{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T16:02:54Z","timestamp":1779292974843,"version":"3.51.4"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,10,14]],"date-time":"2024-10-14T00:00:00Z","timestamp":1728864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"Purpose<\/jats:title>Hashimoto\u2019s thyroiditis (HT) is one of the most commonly encountered types of autoimmune thyroid disorders (AITDs), influenced by environmental factors, genetics, and the immune system. Previous research has shown a correlation between gut microbiota and HT, as well as the involvement of immune cells in its onset and progression. We aimed to investigate whether immune cells act as intermediaries in the causal relationship between gut microbiota and HT.<\/jats:p><\/jats:sec>Methods<\/jats:title>In this study, we conducted bidirectional two-sample Mendelian randomization (MR) analyses to explore the relationship between gut microbiota and HT using data from genome-wide association studies (GWAS) and the MiBioGen study. Subsequently, MR analyses were performed to investigate the interactions between 731 immune cells and gut microbiota. Additionally, an MR analysis was performed to examine the association between HT and these 731 immune cells, using a GWAS dataset that included 3,757 European subjects. This approach provided insights into the impact of 22 million genetic variants on 731 immune cell signatures.<\/jats:p><\/jats:sec>Results<\/jats:title>There was a causal relationship between the increase in the number of 15 gut microbiota and HT. We observed that the genus Akkermansia<\/jats:italic>, family Alcaligenaceae, family Desulfovibrionaceae, family Verrucomicrobiaceae, class Verrucomicrobiae, order Verrucomicrobiales, phylum Verrucomicrobia, class Alphaproteobacteria, order Desulfovibrionales, genus Ruminococcus torques<\/jats:italic> group, genus Butyrivibrio<\/jats:italic>, and genus Coprococcus3<\/jats:italic> were negatively correlated with HT. In addition, the genus Intestinimonas<\/jats:italic>, genus Turicibacter<\/jats:italic>, and genus Anaerostipes<\/jats:italic> were positively correlated with HT. We identified EM CD4\u2009+\u2009T cells as a mediator between the gut microbiota and HT.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>In conclusion, we presented causal associations between the EM CD4\u2009+\u2009T cell-mediated gut microbiota and HT, as inferred from the MR findings derived from extensive aggregated GWAS data. Our research offers guidance and direction for treating and preventing HT.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmicb.2024.1463394","type":"journal-article","created":{"date-parts":[[2024,10,14]],"date-time":"2024-10-14T10:17:48Z","timestamp":1728901068000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Role of immune cells in mediating the effect of gut microbiota on Hashimoto\u2019s thyroiditis: a 2-sample Mendelian randomization study"],"prefix":"10.3389","volume":"15","author":[{"given":"Xiao-Qing","family":"Pei","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen-Hao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue-Hua","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tong-Xin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing-Yu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhen-Dan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hua-Wei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,10,14]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1055\/s-0035-1548832","article-title":"The pathogenesis of Hashimoto's thyroiditis: further developments in our understanding","volume":"47","author":"Ajjan","year":"2015","journal-title":"Horm. Metab. Res."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1016\/j.intimp.2012.02.003","article-title":"The combination of \u0131nterleukin-10 \u22121082 and tumor necrosis factor \u03b1 \u2212308 or \u0131nterleukin-6 \u2212174 genes polymorphisms suggests an association with susceptibility to Hashimoto's thyroiditis","volume":"12","author":"Baki","year":"2012","journal-title":"Int. Immunopharmacol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1007\/s12079-018-0486-y","article-title":"Comprehensive network map of interferon gamma signaling","volume":"12","author":"Bhat","year":"2018","journal-title":"J. Cell Commun. Signal."},{"key":"ref4","doi-asserted-by":"publisher","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":"ref5","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1002\/gepi.21965","article-title":"Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator","volume":"40","author":"Bowden","year":"2016","journal-title":"Genet. Epidemiol."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1038\/s41575-022-00631-9","article-title":"Akkermansia muciniphila: paradigm for next-generation beneficial microorganisms","volume":"19","author":"Cani","year":"2022","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1016\/j.autrev.2014.01.007","article-title":"Hashimoto thyroiditis: clinical and diagnostic criteria","volume":"13","author":"Caturegli","year":"2014","journal-title":"Autoimmun. Rev."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"7455494","DOI":"10.1155\/2022\/7455494","article-title":"Saikosaponin-d attenuates Hashimoto's thyroiditis by regulating macrophage polarization","volume":"2022","author":"Du","year":"2022","journal-title":"J Immunol Res"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1046159","DOI":"10.3389\/fendo.2022.1046159","article-title":"Serum metabolomic analysis in patients with Hashimoto\u2019s thyroiditis","volume":"13","author":"Jiang","year":"2022","journal-title":"Front. Endocrinol."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"4851","DOI":"10.1093\/bioinformatics\/btz469","article-title":"PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations","volume":"35","author":"Kamat","year":"2019","journal-title":"Bioinformatics"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1642","DOI":"10.1038\/s41440-024-01627-5","article-title":"Akkermansia muciniphila extracellular vesicles have a protective effect against hypertension","volume":"47","author":"Kim","year":"2024","journal-title":"Hyper. Res."