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Current interventions remain largely limited to symptomatic treatments including pharmacological analgesia and surgical intervention. The recently proposed \u201cgut\u2013disc axis\u201d suggests that the gut microbiome can reshape the endplate\u2013disc microenvironment by influencing intestinal barrier integrity, microbial metabolite profiles, and host immune\u2013metabolic status. Existing evidence indicates that dysbiosis\u2010related increases in endotoxin load, dysregulated metabolism of short\u2010chain fatty acids, tryptophan, and bile acids, systemic low\u2010grade inflammation, and shifts in immune cell lineages may collectively promote nucleus pulposus cell senescence and apoptosis, matrix degradation, and endplate pathology. Mendelian randomization studies have also suggested potential causal links between certain gut microbiota and disc diseases. However, the determination of whether \u201cmicrobial signals\u201d detected within the intervertebral disc represent true colonization is currently hindered by methodological limitations, particularly low\u2010biomass contamination. This review focuses on mechanisms through which gut microbiota influence the endplate\u2013disc microenvironment via immune\u2013metabolic pathways, including the LPS\/TLR4\/NF\u2010\u03baB axis, SCFAs\u2013AhR axis, and lipid\/iron metabolism, while only briefly addressing studies related to mechanical injury and surgery. Building on these insights, we integrate advances from clinical cohorts, animal models, and multiomics studies, summarize key actionable intervention nodes, and propose a preliminary patient stratification framework and validation pathway based on gut\u2013immune\u2013metabolic typing, providing a theoretical foundation for developing microbiome\u2010guided disease\u2010modifying interventions.<\/jats:p>","DOI":"10.1002\/jcp.70222","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T18:13:41Z","timestamp":1788459221000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Gut\u2010Intervertebral Disc Axis: Gut Microbiome\u2010Driven Immune\u2010Metabolic Imbalance and Intervertebral Disc Degeneration"],"prefix":"10.1002","volume":"241","author":[{"given":"Xinhui","family":"Cui","sequence":"first","affiliation":[{"name":"Gansu Health Vocational College Lanzhou Gansu Province PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2564-2765","authenticated-orcid":false,"given":"Wenjia","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Orthopedics The Second Hospital of Lanzhou University Lanzhou Gansu Province PR 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