Investigating the mediating effect of plasma metabolites on the gut microbiome in influencing Behçet disease: A multi-omics validated Mendelian randomization study

Although an established correlation between gut microbiota (GM) and Behçet syndrome exists, the potential mediating involvement of plasma metabolites remains unclear. Using the most recent statistical data from genome-wide association studies conducted in 2024, we investigated the causal relationships between 473 GM taxa, 233 circulating metabolites, and Behçet syndrome (Behçet disease [BD]) through a 2-sample Mendelian randomization approach. This analysis was further supported by incorporating transcriptome and metagenomic data related to BD. A 2-step methodology was employed to evaluate the extent to which the effect of GM on BD is mediated through plasma metabolites. These results were subsequently validated in a separate validation set. Our Mendelian randomization results demonstrated correlations between various GM and the risk of Behçet syndrome. The potential link between GM and BD risk may be mediated through plasma circulating metabolite levels. Specifically, for every standard deviation, an increase in the abundance of Turicibacter sp001543345 was correlated with a 403% increase in BD risk (odds ratio : 5.03 [95% confidence interval, 1.77-14.25]). Meanwhile, the cholesteryl esters to total lipids ratio in large very low-density lipoprotein and the total cholesterol to total lipids ratio in very large very low-density lipoprotein increased by 4%. The proportion of indirect effects is 3.026% and 3.338%, respectively. Our study established a causal link between distinct GM and BD and quantified the proportion of effects mediated through plasma metabolites. These findings provide further insights for the treatment of BD.