Host genetics and diet jointly shape the microbiome of Drosophila melanogaster but do not predict lifespan or age-related traits

Abstract The microbiome is a key determinant of organismal health, yet inter-individual variability and heterogeneous responses to environmental conditions complicates the understanding of its effects on hosts. Here, we present a comprehensive analysis using the Drosophila Genetic Reference Panel (DGRP) to investigate how the interplay between host genetic variation and diet influences microbiome composition, and to assess whether microbiome features in young flies can be used to predict lifespan and age-related traits. Our findings show that adult flies reared on a nutritionally rich control diet exhibited higher microbial richness but lower evenness compared to those on a nutritionally poor restricted diet. Principal component analysis (PCA) highlighted substantial diversity among lines reared on the same diet, and this variation was heritable supported by high heritability estimates for all measured α-diversity metrics, including Unique OTU counts, Shannon and Simpson indices, as well as the relative abundances of genera and species with relative abundances exceeding 1%. These results underscore the critical roles of both environmental factors and genetic variation in shaping microbiome composition under different dietary conditions. Moreover, we identified widespread genotype-by-diet interactions, suggesting that the genetic regulation of the microbiome is highly complex. Finally, we found that the microbiome features of young flies including diversity indices, taxonomic abundances, or ordination scores cannot predict age-associated phenotypes (lifespan, locomotor activity, dry weight, and heat knockdown time). Our findings offer valuable insights into the genetic architecture that governs microbiome composition, dietary responses, and aging in Drosophila melanogaster . Author Summary The community of microbes living on or inside animals - the microbiome - plays an important role in health and aging, but its composition varies greatly between individuals and across environments, making it challenging to fully understand its importance. In this study, we examined how host genetics and diet shape the microbiome of the fruit fly, Drosophila melanogaster , using a large panel of genetically diverse lines. We found that the microbiome of flies on a restricted nutritionally poor diet were relatively evenly distributed, while the microbiome of flies on a nutritionally rich diet had a higher species diversity. Many features of the microbiome were strongly influenced by the flies’ genes, and these genetic effects often depended on diet. Finally, we tested whether microbiome features obtained from young flies could predict age-related traits such as lifespan and activity at similar aged flies or later in life, but found no evidence for such links. These results highlight how genetic variation and diet interact to shape the microbiome and its role in aging.