Genetic prediction of blood metabolites mediating the relationship between gut microbiota and Alzheimer's disease: a Mendelian randomization study.

Background: Observational studies have suggested an association between gut microbiota and Alzheimer's disease (AD); however, the causal relationship remains unclear, and the role of blood metabolites in this association remains elusive. Purpose: To elucidate the causal relationship between gut microbiota and AD and to investigate whether blood metabolites serve as potential mediators. Materials and methods: Univariable Mendelian randomization (UVMR) analysis was employed to assess the causal relationship between gut microbiota and AD, while multivariable MR (MVMR) was utilized to mitigate confounding factors. Subsequently, a two-step mediation MR approach was employed to explore the role of blood metabolites as potential mediators. We primarily utilized the inverse variance-weighted method to evaluate the causal relationship between exposure and outcome, and sensitivity analyses including Contamination mixture, Maximum-likelihood, Debiased inverse-variance weighted, MR-Egger, Bayesian Weighted Mendelian randomization, and MR pleiotropy residual sum and outlier were conducted to address pleiotropy. Results: After adjustment for reverse causality and MVMR correction, class Actinobacteria (OR: 1.03, 95% CI: 1.01-1.06, Conclusion: Our mediation MR analysis provides genetic evidence suggesting the potential mediating role of blood metabolites in the causal relationship between gut microbiota and AD. Further large-scale randomized controlled trials are warranted to validate the role of blood metabolites in the specific mechanisms by which gut microbiota influence AD.