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The metabolic phenotype of an organism depends on a complex regulatory network, which integrates the plethora of intrinsic and external information and prioritizes the flow of nutrients accordingly. Given the rise of metabolic disorders including obesity, a detailed understanding of this regulatory network is in urgent need. Yet, our level of understanding is far from completeness and complicated by the discovery of additional layers in metabolic regulation, such as the impact of the microbial community present in the gut on the hosts’ energy storage levels. Here, we investigate the interplay between genome variation, diet and the gut microbiome in the shaping of a metabolic phenotype. For this purpose, we reared a set of fully sequenced wild type  Drosophila melanogaster  flies under basal and nutritionally challenged conditions and performed metabolic and microbiome profiling experiments. Our results introduce the fly as a model system to investigate the impact of genome variation on the metabolic response to diet alterations and reveal candidate single nucleotide polymorphisms associated with different metabolic traits, as well as metabolite-metabolite and metabolite-microbe correlations. Intriguingly, the dietary changes affected the microbiome composition less than anticipated. These results challenge the current view of a rapidly changing microbiome in response to environmental fluctuations.

The impact of genome variation and diet on the metabolic phenotype and microbiome composition of Drosophila melanogaster