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 (WMHs), white matter microstructure, white matter connectivity, and multiple neurological diseases via Mendelian randomization study. We identified four WMH-related bacterial taxa, including class <i>Melainabacteria</i>, order <i>Gastranaerophilales</i>, family <i>Alcaligenaceae</i>, and genus <i>Ruminiclostridium 6</i> In addition, three 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, the family <i>Clostridiaceae 1</i> demonstrated a protective effect against ischemic stroke (IS). The genus <i>Barnesiella</i> showed protective effect on IS and small vessel stroke 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). The order <i>Desulfovibrionales</i> and family <i>Desulfovibrionaceae</i> showed protective effect against cardioembolic stroke, and the genus <i>Ruminococcus gnavus group</i> showed a protective effect on amyotrophic lateral sclerosis. In terms of the mapped genes of statistically significant bacterial taxa, genes such as <i>CPNE1</i>, <i>PIGU</i>, <i>MED22</i>, <i>SURF6</i>, <i>DOCK10</i>, and <i>COPS3</i> 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, and 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.