Inflammatory protein mediators linking gut microbiota to degenerative lumbar spine disorders: cross-disease genetic evidence

BackgroundDegenerative lumbar spine disorders (DLSD), including intervertebral disc disorders (IDD), degenerative spondylolisthesis, and lumbar spinal stenosis (LSS), are major contributors to low back pain and disability. Associations among gut microbiota (GM), inflammatory proteins, and DLSD have been demonstrated in prior studies.

Yet, two key questions persist: whether specific circulating inflammatory proteins (IPs) mediate this association, and whether such mediation is shared across different diseases.MethodsWe performed two-sample Mendelian randomization (MR) to evaluate causal associations among 473 GM taxa, 91 circulating IPs, and three DLSD outcomes using FinnGen R12 summary statistics. Causal estimates were obtained using inverse-variance weighted MR with complementary sensitivity analyses, pleiotropy and heterogeneity testing, and bidirectional MR.

Two-step MR mediation was applied to quantify indirect effects of GM through IPs. Experimental validation was performed using rat models, with qPCR and ELISA assessing inflammatory markers in lumbar tissues and metagenomic sequencing evaluating gut microbiota profiles.ResultsGenetically predicted GM taxa were associated with LSS (28 taxa), spondylolisthesis (20 taxa), and IDD (41 taxa).