{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T12:05:04Z","timestamp":1781525104078,"version":"3.54.1"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,28]],"date-time":"2021-05-28T00:00:00Z","timestamp":1622160000000},"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. Cell Dev. Biol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Hashimoto\u2019s thyroiditis (HT) is a common autoimmune disease characterized by high levels of thyroid peroxidase antibody (TPOAb) and thyroid globulin antibody (TgAb) as well as infiltration of lymphocytes in thyroid. In recent years, metformin has been proven to be effective in a variety of autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This study systematically explored the therapeutic effect of metformin on HT and its underlying mechanism by comprehensively utilizing methods including animal model, <jats:italic>in vitro<\/jats:italic> cell culture and differentiation, mRNA sequencing and 16S rRNA sequencing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Findings<\/jats:title><jats:p>We found that metformin indeed had a therapeutic effect on mice with HT mainly by reducing TgAb and lymphocyte infiltration in thyroid tissue. In addition, metformin also significantly suppressed the number and function of Th17 cells and M1 macrophages polarization in HT mice. Furthermore, metformin can inhibit the differentiation and function of Th17 <jats:italic>in vitro<\/jats:italic>. The results of mRNA sequencing of thyroid tissue illustrated that the therapeutic effect of metformin on HT was mainly achieved by regulating immune pathways. 16S RNA sequencing of the intestinal flora found that the intestinal flora of HT mice differs significantly from that of the normal mice and also were altered by metformin treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>These experiments provided a preliminary theoretical basis for the clinical application of metformin in the treatment of HT.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcell.2021.685522","type":"journal-article","created":{"date-parts":[[2021,5,28]],"date-time":"2021-05-28T08:21:47Z","timestamp":1622190107000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":23,"title":["Metformin Reverses Hashimoto\u2019s Thyroiditis by Regulating Key Immune Events"],"prefix":"10.3389","volume":"9","author":[{"given":"Xi","family":"Jia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyu","family":"Zhai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunjie","family":"Qu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianjun","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuerong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-an","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaohui","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1016\/j.autrev.2014.10.016","article-title":"Autoimmune thyroid disorders.","volume":"14","author":"Antonelli","year":"2015","journal-title":"Autoimmun. Rev."},{"key":"B2","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1007\/s11154-016-9363-2","article-title":"Molecular mimicry and autoimmune thyroid disease.","volume":"17","author":"Benvenga","year":"2016","journal-title":"Rev. Endocr. Metab. Disord."},{"key":"B3","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1016\/j.autrev.2014.11.009","article-title":"Behcet\u2019s syndrome patients exhibit specific microbiome signature.","volume":"14","author":"Consolandi","year":"2015","journal-title":"Autoimmun. Rev."},{"key":"B4","doi-asserted-by":"publisher","first-page":"54","DOI":"10.2337\/dc16-1324","article-title":"Metformin is associated with higher relative abundance of mucin-degrading Akkermansia muciniphila and several short-chain fatty acid-producing microbiota in the gut.","volume":"40","author":"de la Cuesta-Zuluaga","year":"2017","journal-title":"Diabetes Care"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics9010012","article-title":"Helicobacter pylori infection and autoimmune thyroid diseases: the role of virulent strains.","volume":"9","author":"Figura","year":"2019","journal-title":"Antibiotics (Basel)"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1007\/s11892-017-0829-8","article-title":"Metformin: new preparations and nonglycemic benefits.","volume":"17","author":"Fujita","year":"2017","journal-title":"Curr. Diab. Rep."},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15628","article-title":"JunB is essential for IL-23-dependent pathogenicity of Th17 cells.","volume":"8","author":"Hasan","year":"2017","journal-title":"Nat. Commun."