{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T14:09:57Z","timestamp":1790086197569,"version":"4.0.1"},"reference-count":77,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Chronic low back pain secondary to intervertebral disc degeneration (IVDD) is the leading cause of disability across all musculoskeletal disorders worldwide. For decades, gut-disc crosstalk research has been framed almost exclusively by a systemic inflammatory paradigm, in which circulating pro-inflammatory cytokines (e.g., TNF-\u03b1, IL-1\u03b2) act as obligate mediators linking gut microbial dysbiosis to intervertebral disc degeneration. However, multi-cohort two-sample Mendelian randomization (MR) analyses have not identified significant mediation by the circulating inflammatory factors tested to date, exposing a gap in current mechanistic frameworks. A null indirect effect indicates that the measured mediators did not statistically explain the exposure-outcome association; it does not exclude a contribution from untested systemic pathways. Two core protective commensal taxa,\n                    <jats:italic>Akkermansia muciniphila<\/jats:italic>\n                    (Akk) and\n                    <jats:italic>Eubacterium coprostanoligenes<\/jats:italic>\n                    , have been genetically validated to reduce IVDD risk, yet their beneficial effects cannot be explained by systemic immune activation. Focusing on mucosal immunology and tissue-localized immune homeostasis, this review integrates human genetic data,\n                    <jats:italic>in vitro<\/jats:italic>\n                    nucleus pulposus experiments,\n                    <jats:italic>in vivo<\/jats:italic>\n                    bacterial extracellular vesicle (EV) evidence, and clinical endplate microbiome profiles to delineate three candidate gut mucosa-derived immune regulatory axes that are not explained by the circulating cytokines measured to date: (1) microbe-derived soluble metabolites\u2014which are themselves circulating mediators\u2014reshape local disc metabolic and immune responses via epigenetic modulation and receptor signaling; (2) EVs secreted by\n                    <jats:italic>A. muciniphila<\/jats:italic>\n                    act as cross-barrier immune messengers targeting the avascular disc tissue; (3) gut bacterial fragments translocate across damaged endplate barriers to trigger site-specific immune remodeling without elevating systemic inflammatory markers. This three-pathway framework offers one possible reconciliation of the null mediation findings from MR studies with the collapse of intrinsic disc immune privilege. Each proposed axis remains incompletely validated, and the available evidence does not establish that they operate independently of untested systemic immune pathways. We further summarize methodological limitations of gut-spine microbiome research and outline mucosa-targeted microbial immunotherapies for chronic low back pain. Collectively, this framework helps shift the field away from over-reliance on systemic inflammation as the sole mechanistic explanation for IVDD pathogenesis.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1938023","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:55:10Z","timestamp":1790085310000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Gut mucosal microbiota and local intervertebral disc immunity: candidate circulating-cytokine-independent pathways informed by Mendelian randomization evidence"],"prefix":"10.3389","volume":"17","author":[{"given":"Rui","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Orthopedics, The First Naval Hospital of Southern Theatre Command","place":["Zhanjiang, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deduo","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Second Affiliated Hospital of Naval Medical University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhua","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Naval Hospital of Southern Theatre Command","place":["Zhanjiang, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(23)00098-X","article-title":"Global, regional, and national burden of low back pain, 1990-2020, its attributable risk factors, and projections to 2050","volume":"5","year":"2023","journal-title":"Lancet Rheumatol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2024.102382","article-title":"Trends and cross-country inequalities in the global burden of osteoarthritis, 1990-2019","volume":"99","author":"Cao","year":"2024","journal-title":"Ageing Res Rev"},{"key":"B3","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/S0140-6736(21)00733-9","article-title":"Low back pain","volume":"398","author":"Knezevic","year":"2021","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1097\/BRS.0000000000000937","article-title":"ISSLS prize winner: vertebral end (Modic) change is an independent risk factor for episodes of severe and disabling low back pain","volume":"40","author":"Maatt","year":"2015","journal-title":"Spine (Phila Pa 1976)"},{"key":"B5","doi-asserted-by":"publisher","first-page":"FS0389","DOI":"10.2144\/fsoa-2019-0022","article-title":"New insights link low-virulent disc infections to the etiology of severe disc degeneration and Modic changes","volume":"5","author":"Manniche","year":"2019","journal-title":"Future Sci OA"},{"key":"B6","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/s41413-020-00125-x","article-title":"Painful intervertebral disc degeneration and inflammation: from laboratory evidence to clinical interventions","volume":"9","author":"Lyu","year":"2021","journal-title":"Bone Res"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2024.1400847","article-title":"Causal effects of specific gut microbiota on spinal stenosis diseases: a two-sample mendelian randomization study","volume":"15","author":"Luo","year":"2024","journal-title":"Front Genet"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1007\/s00586-022-07152-8","article-title":"Gut-disc axis: a cause of intervertebral disc degeneration and low back pain","volume":"31","author":"Li","year":"2022","journal-title":"Eur Spine J"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2023.1290858","article-title":"Gut-spine axis: a possible correlation between gut microbiota and spinal degenerative diseases","volume":"14","author":"Morimoto","year":"2023","journal-title":"Front Microbiol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.spinee.2022.05.001","article-title":"Bacteria in human lumbar discs - subclinical infection or contamination? 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