ECCO Fellowship Effect of diet on disease development and faecal microbiota transplantation efficacy in humanized SAMP/Yit and DSS mice models

Abstract

Abstract Background and Aims The gut microbiome and diet have been shown to be associated with IBD pathogenesis, and to be implicated as triggers in disease development. Increasing evidence shows that dysbiosis and Western diets may drive and sustain intestinal inflammation. Therefore, faecal microbiota transplantation (FMT) has been hypothesized to restore a balanced microbiome, leading to reduced inflammation and improved intestinal function. The mechanisms by which FMT exerts its therapeutic effects in IBD are not fully understood. Yet, FMT has shown promising effects in controlling disease in randomized controlled studies in UC. In contrast, data on FMT in CD are scarce and worsening of disease has even been described (Vermeire et al., 2016). Unfortunately, up to day, this different effect of FMT in UC versus CD remains unexplained. Therefore, the aim of this project is to evaluate the effect of FMT in a preclinical model of CD, and compare it to a UC-model and study the effect of ultra-processed Western diets. Methods The mice models which will be used include the acute DSS-induced colitis model for UC and the spontaneous terminal ileitis (SAMP/Yit) model for CD. Upon humanization of the mice with UC or CD patient’s stool, mice will be randomized to dietary interventions being a Western diet, a regular diet, or a Mediterranean diet. Subsequently, the mice will be randomized to receive either autologous (patient) FMT or one out of four healthy donor FMTs possessing different enterotypes. Anticipated Impact By evaluating, clinical endpoints, as well as microbiota and transcriptomic endpoints, this project will provide insights in the differences between FMT success in UC and CD, as well as in the importance of donor selection (enterotype matching) and additional effect of dietary interventions on inflammation. Herewith predicting that this project will aid to bring microbiota-targeted treatment strategies to the IBD clinic.