Causal relationships between gut microbiota and dementia: A two-sample, bidirectional, Mendelian randomization study

Abstract

BACKGROUND Existing evidence suggests that gut microbiota represent a significant environmental risk factor for various forms of dementia, including Alzheimer's dementia, vascular dementia, and dementia in other diseases classified elsewhere. However, the exact causal relationships between gut microbiota and the different forms of dementia or their subtypes remain unclear. AIM To investigate putative causal relationships between gut microbiota and dementia or its subtypes using Mendelian randomization (MR) analysis. METHODS A bidirectional, two-sample, MR analysis was conducted utilizing publicly available gut microbiota-related genome-wide association study (GWAS) summary data from the MiBioGen consortium alongside GWAS summary statistics for dementia and its subtypes from the FinnGen consortium. Instrumental variables were selected according to the fundamental tenets of MR and their strengths were evaluated using the F -statistic. Five MR methods were employed, and the robustness of our findings was validated. To account for multiple comparisons, we applied the Bonferroni method for P -value adjustment. RESULTS We identified several gut microbiota taxa exhibiting putative causal relationships with dementia or its subtypes, potentially serving as risk or protective factors for the disease. In addition, reverse MR analysis indicated that the relative abundance of several gut microbiota taxa might be influenced by dementia or its subtypes. An exhaustive sensitivity analysis confirmed the absence of heterogeneity and horizontal pleiotropy. After applying correction for multiple testing, we observed that the order Bacillales (odds ratio: 0.830, 95% confidence interval: 0.740-0.932, P = 0.00155, P adjust = 0.0311) exhibited a strong association with Alzheimer’s disease-related dementia. CONCLUSION The results suggest that gut microbiota is causally associated with dementia. Our findings provide novel insights into the pathophysiology of dementia and have important implications for its treatment and prevention.