How gut microbiome and blood metabolites drive ossification of the posterior longitudinal ligament of the spine: a genome-wide association study based on the East Asian population

This study explored the associations between the gut microbiome, blood metabolites, and ossification of the posterior longitudinal ligament of the spine (OPLL), and investigated potential causal pathways mediated by blood metabolites. Using summary-level genome-wide association study (GWAS) data for the gut microbiome, blood metabolites, and OPLL, we employed a two-sample Mendelian randomization (MR) approach to identify gut microbial taxa and blood metabolites potentially associated with OPLL development. Additionally, we evaluated blood metabolites as potential mediators of the causal pathway by which the gut microbiome influences OPLL. The inverse-variance weighted (IVW) method served as the primary MR estimator. Sensitivity analyses, including Cochran’s Q test, MR-Egger regression, and MR-PRESSO, were performed to assess the robustness of the results. MR analyses suggested potential causal associations between 20 gut microbial taxa and OPLL, and between 8 blood metabolites and OPLL, but none survived correction for multiple testing (FDR > 0.05). These findings are suggestive and require further validation. Among these, 6 taxa were positively associated with an increased risk of OPLL, while 14 taxa were negatively associated with risk. Additionally, 8 blood metabolites exhibited potential causal associations with OPLL, with 5 showing positive and 3 showing negative associations. Mediation analyses suggested that 6 gut microbial taxa might influence OPLL development through 4 intermediary metabolites. Specifically, manganese might mediate the effect of Bacilli on OPLL, aspartic acid might mediate the effects of Megasphaera and Prevotella oris, cystine might mediate the effect of MF0036, and Vitamin B2 (VB2) might mediate the effects of MF0052 and MF0047 on OPLL. This study provides evidence supporting potential causal links between specific gut microbial taxa and OPLL, highlighting the potential mediating role played by blood metabolites. Mediation analyses suggested that 4 blood metabolites might mediate the effects of 6 microbial taxa on OPLL, but none of the indirect effects were statistically significant ( P = 0.091–0.148), indicating these are hypothesis-generating findings requiring validation in larger datasets.