Final Report Summary - HOMEOEPITH (Homeostasis and rupture of the gut epithelium in the presence of commensals and pathogens)
HOMEOEPITH helped our group to successfully establish a transition from its classical topic, the cellular microbiology of pathogenic infections, particularly its aim to decipher the mechanisms of rupture, invasion and inflammatory destruction of the intestinal epithelium by Shigella, to a new topic encompassing the cellular microbiology of the symbiotic interactions established by the gut microbiota. Hence we could establish a balanced program encompassing both pathology and homeostasis. Several major objectives could be achieved. On the side of homeostasis, we identified a murine “crypt-specific core microbiota” that resides in the crypts of the caecum and proximal colon, we demonstrated that intestinal epithelial regeneration depends upon a cross-talk between the microbiota and the stem cells located in the intestinal crypt, we also identified, following global functional genomics analysis, the major genes required for a bacterial symbiont, Lactobacillus casei, to colonize the gut. On the side of pathology, we identified essential subversive functions of Shigella that alter the polarity, secretory capacity, and apical integrity of the intestinal epithelium. We also identified and analysed, both in vitro and in vivo, some major immunosuppressive functions of Shigella. We could identify the release of intracellular ATP by infected cells as a key early danger signal and its interruption by Shigella as a novel stealth strategy to subvert the innate immune response. We also demonstrated, again in vitro and in vivo, that Shigella actively suppressed the adaptive immune response by arresting T lymphocytes migration and inducing B lymphocytes apoptosis. Altogether, these results shed a new light on the complex balance that regulates health and disease in the gut.