The Causal Relationship Between Gut Microbiomes, Inflammatory Mediators, and Traumatic Brain Injury in Europeans: Evidence from Genetic Correlation and Functional Mapping Annotation Analyses

<b>Background:</b> The gut microbiome (GM) has been reported to play a role in traumatic brain injury (TBI). To investigate the causal relationship between GMs, inflammatory mediators, and TBI, a comprehensive Mendelian randomization (MR) analysis was conducted. <b>Methods:</b> We utilized Genome-Wide Association Study (GWAS) summary statistics to examine the causal relationships between GM and TBI. To assess the potential causal associations between GM and TBI, we employed the inverse-variance-weighted, MR-Egger, and weighted median methods. Mediation analysis was used to assess the possible mediating factors. Several sensitivity analyses methods were implemented to verify the stability of the results. Additionally, we utilized FUMA GWAS to map single-nucleotide polymorphisms to genes and conduct transcriptomic MR analysis. <b>Results:</b> We identified potential causal relationships between nine bacterial taxa and TBI. Notably, class <i>Methanobacteria</i>, family <i>Methanobacteriaceae</i>, and order <i>Methanobacteriales</i> (<i>p</i> = 0.0003) maintained a robust positive correlation with TBI. This causal association passed false discovery rate (FDR) correction (FDR < 0.05). Genetically determined 1 inflammatory protein, 30 immune cells and 3 inflammatory factors were significantly causally related to TBI. None of them mediated the relationship between GMs and TBI. The outcome of the sensitivity analysis corroborated the findings. Regarding the mapped genes of significant GMs, genes such as <i>CLK4</i>, <i>MTRF1</i>, <i>NAA16</i>, <i>SH3BP5</i>, and <i>ZNF354A</i> in class <i>Methanobacteria</i> showed a significant causal correlation with TBI. <b>Conclusions:</b> Our study reveals the potential causal effects of nine GMs, especially <i>Methanogens</i> on TBI, and there was no link between TBI and GM through inflammatory protein, immune cells, and inflammatory factors, which may offer fresh insights into TBI biomarkers and therapeutic targets through specific GMs.