{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T03:24:40Z","timestamp":1791516280993,"version":"4.3.4"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:00:00Z","timestamp":1780444800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Degenerative 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Genetically predicted GM taxa were associated with LSS (28 taxa), spondylolisthesis (20 taxa), and IDD (41 taxa). IP MR identified risk-increasing associations for LSS (4E-BP1 and interleukin-4), spondylolisthesis (CXCL1, CXCL5, FGF-5, IL-15RA, and IL-4) and IDD (IL-20RA and IL-6), while IL-18 showed a protective association with IDD that remained robust after multiple-testing correction. Mediation analyses identified 13 genetically supported putative GM\u2013IPs\u2013DLSD pathways, highlighting convergent mediators including PD-L1 for spondylolisthesis and IL-6 and IL-18 for IDD, with mediation proportions ranging from 7.55% to 13.22% across key pathways. Experimental results showed inflammatory activation and gut microbiota alterations in disease models, with partial concordance with the MR findings.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings support a genetically determined microbiota\u2013inflammation axis in DLSD. Furthermore, they identify circulating inflammatory proteins as mediators to prioritize mechanistic studies and guide translational follow-up research.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1855966","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T04:51:11Z","timestamp":1780462271000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Inflammatory protein mediators linking gut microbiota to degenerative lumbar spine disorders: cross-disease genetic evidence"],"prefix":"10.3389","volume":"17","author":[{"given":"Yongfu","family":"Lou","sequence":"first","affiliation":[{"name":"Department of Orthopedics, The Second Qilu Hospital of Shandong University","place":["Jinan, Shandong, China"]},{"name":"Shandong University Centre for Orthopaedics, Cheeloo College of Medicine Shandong University","place":["Jinan, Shandong, 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Shandong, China"]},{"name":"Shandong University Centre for Orthopaedics, Cheeloo College of Medicine Shandong University","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Xiao","sequence":"additional","affiliation":[{"name":"Shandong University Centre for Orthopaedics, Cheeloo College of Medicine Shandong University","place":["Jinan, Shandong, China"]},{"name":"Department of Orthopaedics, Qilu Hospital of Shandong University","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junzhuo","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, The Second Qilu Hospital of Shandong University","place":["Jinan, Shandong, China"]},{"name":"Shandong University Centre for Orthopaedics, Cheeloo College of Medicine Shandong University","place":["Jinan, Shandong, 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