{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T15:19:23Z","timestamp":1781623163446,"version":"3.54.5"},"reference-count":39,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T00:00:00Z","timestamp":1744675200000},"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":["82305172"],"award-info":[{"award-number":["82305172"]}],"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":["82230119"],"award-info":[{"award-number":["82230119"]}],"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":["SZ2022KF03"],"award-info":[{"award-number":["SZ2022KF03"]}],"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":["2020B1515130005"],"award-info":[{"award-number":["2020B1515130005"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Technology Research Projects of the State Key Laboratory of Dampness Syndrome of Chinese Medicine","award":["82305172"],"award-info":[{"award-number":["82305172"]}]},{"name":"Technology Research Projects of the State Key Laboratory of Dampness Syndrome of Chinese Medicine","award":["82230119"],"award-info":[{"award-number":["82230119"]}]},{"name":"Technology Research Projects of the State Key Laboratory of Dampness Syndrome of Chinese Medicine","award":["SZ2022KF03"],"award-info":[{"award-number":["SZ2022KF03"]}]},{"name":"Technology Research Projects of the State Key Laboratory of Dampness Syndrome of Chinese Medicine","award":["2020B1515130005"],"award-info":[{"award-number":["2020B1515130005"]}]},{"name":"Guangdong Basic and Applied Basic Research Foundation","award":["82305172"],"award-info":[{"award-number":["82305172"]}]},{"name":"Guangdong Basic and Applied Basic Research Foundation","award":["82230119"],"award-info":[{"award-number":["82230119"]}]},{"name":"Guangdong Basic and Applied Basic Research Foundation","award":["SZ2022KF03"],"award-info":[{"award-number":["SZ2022KF03"]}]},{"name":"Guangdong Basic and Applied Basic Research Foundation","award":["2020B1515130005"],"award-info":[{"award-number":["2020B1515130005"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>Background: Previous studies have demonstrated that the gut microbiota (GM) and rheumatoid arthritis (RA) are significantly associated, but the causal relationship has not been fully elucidated. Methods: We investigated the association between GM and RA using Mendelian randomization (MR) with two independent samples. Our study aimed to determine the causal relationship between gut microbiota and RA, including its seronegative and seropositive subtypes. Using data from a genome-wide association study (GWAS), we identified instrumental variables for 211 gut bacteria types. We then analyzed the FinnGen GWAS dataset, which included 3877 seronegative RA cases and 285,035 controls, along with 4290 seropositive RA cases and 368,362 controls, employing the inverse variance weighted (IVW) method and rigorous tests for pleiotropy and heterogeneity to ensure reliability. Results: The IVW results revealed that Prevotella 9, Sutterella, and Christensenellaceae R.7 exhibited an adverse correlation with seronegative RA (p &lt; 0.05). Additionally, Lachnospira, Slackia, Roseburia, Barnesiella, and Prevotella 7 were associated with a reduced occurrence of seropositive RA (p &lt; 0.05). Conversely, Ruminococcaceae UCG002 and Ruminococcus gauvreauii were linked to an increased susceptibility to seropositive RA (p &lt; 0.05). Notably, no significant heterogeneity (p &gt; 0.05) or pleiotropy (p &gt; 0.05) was detected in the analysis of the significant MR estimates. Conclusions: Our study suggested significant associations between several gut bacteria and RA subtypes, indicating a potential microbial influence on RA development. These findings enhance our understanding of the gut-joint axis in RA and highlight promising targets for future microbiota-based therapies.<\/jats:p>","DOI":"10.3390\/pathogens14040385","type":"journal-article","created":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T03:59:06Z","timestamp":1744689546000},"page":"385","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Investigating Correlation Between Gut Microbiota and Rheumatoid Arthritis Subtypes by Mendelian Randomization"],"prefix":"10.3390","volume":"14","author":[{"given":"Jiaqi","family":"Wu","sequence":"first","affiliation":[{"name":"School of Pharmacy, Faculty of Medicine, Macau University of Science and Technology, Macau 999078, China"},{"name":"The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Peng","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Faculty of Medicine, Macau University of Science and Technology, Macau 999078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruimin","family":"Tian","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Faculty of Medicine, Macau University of Science and Technology, Macau 999078, China"},{"name":"The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5772-072X","authenticated-orcid":false,"given":"Hao","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Faculty of Medicine, Macau University of Science and Technology, Macau 999078, China"},{"name":"Macau Institute for Translational Medicine and Innovation, University of Macau, Macau 999078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huating","family":"Hu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Faculty of Medicine, Macau University of Science and Technology, Macau 999078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingchun","family":"Huang","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youhua","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Faculty of Medicine, Macau University of Science and Technology, Macau 999078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Liu","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hudan","family":"Pan","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"18001","DOI":"10.1038\/nrdp.2018.1","article-title":"Rheumatoid arthritis","volume":"4","author":"Smolen","year":"2018","journal-title":"Nat. Rev. Dis. Primers."