The causal relationship between gut microbiota, brain volume, and intelligence: a two-step Mendelian randomization analysis

Growing evidence indicates that dynamic changes in gut microbiome can affect intelligence; however, whether these relationships are causal remains elusive. We aimed to disentangle the poorly understood causal relationship between gut microbiota and intelligence.We performed a two-sample Mendelian randomization (MR) analysis using genetic variants from the largest available genome-wide association studies of gut microbiota (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. Considering the close relationship between brain volume and intelligence, we applied two-step MR to evaluate whether the identified effect was mediated by regulating the brain volume (n = 47,316) RESULTS: We found a risk effect of the genus Oxalobacter on intelligence (odds ratio (OR), 0.968 change in intelligence per standard deviation increase in taxa; 95% confidence interval, 0.952 to 0.985; P = 1.88×10-4) and a protective effect of the genus Fusicatenibacter on intelligence (OR, 1.053; 95% confidence interval, 1.024 to 1.082; P = 3.03×10-4). The two-step MR analysis further showed that the effect of genus Fusicatenibacter on intelligence was partly mediated by regulating the brain volume, with a mediated proportion of 33.6% (95% confidence interval, 6.8% to 60.4%; P = 0.014).Our results provide causal evidence indicating the role of the microbiome in intelligence. Our findings may help reshape our understanding of the microbiota-gut-brain axis and development of novel intervention approaches for preventing cognitive impairment.