Inter-determination of blood metabolite levels and gut microbiome supported by Mendelian randomization

BACKGROUND:The gut microbiome has been implicated in a variety of physiological states. Controversy over causality, however, has always haunted microbiome studies. Here, we utilized the bidirectional Mendelian randomization (MR) approach to address questions that are not yet mature for more costly randomized interventions. From a total of 3,432 Chinese individuals with shotgun sequencing data for whole genome and whole metagenome, as well as anthropometric and blood metabolic traits, we identified 58 causal relationships between the gut microbiome and blood metabolites, and replicated 43 out of the 58. Gut microbiome could determine features in the blood. For example, increased fecal relative abundances of Oscillibacter and Alistipes were causally linked to decreased triglyceride concentration, and fecal microbial module pectin degradation might increase serum uric acid. On the other hand, blood features may determine gut microbial features, e.g. glutamic acid appeared to decrease Oxalobacter, and a few members of Proteobacteria were unidirectionally influenced by cardiometabolically important metabolites such as 5-methyltetrahydrofolic acid, alanine, as well as selenium. This study illustrates the value of human genetic information to help prioritize gut microbial features for mechanistic and clinical studies. The results are consistent with whole-body cross-talks of the microbiome and the circulating molecules. Data Access:Summary statistics that support the findings of this study including the associations between host genetics and microbiomes, host genetics and metabolites are publicly available. The release of the data was approved by the Ministry of Science and Technology of China (Project ID: 2020BAT1137). Sequencing data are available via application on request.