Genome-microbiome interplay provides insight into the determinants of the human blood metabolome

This submission includes 313 additional 16S amplicon seqeuncing samples that supplement PRJNA826530 and PRJNA826648.---Variation in the blood metabolome is intimately related to human health. However, few details are known about the interplay between genetics and the microbiome in explaining this variation on a metabolite-by-metabolite level. Here, we perform analyses of variance for each of the 930 blood metabolites robustly detected across a cohort of 1,569 individuals with paired genomic and microbiome data, while controlling for a number of relevant covariates. We find that 595 (64%) of these blood metabolites are significantly associated with either host genetics or the gut microbiome, with 69% of these associations driven solely by the microbiome, 15% driven solely by genetics, and 16% under hybrid genome-microbiome control. Additionally, interaction effects, where a metabolite-microbe association is specific to a particular genetic background, are quite common, albeit with modest effect sizes. This knowledge will help to guide targeted interventions designed to alter the composition of the human blood metabolome.