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.