Exploring the Causal Role of Gut Microbiota and Inflammatory Proteins in Neuromyelitis Optica Spectrum Disorder: a Mendelian randomization study with mediation analysis

Abstract Background: Observational studies have highlighted a strong association between gut microbiota (GM) and the onset of neuromyelitis optica spectrum disorder (NMOSD), however, the causality remains unclear. Method: A Mendelian randomization (MR) study was conducted to determine the causal effect of GM on NMOSD and to explore the role of inflammatory proteins as mediators. Genetic data from GWAS were analyzed using the Inverse Variance Weighted (IVW) method, alongside weighted median andMR-Egger methods. Sensitivity analyses, including MR-Egger intercept, leave-one-out, Cochrane’s Q-test, and MR-PRESSO, were performed to validate the MR estimations. Two-sample MR and reverse MR were utilized to assess causality and potential reverse causation. Result: The MR analysis revealed nine significant causal links between GM and NMOSD. Four inflammatory proteins were also found to have positive causal associations with NMOSD. Sensitivity analyses confirmed these findings. However, mediated MR analysis did not find evidence supporting inflammatory proteins as mediators in the GM-NMOSD pathway. Conclusion: The study presents evidence for a causal relationship between GM, inflammatory proteins, and NMOSD. Notably, inflammatory proteins do not mediate the pathway from GM to NMOSD, contributing to a deeper understanding of the interplay between GM and NMOSD.