"How the immune system controls the partnership established between mammalian hosts and the complex microbial community that colonizes their distal intestine is a fascinating topic with wide implications in physiology and pathology. In order to delineate how the two partners build and maintain mutualistic relationships, we intend to combine bench to bed-site approaches in humans and mechanistic studies in mice.

The first part of the proposal aims at dissecting human host pathways mandatory to maintain homeostatic relationships with the microbiota through the analysis of a cohort of young children with colites of early onset likely caused by Mendelian mutations. In this part, we expect to take advantage from recent development of powerful tools in genome analysis to extend our expertise in human intestinal immunopathology, provide novel basic insight into immuno-regulation in the human gut and delineate new tools and strategies for the diagnosis and care of inflammatory bowel diseases in children.

In the second part of the proposal, we intend to capitalise on our recent results highlighting the key role of Segmented Filamentous Bacterium in the post-natal maturation of the gut immune system in mice and on very recent evidence of a host-specific version of this bacterium in the human microbiota. First, we want to combine analyses in gnotobiotic mice and molecular approaches to provide a comprehensive view of the mechanisms underlying the outstanding immunostimulatory functions of this unusual symbiont. We hope thereby to identify the bacterial attributes that drive the physiological activation of the host immune system and to gain insight into the rules that govern host-microbiota interactions. Second, we intend to put all possible efforts to characterise the human version of Segmented Filamentous bacterium and to analyse how this bacterium may influence the normal or pathological development of the gut immune system in humans."