The Gut–spine–disc Axis in Intervertebral Disc Degeneration: Integrating Microbiome, Immune-Metabolic Mechanisms, Clinical Evidence, and Therapeutic Perspectives — A Narrative Review

Intervertebral disc degeneration (IDD) is a significant contributor to chronic low back pain and involves complex, interacting mechanisms that involve mechanical, inflammatory, metabolic, and cellular mechanisms. The growing evidence indicates that disturbances of the intestinal flora can be a modification of these processes via the gut–disc axis. This structured narrative review collates human microbiome, metabolomic, Mendelian-randomization and experimental data since 2014, and up to September 2026. The search of literature was done primarily via PubMed/MEDLINE, and cross checked in PubMed Central and publisher records, using combinations of terms such as ‘gut microbiome', ‘gut microbiota', ‘dysbiosis', ‘gut-disc axis', ‘intervertebral disc degeneration', ‘Modic changes', ‘metabolomics', ‘short-chain fatty acids', ‘lipopolysaccharide', ‘Mendelian randomization', and ‘fecal microbiota transplantation'. There are several biologically plausible pathways suggested by the 22-study core evidence set: intestinal-barrier impairment and systemic exposure to lipopolysaccharide; activation of toll-like-receptor 4/NF-kB signaling pathways; Th17/Treg and macrophage-polarization shifts; altered short-chain-fatty-acid, tryptophan–indole/AhR and bile-acid/FXR–TGR5 signaling; oxidative stress and mitochondrial dysfunction; and potential microbial signaling at the disc–endplate interface. Microbiome disease-associated profile in human studies and genetic causal-inference and animal studies are complementary and show that specific microbial phenotypes or microbiome manipulation could affect phenotypes associated with degeneration. But existing clinical data has limitations in that small, cross-sectional cohorts, geographic and dietary factors, medication and body-composition confounding, sequencing differences and risk of contamination in low-biomass disc samples of the sample were present. IDD is an area that is currently under investigation with the use of microbiome-directed interventions such as dietary changes, probiotics, postbiotics, and fecal microbiota transplantation. However, before the microbiome can be recommended as a diagnostic or disease-modifying therapeutic target, future studies should include integrated metagenomic, metatranscriptomic, metabolomic, immune, and quantitative-MRI profiling of prospective multicenter cohorts.