Genetic prediction of the effect of gut microbiota on uveitis via blood metabolites: A mediated Mendelian randomization investigation

The gut microbiota (GM) may be associated with uveitis. However, the causal relationship between the GM and uveitis and whether blood metabolites act as mediators of the GM remain unclear. We extracted the GM, blood metabolites, and uveitis data from genome-wide association study (GWAS) summary data. We used Mendelian randomization (MR) to investigate the causal relationships among GM, blood metabolites, and uveitis. The primary statistical method used was the inverse variance weighted (IVW) method. In addition, we used 2-sample MR, bidirectional MR, 2-step method and multiple MR to explore whether blood metabolites were mediators of the association between the GM and uveitis. After removing confounding factors, the abundances of the order Bacillales and the genus Holdemanella are risk factors for uveitis, and the abundances of Peptococcus and Ruminococcaceae UCG010 are protective factors. The inverse analysis revealed that uveitis affected 6 GM taxa - 4 positively and 2 negatively. In addition, N-methyl proline and 2-hydroxy sebacate were identified as risk factors for uveitis, and N-formy1 phenylalanine, 1-ribosyl-imidazole acetate, 1-palmitoyl-2-arachidonoyl-GPE (16:0/20:4) and alpha-ketoglutarate/pyruvate were identified as protective factors for uveitis. Finally, there was a causal association between 3 GM taxa and 6 blood metabolites, with 6 positive and 2 negative effects. N-methylproline possessed the greatest mediated effect (9.41%) between Ruminococcaceae UCG010 and uveitis. These results provide new insights into the pathogenesis of uveitis and offer a new approach to uveitis prevention and treatment from GM and blood metabolites perspective.