Causal effects of gut microbiota on physical growth and cognitive performance via plasma metabolites: A Mendelian randomization study

Herein, we used plasma metabolites as potential mediators to determine the causal relationship between gut microbiota, cognitive performance, and physical growth. The relationship between gut microbiota and these 3 factors has not been accurately established in human experiments and studies; our study may provide some new insights. Two-sample Mendelian randomization was performed to evaluate causal associations between gut microbial composition and 3 core phenotypes (height, body weight, cognitive performance). Publicly available GWAS-identified significant SNPs were applied as instrumental variables, and mediation analyses were further conducted to quantify the proportional metabolite-mediated effects. Causal analyses confirmed 3 microbial taxa associated with height: Enterococcus B showed a positive correlation, while CAG-485 and Rhodococcus exhibited negative effects. Six microbial signatures were significantly linked to body weight, with four taxa displaying protective associations and 2 showing adverse impacts. Rhodanobacter and UBP9 were positively associated with cognitive performance. Mediation analyses verified that distinct microbial taxa regulated the 3 phenotypes through specific metabolites, with varied mediating percentages for growth and cognitive outcomes. The study findings highlight the metabolite pathways of the gut microbiota as potential targets for precise nutritional interventions, growth optimization, and cognitive health enhancement.