Identification of epigenetically-regulated host factors favoring the interaction between Enterobacteria and intestinal epithelial cells in Crohn’s disease patients in western countries – HDACrohn

A high prevalence of invasive Escherichia coli strains, designated as adherent-invasive E. coli (AIEC), has been frequently observed in the ileal mucosa of Crohn’s disease patients. Preventing the colonization of ileal mucosa by AIEC could be a strategy to limit recurrence of CD. Based on solid preliminary data, our hypothesis is that deregulated Histone deacetylase (HDAC) expression/activity in intestinal epithelial cells of CD patients, induced by environmental factors such as western diet, leads to altered gene expression facilitating Enterobacteria colonization. The main objective of this proposal is to highlight the molecular mechanisms leading to AIEC colonization in CD patients to propose new therapeutic targets to limit/prevent AIEC intestinal colonization. To reach this objective, we aim (1) to study the role of HDAC1 and HDAC5 in the control of AIEC intestinal colonization and in inflammatory response, (2) to identify HDAC1- and HDAC5-regulated genes involved in the process of AIEC invasion, and (3) to identify the molecular mechanisms favoring AIEC colonization of intestinal mucosa in mice fed a western diet with a focus on the role of HDAC. This work will be carried out in various cellular models and in genetically modified mice models. In addition, the results will be validated in a cohort of 180 patients for which transcriptomics data and intestinal colonization by Enterobacteriaceae / AIEC levels are available. The identification of host factors favoring Enterobacteria and more specifically AIEC encroachment to intestinal mucosa should lead to the proposal of new alternative strategies to prevent AIEC colonization in CD patients.