The influence of an individual’s genetics, diet and gut microbiome on their plasma metabolome was studied in 1,368 individuals and Mendelian randomization and mediation analyses were used to unveil causal relationships univgroningen jingyuan_fu
. Using gutSMASH and microbial SVs, we identified putative metabolic functionalities for previously unannotated microbial genetic sequences. In addition, through bi-directional mediation analysis, we identified hundreds of mediation linkages that provide insight into diet‒microbiome interactions in human metabolic health, as illustrated by several metabolites that have previously been related to cardiometabolic and kidney diseases.
Apart from diet and the gut microbiome, human genetics also acts as a potential determinant of the plasma metabolome. With this metabolome dataset, we not only replicated previously reported mQTLs, but we also identified three mQTLs involving three loci not previously known to be associated with any metabolites. The mQTLs we characterized could be linked to cardiometabolic and chronic kidney diseases, as illustrated by the tissue-specific gene expression analysis and pleotropic mQTL effects.
We acknowledge several limitations in our study. Untargeted plasma metabolome was profiled using FI-MS without compound separation using liquid chromatography columns, and no genuine standards were used. Although the abundances of a few metabolites were well validated using the LC-MS/MS or NMR platforms, identification and quantification of mass peaks using the FI-MS approach is still generally less accurate than in the classical LC-MS/MS platform.
Taken together, the dietary, genetic and microbial associations with plasma metabolites and the causal and mediation linkages that we report here provide a comprehensive resource that can guide follow-up studies aimed at designing preventive and therapeutic strategies for human metabolic health.
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