The Gut-Disc Axis: Mendelian Randomization Study Reveals Causal Effects of Gut Microbiota on Intervertebral Disc Degeneration Not Mediated by Systemic Inflammation

Background: Intervertebral disc degeneration (IVDD) is a major cause of low back pain. Observational studies suggest a link with gut microbiota (GM), possibly mediated by systemic inflammation, but causality remains unclear. Objective: To assess the suggestive associations of GM and inflammatory cytokines (ICs) on IVDD using Mendelian randomization (MR), and evaluate potential mediation by ICs. Methods: We performed a two-sample MR analysis. Genetic instruments for GM came from MiBioGen (n=18,340), for 41 ICs from a meta-analysis (n=8337), and for IVDD from FinnGen (29,508 cases/227,388 controls). Inverse-variance weighted (IVW) was the primary method. Mediation was assessed via two-step MR, with sensitivity analyses (MR-Egger, MR-PRESSO). Results: At the nominal significance level ( P< 0.05 ), 11 microbial taxa showed suggestive causal associations with IVDD risk, of which only Eubacterium coprostanoligenes group approached the Bonferroni-corrected threshold ( P=3.0× 10− 5 ). Seven inflammatory cytokines showed suggestive associations with IVDD; however, none remained statistically statistically significant after Bonferroni correction. Mediation analysis revealed no statistically statistically significant indirect effect of cytokines linking gut microbiota to IVDD. Conclusion: This study provides genetic evidence supporting a potential gut-disc axis. The lack of evidence for cytokine mediation does not exclude alternative pathways but indicates insufficient support for systemic cytokine-mediated mechanisms among those examined; future mechanistic studies should explore microbial metabolites and local immune activity. Keywords: intervertebral disc degeneration, gut microbiota, inflammatory cytokines, Mendelian randomization, mediation analysis, causality