Pathogens and symbionts: War and Peace at mucosal surface in intestinal crypts.In the proposed program called DECRYPT, I wish to strengthen novel orientations of our laboratory aimed at decrypting the dialogue between the microbiota and the host, while keeping a balance with the study of pathogens, both being analyzed at their interface with the gut mucosa to further our knowledge of the homeostatic and pathogenic mechanisms that respectively characterize a healthy and a diseased gut. The intestinal crypt is a key location to study this dialogue because it contains the stem cells, the differentiation and transit amplifying/proliferative compartments that are essential for epithelial regeneration at homeostasis, and restitution following an aggression. It is also embedded in a niche of immune cells that participate in homeostatic and pathological processes under microbial stimuli. Thus the breaking nature of my project will bear on the demonstration that crypt homeostasis depends on signals “emitted” by the microbiota, thereby stressing the depth of our symbiosis with the microbial world, and on the demonstration that the crypt is also the target of enteric pathogens like Shigella, thus introducing the novel paradigm that pathogenesis is not only matter of inflammatory destruction of infected tissues, but also of altered epithelial restitution. An extension of this paradigm is that loss or subversion of the microbiota-crypt homeostasis may account not only for inflammatory bowel diseases (IBD), but also for colon cancer. This fundamental knowledge will also be the basis for translational research, particularly the search for molecules that boost antimicrobial defenses and comfort homeostasis. In summary, I propose a balanced combination between the “cellular microbiology of pathogens” and the “cellular microbiology of symbionts”.