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1038\/nri.2016.124","article-title":"The immunopathogenesis of seropositive rheumatoid arthritis: From triggering to targeting","volume":"17","author":"Catrina","year":"2017","journal-title":"Nat. Rev. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1186\/s13075-015-0736-9","article-title":"Rheumatoid factor, not antibodies against citrullinated proteins, is associated with baseline disease activity in rheumatoid arthritis clinical trials","volume":"17","author":"Aletaha","year":"2015","journal-title":"Arthritis Res. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2113","DOI":"10.1002\/art.20316","article-title":"Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of rheumatoid arthritis","volume":"50","author":"Huizinga","year":"2004","journal-title":"Arthritis Rheum."},{"key":"ref_5","first-page":"1009","article-title":"Mortality trends in rheumatoid arthritis: The role of rheumatoid factor","volume":"35","author":"Gonzalez","year":"2008","journal-title":"J. Rheumatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1016\/j.autrev.2018.02.014","article-title":"ACPA mediates the interplay between innate and adaptive immunity in rheumatoid arthritis","volume":"17","author":"Dong","year":"2018","journal-title":"Autoimmun. Rev."},{"key":"ref_7","first-page":"554","article-title":"Seronegative rheumatoid arthritis: One year in review 2023","volume":"41","author":"Gandolfo","year":"2023","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1038\/sj.embor.7400731","article-title":"The gut flora as a forgotten organ","volume":"7","author":"Shanahan","year":"2006","journal-title":"EMBO Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1038\/s41584-021-00585-3","article-title":"The gut-joint axis in rheumatoid arthritis","volume":"17","author":"Zaiss","year":"2021","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1038\/s41584-018-0070-0","article-title":"Rheumatoid arthritis and the mucosal origins hypothesis: Protection turns to destruction","volume":"14","author":"Holers","year":"2018","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e418","DOI":"10.1016\/S2665-9913(20)30064-3","article-title":"Associations between gut microbiota and genetic risk for rheumatoid arthritis in the absence of disease: A cross-sectional study","volume":"2","author":"Wells","year":"2020","journal-title":"Lancet Rheumatol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Rogier, R., Ederveen, T.H.A., Boekhorst, J., Wopereis, H., Scher, J.U., Manasson, J., Frambach, S.J., Knol, J., Garssen, J., and van der Kraan, P.M. (2017). Aberrant intestinal microbiota due to IL-1 receptor antagonist deficiency promotes IL-17- and TLR4-dependent arthritis. Microbiome, 5.","DOI":"10.1186\/s40168-017-0278-2"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1038\/nm.3914","article-title":"The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment","volume":"21","author":"Zhang","year":"2015","journal-title":"Nat. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e86416","DOI":"10.7554\/eLife.86416","article-title":"The next step in Mendelian randomization","volume":"12","author":"Weith","year":"2023","journal-title":"Elife"},{"key":"ref_15","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_16","doi-asserted-by":"crossref","unstructured":"Wang, J., Kurilshikov, A., Radjabzadeh, D., Turpin, W., Croitoru, K., Bonder, M.J., Jackson, M.A., Medina-Gomez, C., Frost, F., and Homuth, G. (2018). Meta-analysis of human genome-microbiome association studies: The MiBioGen consortium initiative. Microbiome, 6.","DOI":"10.1186\/s40168-018-0479-3"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1038\/s41588-020-00763-1","article-title":"Large-scale association analyses identify host factors influencing human gut microbiome composition","volume":"53","author":"Kurilshikov","year":"2021","journal-title":"Nat. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Ji, X., Yang, Q., Zhu, X.L., Xu, L., Guo, J.Y., Rong, Y., and Cai, Y.L. (2023). Association between gut microbiota and endometriosis: A two-sample Mendelian randomization study. Front. Microbiol., 14.","DOI":"10.3389\/fmicb.2023.1188458"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Li, P., Wang, H., Guo, L., Gou, X., Chen, G., Lin, D., Fan, D., Guo, X., and Liu, Z. (2022). Association between gut microbiota and preeclampsia-eclampsia: A two-sample Mendelian randomization study. BMC Med., 20.","DOI":"10.1186\/s12916-022-02657-x"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1038\/s41588-019-0350-x","article-title":"Causal relationships among the gut microbiome, short-chain fatty acids and metabolic diseases","volume":"51","author":"Sanna","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/s41588-018-0099-7","article-title":"Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases","volume":"50","author":"Verbanck","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1093\/ije\/dyq151","article-title":"Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants","volume":"40","author":"Pierce","year":"2011","journal-title":"Int. J. Epidemiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1880","DOI":"10.1002\/sim.6835","article-title":"Combining information on multiple instrumental variables in Mendelian randomization: Comparison of allele score and summarized data methods","volume":"35","author":"Burgess","year":"2016","journal-title":"Stat. