Tracing the pathways: how inflammatory cytokines and blood metabolites drive intervertebral disc degeneration

The precise mechanisms driving intervertebral disc degeneration (IVDD) development remain unclear, but evidence suggests a significant involvement of inflammatory cytokines and blood metabolites. We aimed to investigate the causal relationships between inflammatory cytokines, IVDD, and blood metabolites using Mendelian randomization (MR) analysis.

We utilized inflammatory cytokines from a GWAS summary containing 8293 healthy participants, 1400 blood metabolites from the genome-wide association studies (GWAS) Catalog, and IVDD data from the FinnGen repository, all of which are sourced from the largest genome-wide association studies conducted to date. Employing bidirectional MR analyses, we investigated the causal relationships between inflammatory cytokines and IVDD. Additionally, we conducted two mediation analyses, two-step MR and multivariable MR (MVMR), to identify potential mediating metabolites.

Four inflammatory cytokines were causally associated with IVDD, while IVDD did not have a significant causal effect on them. In the two-step MR analysis, IFN-γ, IL-1β, IL-6, and TNF-β, along with metabolites N-methyltaurine, Glycosyl-N-behenoyl-sphingadienine (d18:2/22:0), 3-methoxycatechol sulfate (1), 5alpha-androstan-3beta, 17beta-diol monosulfate (2), X-17653, and 1-palmitoleoylglycerol (16:1), were all significantly associated with IVDD (all P < 0.05). MVMR analysis revealed that the associations between IFN-γ and IVDD were mediated by Glycosyl-N-behenoyl-sphingadienine (d18:2/22:0) (5.1%, P = 0.010); IL-1β and IVDD were mediated by 3-methoxycatechol sulfate (1) (8.8%, P = 0.048); IL-6 and IVDD were mediated by X-17653 (- 8.0%, P  = 0.007), and 5alpha-androstan-3beta, 17beta-diol monosulfate (2) (5.2%, P  = 0.028); TNF-β and IVDD were mediated by 1-palmitoleoylglycerol (16:1) (8.1%, P = 0.011).

The present MR study offers evidence supporting the causal relationships between several specific inflammatory cytokines and IVDD, as well as identifying potential mediating metabolites.