Gut microbiota and white matter integrity: a two-sample Mendelian randomization analysis

The causal relationship between gut microbiota (GM) and white matter injury and communication remains unclear. We aimed to scrutinize the plausible causal impact of GM on white matter hyperintensities (WMH), white matter microstructure, white matter connectivity and multiple neurological diseases via Mendelian randomization (MR) study. We identified 4 WMH-related bacterial taxa, including class Melainabacteria, order Gastranaerophilales, family Alcaligenaceae and genus Ruminiclostridium 6 In addition, 3 bacterial taxa were discovered that have consistent effect on multiple aspects of white matter microstructure. Furthermore, we found 12 strong associations between genetic liability in GM and white matter connectivity. Among these bacterial taxa, family Clostridiaceae 1 demonstrated a protective effect against ischemic stroke (IS). Genus Barnesiella showed protective effect on IS and small vessel stroke (SVS) while posed a risk effect on neuromyelitis optica spectrum disorder (NMOSD), as well as on aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-IgG + NMOSD). Order Desulfovibrionales and family Desulfovibrionaceae showed protective effect against cardioembolic stroke (CES) and genus Ruminococcus gnavus group showed a protective effect on amyotrophic lateral sclerosis (ALS). In terms of the mapped genes of statistically significant bacterial taxa, genes such as CPNE1, PIGU, MED22, SURF6, DOCK10, COPS3 exhibited a significant causal correlation with the corresponding white matter connectivity. This study demonstrated a genetically predicted causal relationship between GM and WMH, white matter microstructure, white matter connectivity, multiple neurological diseases, based on GWAS data from mixed-sex cohorts without sex-stratified summary statistics. These findings highlight the potential role of GM in influencing brain structural integrity.Significance Statement This is the first Mendelian randomization (MR) study to establish a relationship between the gut microbiota (GM) and brain white matter, identifying specific bacterial taxa with genetic responsibility for causal relationships with brain white matter. Our results indicate that 17 bacterial taxa associated with several white matter integrity and communication-related indexes. The MR study also identifies potential effects of GM in multiple neurological diseases, especially family Clostridiaceae 1, order Desulfovibrionales and family DesulfovibrionaceaeThis is the first study to utilize MR analysis in combination with Functional Mapping and Annotation analysis to explore the causal relationship between GM and brain white matter. Genes such as CPNE1, PIGU, MED22, SURF6, DOCK10, COPS3 exhibit a significant causal correlation with white matter connectivity.