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"1769","DOI":"10.3390\/nu12061769","article-title":"Thyroid-gut-Axis: how does the microbiota influence thyroid function?","volume":"12","author":"Knezevic","year":"2020","journal-title":"Nutrients"},{"key":"ref13","doi-asserted-by":"publisher","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":"ref14","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1186\/s12916-022-02657-x","article-title":"Association between gut microbiota and preeclampsia-eclampsia: a two-sample Mendelian randomization study","volume":"20","author":"Li","year":"2022","journal-title":"BMC Med."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1186\/s12866-022-02739-z","article-title":"Analysis of gut microbiota diversity in Hashimoto's thyroiditis patients","volume":"22","author":"Liu","year":"2022","journal-title":"BMC Microbiol."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"21674","DOI":"10.3390\/ijms151221674","article-title":"Th17\/Treg cells imbalance and GITRL profile in patients with Hashimoto's thyroiditis","volume":"15","author":"Liu","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"e0081623","DOI":"10.1128\/msphere.00816-23","article-title":"Anaerostipes hadrus, a butyrate-producing bacterium capable of metabolizing 5-fluorouracil","volume":"9","author":"Liu","year":"2024","journal-title":"Clin. Vaccine Immunol."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1186\/s12916-023-02761-6","article-title":"Causal relationship between gut microbiota and cancers: a two-sample Mendelian randomisation study","volume":"21","author":"Long","year":"2023","journal-title":"BMC Med."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"3669","DOI":"10.1038\/s41467-023-39403-7","article-title":"Gut microbiota Turicibacter strains differentially modify bile acids and host lipids","volume":"14","author":"Lynch","year":"2023","journal-title":"Nat. Commun."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.cyto.2016.08.003","article-title":"TNF activity and T cells","volume":"101","author":"Mehta","year":"2018","journal-title":"Cytokine"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1186\/s12964-022-00849-9","article-title":"The activation of PPAR\u03b3 enhances Treg responses through up-regulating CD36\/CPT1-mediated fatty acid oxidation and subsequent N-glycan branching of T\u03b2RII\/IL-2R\u03b1","volume":"20","author":"Miao","year":"2022","journal-title":"Cell Commun. Signal"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"6580","DOI":"10.3390\/ijms23126580","article-title":"Metabolic characteristics of Hashimoto's thyroiditis patients and the role of microelements and diet in the disease management-an overview","volume":"23","author":"Mikulska","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"2708","DOI":"10.4103\/jfmpc.jfmpc_456_19","article-title":"Prevalence of depression among hypothyroid patients attending the primary healthcare and endocrine clinics of king Fahad Hospital of the University (KFHU)","volume":"8","author":"Mohammad","year":"2019","journal-title":"J. Family Med. Prim. Care"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"3237","DOI":"10.1038\/s41598-023-30266-y","article-title":"Akkermansia muciniphila exerts immunomodulatory and anti-inflammatory effects on gliadin-stimulated THP-1 derived macrophages","volume":"13","author":"Molaaghaee-Rouzbahani","year":"2023","journal-title":"Sci. Rep."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/j.cyto.2008.05.002","article-title":"Mycobacterium tuberculosis-specific CD4+, IFN\u03b3+, and TNF\u03b1+ multifunctional memory T cells coexpress GM-CSF","volume":"43","author":"Mueller","year":"2008","journal-title":"Cytokine"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"932","DOI":"10.1080\/16078454.2022.2113356","article-title":"A mouse model of irradiation and spleen-thymus lymphocyte infusion induced aplastic anemia","volume":"27","author":"Ni","year":"2022","journal-title":"Hematology"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1177\/0962280210394459","article-title":"Using multiple genetic variants as instrumental variables for modifiable risk factors","volume":"21","author":"Palmer","year":"2012","journal-title":"Stat. Methods Med. Res."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1182\/bloodadvances.2019000836","article-title":"Robust CD4+ T-cell recovery in adults transplanted with cord blood and no antithymocyte globulin","volume":"4","author":"Politikos","year":"2020","journal-title":"Blood Adv."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"101367","DOI":"10.1016\/j.beem.2019.101367","article-title":"Hashimotos\u2019 thyroiditis: epidemiology, pathogenesis, clinic and therapy","volume":"33","author":"Ragusa","year":"2019","journal-title":"Best Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"102649","DOI":"10.1016\/j.autrev.2020.102649","article-title":"Hashimoto's thyroiditis: an update on pathogenic mechanisms, diagnostic protocols, therapeutic strategies, and potential malignant transformation","volume":"19","author":"Ralli","year":"2020","journal-title":"Autoimmun. Rev."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"1415","DOI":"10.1038\/s41588-021-00931-x","article-title":"A cross-population atlas of genetic associations for 220 human phenotypes","volume":"53","author":"Sakaue","year":"2021","journal-title":"Nat. Genet."},{"key":"ref32","first-page":"112","article-title":"Serum concentrations of leptin, adiponectin, and interleukin-6 in postmenopausal women with Hashimoto's thyroiditis","volume":"61","author":"Siemi\u0144ska","year":"2010","journal-title":"Endokrynol. Pol."},{"key":"ref33","doi-asserted-by":"publisher","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":"ref34","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1007\/s11154-018-9467-y","article-title":"Gut microbiota and Hashimoto's thyroiditis","volume":"19","author":"Virili","year":"2018","journal-title":"Rev. Endocr. Metab. 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