Nutrition and intestinal barrier in Crohn's disease: impact on microbiota and epigenetic marks – Nutribiote

There is currently an important lack of studies aiming at bringing together human genetics, gut ecosystem microbiology and environmental factors in the context of inflammatory bowel diseases (IBD). Changes in dietary consumption patterns affect many aspects of human biology, including the composition of intestinal microbiota with consequences on intestinal homeostasis and immune responses. Epidemiologic evidence incriminates dietary factors such as the spread of the "Western" diet, high in fat and sugar, but low in fruits and vegetables, as risk factor for IBD. In addition, increased intestinal permeability is associated with an increased relative risk of Crohn’s disease (CD) patients for relapses within 1 year and many studies have demonstrated the major role played by tight junction proteins in intestinal homeostasis. Understanding mechanisms of barrier dysfunction and defects in permeability, in particular by investigating the role of nutrition and epigenetic modifications leading to differential gene expression, have great potential for guiding the development of novel drugs for treatment of IBD.
The goal of this project is to improve the understanding of the mechanisms and the consequences of CEACAM6/Adherent-Invasive Escherichia coli (AIEC) interaction in CD patients by addressing questions of fundamental importance in order to define new specific targets for therapy. Our investigations will proceed according to the following tasks which aimed to: (1) determine mechanisms involved in the alteration of intestinal barrier homeostasis following pathogenic bacterial infection, (2) define the impact of nutrition on intestinal microbiota composition, selection of pathogenic bacteria, and on susceptibility of the host to be colonized by pathogenic bacteria, (3) investigate mechanisms involved in the altered barrier function induced by western diet in mouse model mimicking CD susceptibility, and (4) elucidate modulation of epigenetic marks by specific diet that can influence gene expression involved in the maintenance of barrier function.
The project carries technical and scientific novelties. It constitutes a study taken in account both genetic and nutrition factors to study the impact of bacterial infection on gut homeostasis, that will combine a variety of in vitro and in vivo assays, from molecular biology to animal model. We will decipher how AIEC infection modulates in vivo intestinal permeability in different diet conditions. Second, the ambitious part of the project concerns the modulation of epigenetic marks by nutrition on the expression of various genes involved in the maintenance of barrier integrity. The better understanding of the molecular mechanism involved in the increased intestinal permeability in CD patients in the context of western lifestyle nutrition, associated with CD genetic susceptibility and the presence of adherent-invasive E. coli, should help the development of new drugs targeting specific mechanism identified from these study to treat patients showing abnormal ileal expression of CEACAM6 by preventing AIEC-induced disruption of intestinal barrier integrity.