{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T13:37:31Z","timestamp":1790861851939,"version":"4.1.0"},"reference-count":44,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2024,9,15]],"date-time":"2024-09-15T00:00:00Z","timestamp":1726358400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81072960"],"award-info":[{"award-number":["81072960"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["H2902"],"award-info":[{"award-number":["H2902"]}],"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","award":["ZR2020MH391"],"award-info":[{"award-number":["ZR2020MH391"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Eur J Clin Investigation"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Inflammatory cytokines and migraines have been associated in previous research, but the underlying mechanisms of action are still elusive. The biological functions of metabolites are crucial in the onset of migraine. Our goals were to clarify the cause\u2010and\u2010effect connection between inflammatory cytokines and migraines and explore the potential mediating function of metabolites.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Utilizing summary\u2010level data from genome\u2010wide association studies (GWAS), we conducted two\u2010sample Mendelian randomization (MR) analyses to evaluate the possible causal connection between inflammatory cytokines and migraines. A two\u2010step MR analysis was employed to further investigate the potential mediating pathways of metabolites.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>MR analysis identified a total of 9 inflammatory cytokines that were genetically associated with migraines, and we subsequently identified 21 mediated relationships, with 20 metabolites (13 metabolites, 7 ratios) acting as potential mediators between 8 inflammatory cytokines and migraine. The 9 inflammatory cytokines were beta\u2010nerve growth factor levels (\u03b2\u2010NGF), T\u2010cell surface glycoprotein CD5 levels (CD5), T\u2010cell surface glycoprotein CD6 isoform levels (CD6), C\u2010X\u2010C motif chemokine 11 levels (CXCL11), interleukin\u20104 levels (IL\u20104), oncostatin\u2010M levels (OSM), signalling lymphocytic activation molecule levels (SLAM), C\u2010C motif chemokine 25 levels (CCL25) and monocyte chemoattractant protein\u20101 levels (MCP\u20101).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our research findings provide evidence for both a causal connection between inflammatory cytokines and migraines, as well as a metabolite\u2010mediated pathway. These biomarkers facilitate the detection, diagnosis and treatment of migraines while offering fresh perspectives on their underlying mechanisms.<\/jats:p><\/jats:sec>","DOI":"10.1111\/eci.14316","type":"journal-article","created":{"date-parts":[[2024,9,16]],"date-time":"2024-09-16T06:18:29Z","timestamp":1726467509000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The 1400 metabolite\u2010mediated relationship between 91 inflammatory cytokines and migraine: An exploratory two\u2010step Mendelian randomization study"],"prefix":"10.1111","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-0742-5807","authenticated-orcid":false,"given":"Huiqi","family":"Sun","sequence":"first","affiliation":[{"name":"First school of clinical medicine Shandong University of Traditional Chinese Medicine  Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xutong","family":"Lv","sequence":"additional","affiliation":[{"name":"First school of clinical medicine Shandong University of Traditional Chinese Medicine  Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongbin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Affiliated Hospital of Shandong University of Traditional Chinese Medicine  Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Shen","sequence":"additional","affiliation":[{"name":"First school of clinical medicine Shandong University of Traditional Chinese Medicine  Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongxiu","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Affiliated Hospital of Shandong University of Traditional Chinese Medicine  Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,9,15]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)32162-0"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)32160-7"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)31833-0"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s10194-022-01402-2"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.4103\/0972-2327.182302"},{"issue":"5","key":"e_1_2_11_7_1","first-page":"930","article-title":"Serum levels of endocan, claudin\u20105 and cytokines in migraine","volume":"20","author":"Y\u00fccel M","year":"2016","journal-title":"Eur Rev Med Pharmacol Sci"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2021-327992"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0014-2999(00)00153-9"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12944-018-0665-0"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00968-y"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2017.17219"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-023-01588-w"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01270-1"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.21758"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10654-021-00757-1"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyu176"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/ageing\/afac256"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10654-017-0255-x"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1348347"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2018.12.006"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brs.2017.02.006"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/ped.13636"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI147334"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2990.2010.01089.x"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2018.01.018"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.202201533"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1586\/1744666X.2.5.759"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-04-153627"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-016-0236-7"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0952-7915(00)00201-6"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2020.107158"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1177\/0022034510376041"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.2147\/JIR.S313179"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2016.71"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.490280213"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1186\/s10194-021-01285-9"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abg2752"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1111\/head.13892"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1136\/bcr-2021-243987"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.17.1.701"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.2174\/0115672026284009231120065521"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/ajg.2016.517"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.2174\/1570159X17666181227165722"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.n1448"}],"container-title":["European Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/eci.14316","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,2]],"date-time":"2024-12-02T04:47:29Z","timestamp":1733114849000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/eci.14316"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,15]]},"references-count":44,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2024,12]]}},"alternative-id":["10.1111\/eci.14316"],"URL":"https:\/\/doi.org\/10.1111\/eci.14316","archive":["Portico"],"relation":{},"ISSN":["0014-2972","1365-2362"],"issn-type":[{"value":"0014-2972","type":"print"},{"value":"1365-2362","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,15]]},"assertion":[{"value":"2024-08-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-08-20","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-09-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e14316"}}