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1093\/ije\/dyv080","article-title":"Mendelian randomization with invalid instruments: Effect estimation and bias detection through Egger regression","volume":"44","author":"Bowden","year":"2015","journal-title":"Int. J. Epidemiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/s41579-021-00559-y","article-title":"Prevotella diversity, niches and interactions with the human host","volume":"19","author":"Tett","year":"2021","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1136\/annrheumdis-2018-214514","article-title":"Prevotella copri in individuals at risk for rheumatoid arthritis","volume":"78","author":"Lesker","year":"2019","journal-title":"Ann. Rheum. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1136\/annrheumdis-2019-215743","article-title":"Metagenome-wide association study of gut microbiome revealed novel aetiology of rheumatoid arthritis in the Japanese population","volume":"79","author":"Kishikawa","year":"2020","journal-title":"Ann. Rheum. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Lee, J.Y., Mannaa, M., Kim, Y., Kim, G.T., and Seo, Y.S. (2019). Comparative analysis of fecal microbiota composition between Rheumatoid arthritis and osteoarthritis patients. Genes, 10.","DOI":"10.3390\/genes10100748"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Zhao, Y., Chen, B., Li, S., Yang, L., Zhu, D., Wang, Y., Wang, H., Wang, T., Shi, B., and Gai, Z. (2018). Detection and characterization of bacterial nucleic acids in culture-negative synovial tissue and fluid samples from rheumatoid arthritis or osteoarthritis patients. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-32675-w"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2646","DOI":"10.1002\/art.39783","article-title":"Dysbiosis contributes to arthritis development via activation of autoreactive T cells in the intestine","volume":"68","author":"Maeda","year":"2016","journal-title":"Arthritis Rheumatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1002\/art.40003","article-title":"Evidence of the immune relevance of Prevotella copri, a gut microbe, in patients with Rheumatoid arthritis","volume":"69","author":"Pianta","year":"2017","journal-title":"Arthritis Rheumatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2878","DOI":"10.1002\/art.39785","article-title":"Suppression of inflammatory arthritis by human gut-derived Prevotella histicola in humanized mice","volume":"68","author":"Marietta","year":"2016","journal-title":"Arthritis Rheumatol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Sun, Y., Chen, Q., Lin, P., Xu, R., He, D., Ji, W., Bian, Y., Shen, Y., Li, Q., and Liu, C. (2019). Characteristics of gut microbiota in patients with Rheumatoid arthritis in Shanghai, China. Front. Cell Infect. Microbiol., 9.","DOI":"10.3389\/fcimb.2019.00369"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4695","DOI":"10.1007\/s10238-023-01161-7","article-title":"Alterations of the intestinal microbiome and metabolome in women with rheumatoid arthritis","volume":"23","author":"Yun","year":"2023","journal-title":"Clin. Exp. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1002\/art.42658","article-title":"Shared and Distinct Gut Microbiota in Spondyloarthritis, Acute Anterior Uveitis, and Crohn\u2019s Disease","volume":"76","author":"Essex","year":"2024","journal-title":"Arthritis Rheumatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/nature12726","article-title":"Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation","volume":"504","author":"Arpaia","year":"2013","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Zhang, Q., Zhou, J., Zhang, X., Mao, R., and Zhang, C. (2023). Mendelian randomization supports causality between gut microbiota and chronic hepatitis B. Front. Microbiol., 14.","DOI":"10.3389\/fmicb.2023.1243811"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s13075-023-03260-y","article-title":"Impaired immune tolerance mediated by reduced Tfr cells in rheumatoid arthritis linked to gut microbiota dysbiosis and altered metabolites","volume":"26","author":"Wu","year":"2024","journal-title":"Arthritis Res. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"S287","DOI":"10.1016\/j.joca.2017.02.484","article-title":"Alterations of gut microbiome in rheumatoid arthritis","volume":"25","author":"Wu","year":"2017","journal-title":"Osteoarthr. Cartil."}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/14\/4\/385\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:14:40Z","timestamp":1760030080000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/14\/4\/385"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,15]]},"references-count":39,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["pathogens14040385"],"URL":"https:\/\/doi.org\/10.3390\/pathogens14040385","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,15]]}}}