIEC colonization. HDAC inhibition-mediated H3 hyperacetylation promoted the entry of AIEC bacteria within intestinal epithelial 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. In vivo, MS-275-treated mice were more colonized by AIEC bacteria compared to control mice while LMK-235 treatment favored AIEC intestinal clearance. In CD patients, HDAC1 and HDAC5 expression levels respectively correlated negatively and positively to Enterobacteria load associated to ileal mucosa showing that HDAC1 and HDAC5 regulate pathobiont Enterobacteria colonization in patients.Conclusion: This work highlights the significance of HDAC in the interaction between Enterobacteria and intestinal mucosa in CD patients. HDAC1 and HDAC5 expression levels are misregulated in CD patients, which favors Enterobacteria encroachment. 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.

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