Causal links between multi-domain risk factors and intervertebral disc degeneration: a systematic review and meta-analysis of Mendelian randomization studies

The causal roles of modifiable risk factors in intervertebral disc degeneration (IVDD) remain incompletely understood. Mendelian randomization (MR) studies have advantages over traditional observational studies. However, given the heterogeneity of current MR study designs for IVDD, the causal estimates of these reported effects remain uncertain, thereby obscuring the true biological impact of factors such as bones, metabolism, inflammation, gut microbiota, and lifestyle on IVDD. This study synthesized Mendelian randomization (MR) evidence to evaluate the causal relationship between exposure factors across multiple domains and intervertebral disc degeneration(IVDD). We conducted a systematic review and meta-analysis of MR studies published up to September 30, 2025, with reporting completeness assessed using STROBE-MR. Twenty studies (12 “Excellent”, 8 “Good”) were included. Higher bone mineral density significantly increased IVDD risk, including total body BMD (OR = 1.20, 1.15–1.25), lumbar spine BMD (OR = 1.18, 1.13–1.24), heel eBMD (OR = 1.06, 1.03–1.10), and femoral neck BMD (OR = 1.16, 1.09–1.24). Inflammatory cytokines IFN-γ (OR = 0.87, 0.83–0.91) and IL-18 (OR = 0.96, 0.93–0.98) showed inverse associations with IVDD risk. Specific gut microbiota were causally implicated: genus Marvinbryantia (OR = 1.14, 1.07–1.21) and phylum Bacteroidetes (OR = 1.15, 1.06–1.24) increased risk, whereas Order Rhodospirillales (OR = 0.93, 0.90–0.96), Family Rhodospirillaceae (OR = 0.92, 0.88–0.97), and genus Ruminococcaceae UCG003 (OR = 0.92, 0.87–0.97) were protective. Key lifestyle and metabolic risk factors were time watching TV (OR = 1.78, 1.52–2.08), smoking initiation (OR = 1.22, 1.12–1.33), greater height (OR = 1.14, 1.09–1.20), larger waist circumference (OR = 1.26, 1.04–1.53), body mass index (OR = 1.26, 1.14–1.38), triglycerides (OR = 1.08, 1.03–1.13), and Type 2 diabetes (OR = 1.05, 1.03–1.07). This synthesis summarizes current MR evidence suggesting potential causal links between multi-domain factors and IVDD. Among modifiable lifestyle-related factors, genetically predicted time spent watching TV showed a particularly prominent association with IVDD risk. These findings may help prioritize hypotheses for future mechanistic and prevention-oriented studies.