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

Yuxi Liu; Fei Lei; Daxiong Feng; Jing Luo; Qizu Jin; Hong Zhang; Likun Wang

doi:10.1007/s00586-025-08850-9

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

Eur Spine J. 2025 Apr 26. doi: 10.1007/s00586-025-08850-9. Online ahead of print.

Authors

Yuxi Liu¹, Fei Lei², Daxiong Feng², Jing Luo³, Qizu Jin³, Hong Zhang³, Likun Wang⁴

Affiliations

¹ Santai People's Hospital, Mianyang, China.
² The Affiliated Hospital of Southwest Medical University, Luzhou, China.
³ The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang, China.
⁴ The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang, China. W1252254516@163.com.

PMID: 40287509
DOI: 10.1007/s00586-025-08850-9

Abstract

Objective: 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.

Methods: 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.

Results: 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).

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

Keywords: Cytokines; Inflammation; Intervertebral disc degeneration; Mendelian randomization analysis; Metabolomics.