Gut mucosal microbiota and local intervertebral disc immunity: candidate circulating-cytokine-independent pathways informed by Mendelian randomization evidence

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-α, IL-1β) 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, Akkermansia muciniphila (Akk) and Eubacterium coprostanoligenes , 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, in vitro nucleus pulposus experiments, in vivo 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—which are themselves circulating mediators—reshape local disc metabolic and immune responses via epigenetic modulation and receptor signaling; (2) EVs secreted by A. muciniphila 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.