Metazoans establish reciprocal interactions with the bacterial communities that colonize their mucosal surfaces. These interactions contribute to many aspects of host physiology including the promotion of digestive efficiency and proper immune system development and homeostasis. In return, the microbiota derives benefit from the association with its host by inhabiting a nutrient rich environment. When deregulated this relationship results in pathological outcomes such as episodic infectious diseases, chronic inflammatory diseases, metabolic disorders or even some cancers. Despite recent progress, a clear view of the physiological benefits associated with host/microbiota relationship remains elusive. Hence the molecular mechanisms through which the microbiota exerts its beneficial influences are still largely undefined.The goal of this research proposal is to decipher the molecular dialogue governing the mutualistic interaction between intestinal bacteria and their host. To this end, we will use an animal model, Drosophila melanogaster and one of its natural commensals, Lactobacillus plantarum. We aim to develop a multiscale functional approach to study the molecular mechanisms underlying their mutualistic association. This integrated approach will couple a host and a bacteria centred-view of this beneficial interaction to identify, the bacterial and host genetic networks required to sustain a mutualistic relationship. We will reveal how these molecular activities translate into cellular, tissular and organismal functional benefits and will uncover the interdependency of these benefits. Using a model lactic acid bacteria species and an animal host model with evolutionary conserved molecular and physiological features, our approach is relevant to most lactobacilli/host interactions including those occurring in humans. This project will provide fresh and unbiased insight into the fundamental biological question of host/microbe mutualism.