Mendelian Randomization analyses identify causal associations of human gut microbiome composition on intelligence

BackgroundGrowing evidence indicates that dynamic changes in the gut microbiome can affect intelligence; however, whether the relationships are causal is unknown. MethodsWe conducted a bidirectional two-sample Mendelian randomization (MR) analysis using the summary statistics from the largest GWAS meta-analysis of gut microbiota composition (n = 18,340) and intelligence (n = 269,867). Inverse-variance weighted method was used to conduct the MR analyses complemented by a range of sensitivity analyses to validate the robustness of the results. We further applied a two-step MR analysis to evaluate whether the effect of identified taxa on intelligence was mediated by regulating the brain volume. ResultsMR evidence suggested a risk effect of the genus Oxalobacter on intelligence ({beta} = -0.032; 95% confidence interval, -0.049 to -0.015; P = 1.88 x10-4) and a protective effect of the genus Fusicatenibacter on intelligence ({beta} = 0.051; 95% confidence interval, 0.023 to 0.079; P = 3.03x 10-4). In the other direction, we did not find causal evidence of intelligence on gut microbiome composition. The mediation analysis showed that the effect of genus Fusicatenibacter on intelligence was partly mediated by regulating the brain volume, with a mediated proportion of 26.7% (95% confidence interval, 4.9% to 48.5%). ConclusionsOur findings may help reshape our understanding of the microbiota-gut-brain axis and development of novel intervention approaches for preventing cognitive impairment.