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Host-microbiota interactions across the gut immune system:
lessons from early onset inflammatory bowel diseases
and from gnotobiotic mice

Mid-Term Report Summary - IMMUNOBIOTA (Host-microbiota interactions across the gut immune system:lessons from early onset inflammatory bowel diseases and from gnotobiotic mice)

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. The project Immunobiota aims at delineating how the two partners build and maintain mutualistic relationships based on a combination of bench to bed-side approaches in humans and of 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 severe intestinal inflammation of early onset. Our working hypothesis is that these rare but very severe diseases are caused by mutations in single genes playing a key role to avoid hyperactivation of the immune system by the microbiota. The work led during the first part of the project has allowed us to build up a cohort of presently 273 cases of early onset inflammatory bowel diseases, to create a data base facilitating patients’ analysis and follow-up that can be shared with physicians in charge of the patients, to set up a novel tool which permits rapid identification of known molecular defects. A known molecular defect has been identified in 33% out of the 216 patients fully studied, leading to adapt therapy and to genetic counselling. Several new candidate genes have been identified in patients without molecular diagnosis. On-going work aims at demonstrating that the latter genetic changes are causative of the intestinal diseases. Overall our first results confirm that our strategy is pertinent to help unravelling the complex spectrum of immunoregulatory mechanisms which cooperate to maintain intestinal homeostasis. In addition we have set up a diagnosis platform/pipeline which accelerates molecular diagnosis and thereby the choice of personalized therapies indispensable to reduce mortality and morbidity in these very severe diseases.

In the second part of the proposal, we aim at dissecting the mechanisms by which one unusual symbiotic bacterium, Segmented Filamentous Bacterium (SFB) can selectively orchestrate the post-natal maturation of the gut immune barrier. This barrier is indispensable to protect hosts against the huge and complex community of symbiotic microbes colonizing the intestinal lumen at birth but also to prevent invasion by dangerous pathogens. It is built up progressively during the first months/years of life through a dialogue between hosts and symbiotic microbes. In mice, SFB has emerged as a key member of the symbiotic microbiota to launch this dialogue. During the first part of the project, i) we have shown that, in contrast to other members of the microbiota, SFB has the capacity to stimulate the development of lymphoid organs indispensable to initiate gut immune responses ; ii) we have set up for the first time in 50 years conditions for in vitro culture of SFB on epithelial cells. This first step opens the path for identifying the signaling cascade that underlies the potent immunostimulatory effect of SFB, a work that is now on-going; iii) we have obtained evidence that a human version of SFB exists. We intend to take advantage of the in vitro culture method to identify the signals induced in host epithelial cells by SFB and the bacterial attributes that control signal delivery. In parallel, we will continue our 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. Utlimately, we hope to define whether and how SFB may be used for reinforcing the human gut barrier and protect against enteropathogens.