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

Background Growing evidence indicates that dynamic changes in the gut microbiome can affect intelligence; however, whether the relationships are causal is unknown. Methods We 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. Results MR evidence suggested a risk effect of the genus Oxalobacter on intelligence (β = -0.032; 95% confidence interval, -0.049 to -0.015; P = 1.88×10-4) and a protective effect of the genus Fusicatenibacter on intelligence (β = 0.051; 95% confidence interval, 0.023 to 0.079; P = 3.03×10-4). 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%). Conclusions Our findings may help reshape our understanding of the microbiota-gut-brain axis and development of novel intervention approaches for preventing cognitive impairment. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study is supported by the National Natural Science Foundation of China (82101601, 32170616), the Natural Science Basic Research Program of Shaanxi Province (2021JC-02), China Postdoctoral Science Foundation (2021M702612, 2020M683454, 2021T140546), and the special guidance funds for the construction of world-class universities (disciplines) and characteristic development in central universities. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used ONLY openly available human data that were originally located at: https://www.ebi.ac.uk/gwas; https://ctg.cncr.nl/software/summary_statistics/ I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript