{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T13:09:37Z","timestamp":1789391377956,"version":"build-2803163510"},"reference-count":38,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T00:00:00Z","timestamp":1789257600000},"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","award":["32271214"],"award-info":[{"award-number":["32271214"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["32271214"],"award-info":[{"award-number":["32271214"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"publisher","award":["TGY24H060008"],"award-info":[{"award-number":["TGY24H060008"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]},{"award":["TGY24H060008"],"award-info":[{"award-number":["TGY24H060008"]}],"id":[{"id":"https:\/\/ror.org\/04aqat463","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012175","name":"Zhejiang Provincial Administration of Traditional Chinese Medicine","doi-asserted-by":"publisher","award":["2026092961"],"award-info":[{"award-number":["2026092961"]}],"id":[{"id":"10.13039\/501100012175","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2026092961"],"award-info":[{"award-number":["2026092961"]}],"id":[{"id":"https:\/\/ror.org\/05c3h8q72","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background: Metabolic disturbances have been implicated in intervertebral disc degeneration (IVDD) and low back pain, but the contribution of circulating metabolites remains uncertain. Objectives: We examined associations of genetically proxied plasma metabolites and metabolite ratios with IVDD outcomes defined at different anatomical locations and with a related pain phenotype. Methods: Summary statistics for metabolite exposures were obtained from the Canadian Longitudinal Study on Ageing (CLSA) plasma metabolome genome-wide association study (GWAS). The outcomes were Intervertebral Disc Degeneration of Cervical Spine (IVDD_Cervical), Intervertebral Disc Degeneration of Thoracic, Thoracolumbar, and Lumbosacral Spine (IVDD_TTL), and Low Back Pain (Pain_Lowback). IVDD_Cervical and IVDD_TTL represented IVDD outcomes defined at different anatomical locations of the spine, whereas Pain_Lowback was analysed separately as an IVDD-related pain phenotype. One genome-wide significant sentinel single-nucleotide variant (SNV) was used for each exposure, and Mendelian randomization (MR) estimates were calculated with the Wald ratio. The within-outcome Bonferroni threshold was 6.25 \u00d7 10\u22124. Results: Eighty metabolites and metabolite ratios were evaluated. Two associations were significant, both for IVDD_TTL. Higher genetically proxied dimethylarginine (SDMA + ADMA), mapped to DDAH1, was associated with lower IVDD_TTL risk (odds ratio [OR] = 0.80; 95% confidence interval [CI]: 0.72\u20130.90; p = 2.5 \u00d7 10\u22124), whereas higher alpha-hydroxyisovalerate, mapped to LDHA, was associated with higher risk (OR = 1.08; 95% CI: 1.04\u20131.13; p = 4.6 \u00d7 10\u22124). No significant association was identified for IVDD_Cervical or Pain_Lowback; 23 associations were classified as suggestive significant. DrugBank annotation identified compounds interacting with DDAH1 and LDHA. Conclusions: The results highlight DDAH1-linked methylarginine metabolism and LDHA-linked glycolytic and lactate-related biology as candidate pathways for IVDD_TTL. Findings for IVDD_Cervical, Pain_Lowback, and cross-outcome overlap remain exploratory.<\/jats:p>","DOI":"10.3390\/metabo16090673","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T12:09:51Z","timestamp":1789387791000},"page":"673","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Causal Effects of Plasma Metabolites on Intervertebral Disc Degeneration and Low Back Pain: A Mendelian Randomization Study"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-3719-7183","authenticated-orcid":false,"given":"Shouhe","family":"Zhu","sequence":"first","affiliation":[{"name":"College of Integrated Traditional Chinese and Western Medicine Clinical Medicine, Tongde Hospital of Zhejiang Province, Zhejiang Chinese Medical University; Hangzhou 310012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0218-3893","authenticated-orcid":false,"given":"Chuanzhi","family":"Tang","sequence":"additional","affiliation":[{"name":"College of Integrated Traditional Chinese and Western Medicine Clinical Medicine, Tongde Hospital of Zhejiang Province, Zhejiang Chinese Medical University; Hangzhou 310012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiguo","family":"Ding","sequence":"additional","affiliation":[{"name":"Tongde Hospital of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou 310012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2354-3758","authenticated-orcid":false,"given":"Junxia","family":"Wen","sequence":"additional","affiliation":[{"name":"Tongde Hospital of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou 310012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinwei","family":"Xu","sequence":"additional","affiliation":[{"name":"Tongde Hospital of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou 310012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7713-6262","authenticated-orcid":false,"given":"Xinhui","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Nutrition and Food Safety, School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7128-3333","authenticated-orcid":false,"given":"Weixing","family":"Xu","sequence":"additional","affiliation":[{"name":"Tongde Hospital of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou 310012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","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":"ref_2","doi-asserted-by":"crossref","first-page":"2356","DOI":"10.1016\/S0140-6736(18)30480-X","article-title":"What low back pain is and why we need to pay attention","volume":"391","author":"Hartvigsen","year":"2018","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/s41413-024-00397-7","article-title":"Role of macrophage in intervertebral disc degeneration","volume":"13","author":"Dou","year":"2025","journal-title":"Bone Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e164883","DOI":"10.1172\/jci.insight.164883","article-title":"GLUT1 is redundant in hypoxic and glycolytic nucleus pulposus cells of the intervertebral disc","volume":"8","author":"Johnston","year":"2023","journal-title":"JCI Insight"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1038\/s12276-021-00650-7","article-title":"Mitochondrial quality control in intervertebral disc degeneration","volume":"53","author":"Song","year":"2021","journal-title":"Exp. Mol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"R89","DOI":"10.1093\/hmg\/ddu328","article-title":"Mendelian randomization: Genetic anchors for causal inference in epidemiological studies","volume":"23","author":"Hemani","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1614","DOI":"10.1001\/jama.2021.18236","article-title":"Strengthening the reporting of observational studies in epidemiology using Mendelian randomization: The STROBE-MR statement","volume":"326","author":"Skrivankova","year":"2021","journal-title":"JAMA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"n2233","DOI":"10.1136\/bmj.n2233","article-title":"Strengthening the reporting of observational studies in epidemiology using Mendelian randomisation (STROBE-MR): Explanation and elaboration","volume":"375","author":"Skrivankova","year":"2021","journal-title":"BMJ"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/s41588-022-01270-1","article-title":"Genomic atlas of the plasma metabolome prioritizes metabolites implicated in human diseases","volume":"55","author":"Chen","year":"2023","journal-title":"Nat. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1038\/ng.2982","article-title":"An atlas of genetic influences on human blood metabolites","volume":"46","author":"Shin","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1038\/s41586-022-05473-8","article-title":"FinnGen provides genetic insights from a well-phenotyped isolated population","volume":"613","author":"Kurki","year":"2023","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"k601","DOI":"10.1136\/bmj.k601","article-title":"Reading Mendelian randomisation studies: A guide, glossary, and checklist for clinicians","volume":"362","author":"Davies","year":"2018","journal-title":"BMJ"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"D1265","DOI":"10.1093\/nar\/gkad976","article-title":"DrugBank 6.0: The DrugBank Knowledgebase for 2024","volume":"52","author":"Knox","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1093\/postmj\/qgad052","article-title":"Identification of blood metabolites linked to the risk of intervertebral disc diseases: A comprehensive Mendelian randomization study","volume":"99","author":"Ji","year":"2023","journal-title":"Postgrad. Med. J."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Jiang, N., Wang, Q., Jiang, J., and Li, L. (2024). The role of micronutrients and serum metabolites in intervertebral disk degeneration: Insights from a Mendelian randomization study and mediation analysis. Front. Nutr., 11.","DOI":"10.3389\/fnut.2024.1428403"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3897","DOI":"10.2147\/JPR.S487156","article-title":"Assessing the genetic causal effects between blood metabolites and spinal pain: A bidirectional two-sample Mendelian randomization study","volume":"17","author":"Wu","year":"2024","journal-title":"J. Pain Res."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Teraguchi, M., Yoshimura, N., Hashizume, H., Muraki, S., Yamada, H., Oka, H., Minamide, A., Ishimoto, Y., Nagata, K., and Kagotani, R. (2016). Metabolic syndrome components are associated with intervertebral disc degeneration: The Wakayama Spine Study. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0147565"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1097\/BRS.0000000000004198","article-title":"Association of lumbar MRI findings with current and future back pain in a population-based cohort study","volume":"47","author":"Kasch","year":"2022","journal-title":"Spine"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1161\/HYPERTENSIONAHA.123.22454","article-title":"Asymmetric dimethylarginine enables depolarizing spikes and vasospasm in mesenteric and coronary resistance arteries","volume":"81","author":"Ng","year":"2024","journal-title":"Hypertension"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"116816","DOI":"10.1016\/j.bmc.2022.116816","article-title":"On the kinetic mechanism of dimethylarginine dimethylaminohydrolase","volume":"66","author":"Johnson","year":"2022","journal-title":"Bioorg. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1111\/j.1469-7580.2007.00816.x","article-title":"Inhibition of vertebral endplate perfusion results in decreased intervertebral disc intranuclear diffusive transport","volume":"211","author":"Lezuo","year":"2007","journal-title":"J. Anat."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1002\/jbmr.4009","article-title":"Intervertebral disc degeneration is associated with aberrant endplate remodeling and reduced small molecule transport","volume":"35","author":"Ashinsky","year":"2020","journal-title":"J. Bone Miner. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"9914417","DOI":"10.1155\/2021\/9914417","article-title":"LDHA-mediated glycolytic metabolism in nucleus pulposus cells is a potential therapeutic target for intervertebral disc degeneration","volume":"2021","author":"Wu","year":"2021","journal-title":"BioMed Res. Int."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.freeradbiomed.2024.08.007","article-title":"HIF-1\u03b1 protects nucleus pulposus cells from oxidative stress-induced mitochondrial impairment through PDK-1","volume":"224","author":"Liu","year":"2024","journal-title":"Free Radic. Biol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/s42003-024-06000-3","article-title":"Glutamine suppresses senescence and promotes autophagy through glycolysis inhibition-mediated AMPK\u03b1 lactylation in intervertebral disc degeneration","volume":"7","author":"Zhang","year":"2024","journal-title":"Commun. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e2416149","DOI":"10.1002\/advs.202416149","article-title":"Glycolysis-derived lactate induces ACSL4 expression and lactylation to activate ferroptosis during intervertebral disc degeneration","volume":"12","author":"Sun","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1038\/s41586-019-1678-1","article-title":"Metabolic regulation of gene expression by histone lactylation","volume":"574","author":"Zhang","year":"2019","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"37360","DOI":"10.1038\/srep37360","article-title":"Acidic pH promotes intervertebral disc degeneration: Acid-sensing ion channel-3 as a potential therapeutic target","volume":"6","author":"Gilbert","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e70032","DOI":"10.1002\/jsp2.70032","article-title":"Analysis of key differential metabolites in intervertebral disc degeneration based on untargeted metabolomics","volume":"8","author":"Zhou","year":"2025","journal-title":"JOR Spine"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cmet.2016.08.009","article-title":"One-carbon metabolism in health and disease","volume":"25","author":"Ducker","year":"2017","journal-title":"Cell Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1124\/pharmrev.121.000408","article-title":"Acylcarnitines: Nomenclature, biomarkers, therapeutic potential, drug targets, and clinical trials","volume":"74","author":"Dambrova","year":"2022","journal-title":"Pharmacol. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"101081","DOI":"10.1016\/j.mtbio.2024.101081","article-title":"A natural hydrogel complex improves intervertebral disc degeneration by correcting fatty acid metabolism and inhibiting nucleus pulposus cell pyroptosis","volume":"26","author":"Wang","year":"2024","journal-title":"Mater. Today Bio"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"167635","DOI":"10.1016\/j.bbadis.2024.167635","article-title":"Meteorin-like protein alleviates intervertebral disc degeneration by suppressing lipid accumulation in nucleus pulposus cells via PPAR\u03b1\u2013CPT1A activation","volume":"1871","author":"Huang","year":"2025","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2871","DOI":"10.1038\/s41598-017-03069-1","article-title":"Human dimethylarginine dimethylaminohydrolase 1 inhibition by proton pump inhibitors and the cardiovascular risk marker asymmetric dimethylarginine: In vitro and in vivo significance","volume":"7","author":"Tommasi","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"130149","DOI":"10.1016\/j.bbagen.2022.130149","article-title":"Esomeprazole covalently interacts with the cardiovascular enzyme dimethylarginine dimethylaminohydrolase: Insights into the cardiovascular risk of proton pump inhibitors","volume":"1866","author":"Smith","year":"2022","journal-title":"Biochim. Biophys. Acta Gen. Subj."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1126\/science.aaa1299","article-title":"Epilepsy treatment: Targeting LDH enzymes with a stiripentol analog to treat epilepsy","volume":"347","author":"Sada","year":"2015","journal-title":"Science"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.kint.2022.07.025","article-title":"PHYOX2: A pivotal randomized study of nedosiran in primary hyperoxaluria type 1 or 2","volume":"103","author":"Baum","year":"2023","journal-title":"Kidney Int."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1016\/j.ekir.2021.01.029","article-title":"Hepatic lactate dehydrogenase A: An RNA interference target for the treatment of all known types of primary hyperoxaluria","volume":"6","author":"Ariceta","year":"2021","journal-title":"Kidney Int. Rep."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/16\/9\/673\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T12:56:14Z","timestamp":1789390574000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/16\/9\/673"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,13]]},"references-count":38,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["metabo16090673"],"URL":"https:\/\/doi.org\/10.3390\/metabo16090673","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,13]]}}}