Exploring the causal role of gut microbiota and inflammatory proteins in neuromyelitis optica spectrum disorder: A Mendelian randomization study with mediation analysis

Observational studies highlighted a strong association between gut microbiota (GM) and the onset of neuromyelitis optica spectrum disorder (NMOSD), however, the causality remains unclear. This study investigated the causal relationship between them through two-sample Mendelian randomization (MR) based on genome-wide association studies (GWAS). Two-step MR was used to investigate the potential role of inflammatory cytokines between the causal relationship. Several sensitive analysis were performed to validate the robustness of MR. The MR analysis revealed phylum Tenericutes (P = .0357); class Mollicutes (P = .0357); genus Eubacterium rectale group (P = .0487); genus Barnesiella (P = .03); genus Eubacterium xylanophilum group (P = .037); and genus Ruminococcus torques group (P = .0179) were positively associated with the risk of NMOSD, family Clostridiales vadin BB60 group (P = .0244); genus Eggerthella (P = .0214); and genus Intestinibacter (P = .0308) were negatively correlated with NMOSD. Among 41 inflammatory cytokines, MR showed significant causal effects of Macrophage colony-stimulating factor 1 levels (P = .00256), C-X-C motif chemokine 11 levels (P = .0478), SIR2-like protein 2 levels (P = .00338) and Tumor necrosis factor receptor superfamily member 9 levels (P = .0234) on NMOSD. Sensitivity analyses confirmed the robustness of these findings. However, mediated MR analysis did not find evidence supporting inflammatory proteins as mediators in the GM-NMOSD pathway. 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.