The mutualistic interaction that binds the metozoan host to its resident gut microbiota has an ancient evolutionary origin. This mutualism profoundly shapes many aspects of our biology. One such important aspect is juvenile growth, a complex biological process whose phenotypic outcome is entirely dependent on the intricate interplay between the genotype and the environment. During the juvenile growth phase, acute and chronic undernutrition leads to severe wasting, stunting and in extreme cases, childhood mortality. Survivors of childhood malnutrition suffer adversary health impact and long-term neurological and reproductive consequences. A few recent and noteworthy studies have established that the activities of the gut microbiome clearly play a paramount role in optimizing juvenile growth in different nutritional environment, but the molecular mechanism behind such host-microbiota mutualism is frankly missing. We have previously demonstrated that in the presence of nutritive stress, mono-associating the ex-axenic Drosophila larvae with a natural fly gut commensal bacteria, Lactobacillus plantarum, can fully recapitulate the beneficial effect of an intact conventional microbiota by accelerating larval growth and maturation rate. Here we propose a joint effort between François Leulier's group (IGFL, Lyon, France) and Bart Deplancke's group (EPFL, Lausanne, Switzerland) to couple functional studies to a systems genetics approach to uncover the variants and genetic architecture underlying the L.plantarum-mediated growth benefits, and to functionally characterize the molecular function of the candidate genes associate with such causal variants. To do so, we will screen through the Drosophila melanogaster Genetic Reference Panel (DGRP), a collection of 205 fully sequenced and annotated fly strains that have been extensively inbred to homozygosity. The DGRP collection harbors a large amount of natural variants found in the wild and has been shown to be an excellent tool to study various complex traits. We conducted a pilot study of 54 DGRP lines and provide direct evidence that larval growth in the presence or absence of L.plantarum manifests large phenotypic range among the DGRP lines , which we hypothesize to be a complex trait controlled by natural variations at multiple interacting loci. We therefore propose to (1) extend the phenotypic study to the entire DGRP collection, (2) identify and functionally validate genetic variants associated to L.plantarum-mediated growth promotion among the DGRP lines, and (3) dissect at the system level the transcriptomic changes upon L.plantarum association and identify relevant eQTLs as part of the regulatory network controlling such transcriptomic changes. The results from this proposal will facilitate similar human association studies to discover genetic variants governing mutualism between the gut microbiota and its juvenile host, provide the intellectual framework for future host-microbiota interaction studies in vertebrate models, and hence promote innovative designs for personalized probiotic therapy.