},{"key":"B8","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1080\/08916934.2020.1789969","article-title":"Metformin reduces autoimmune antibody levels in patients with Hashimoto\u2019s thyroiditis: a systematic review and meta-analysis.","volume":"53","author":"Jia","year":"2020","journal-title":"Autoimmunity"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13036-1","article-title":"Evaluation of 16S rRNA gene sequencing for species and strain-level microbiome analysis.","volume":"10","author":"Johnson","year":"2019","journal-title":"Nat. Commun."},{"key":"B10","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1101\/pdb.top084970","article-title":"RNA sequencing and analysis.","volume":"2015","author":"Kukurba","year":"2015","journal-title":"Cold Spring Harb. Protoc."},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0135858","article-title":"Metformin ameliorates inflammatory bowel disease by suppression of the STAT3 signaling pathway and regulation of the between Th17\/Treg balance.","volume":"10","author":"Lee","year":"2015","journal-title":"PLoS One"},{"key":"B12","doi-asserted-by":"publisher","first-page":"2661","DOI":"10.4049\/jimmunol.1403088","article-title":"Metformin suppresses systemic autoimmunity in roquin(san\/san) mice through inhibiting B cell differentiation into plasma cells via regulation of AMPK\/mTOR\/STAT3.","volume":"198","author":"Lee","year":"2017","journal-title":"J. Immunol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1089\/thy.2016.0432","article-title":"Glycyrrhizin, a direct HMGB1 antagonist, ameliorates inflammatory infiltration in a model of autoimmune thyroiditis via inhibition of TLR2-HMGB1 signaling.","volume":"27","author":"Li","year":"2017","journal-title":"Thyroid"},{"key":"B14","doi-asserted-by":"publisher","first-page":"2204","DOI":"10.1002\/jcp.27180","article-title":"The pathogenesis of thyroid autoimmune diseases: new T lymphocytes - cytokines circuits beyond the Th1-Th2 paradigm.","volume":"234","author":"Li","year":"2019","journal-title":"J. Cell Physiol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"746","DOI":"10.1016\/j.celrep.2017.04.004","article-title":"Sirtuin-1 activation controls tumor growth by impeding Th17 differentiation via STAT3 deacetylation.","volume":"19","author":"Limagne","year":"2017","journal-title":"Cell Rep."},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/srep24072","article-title":"Th17 responses and natural IgM antibodies are related to gut microbiota composition in systemic lupus erythematosus patients.","volume":"6","author":"Lopez","year":"2016","journal-title":"Sci. Rep."},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000017371","article-title":"Combination of COX-2 inhibitor and metformin attenuates rate of admission in patients with rheumatoid arthritis and diabetes in Taiwan.","volume":"98","author":"Lu","year":"2019","journal-title":"Medicine (Baltimore)"},{"key":"B18","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/j.tips.2020.01.003","article-title":"Context-dependent pharmacological effects of metformin on the immune system.","volume":"41","author":"Marcucci","year":"2020","journal-title":"Trends Pharmacol. Sci."},{"key":"B19","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1016\/0016-5085(78)90478-x","article-title":"Gut-thyroid interrelationships.","volume":"75","author":"Miller","year":"1978","journal-title":"Gastroenterology"},{"key":"B20","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1165\/rcmb.2013-0086MA","article-title":"Flow cytometric analysis of macrophages and dendritic cell subsets in the mouse lung.","volume":"49","author":"Misharin","year":"2013","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1016\/j.pharmthera.2018.07.007","article-title":"Endothelial function and dysfunction: impact of metformin.","volume":"192","author":"Nafisa","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1202","DOI":"10.1590\/s0100-879x2012007500168","article-title":"The increased but non-predominant expression of Th17- and Th1-specific cytokines in Hashimoto\u2019s thyroiditis but not in Graves\u2019 disease.","volume":"45","author":"Qin","year":"2012","journal-title":"Braz. J. Med. Biol. Res."},{"key":"B23","doi-asserted-by":"publisher","first-page":"116","DOI":"10.2174\/1573397114666180717145745","article-title":"Metformin one in a million efficient medicines for rheumatoid arthritis complications: inflammation, osteoblastogenesis, cardiovascular disease, malignancies.","volume":"15","author":"Rajaei","year":"2019","journal-title":"Curr. Rheumatol. Rev."},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2020.102649","article-title":"Hashimoto\u2019s 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":"B25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3791\/51709","article-title":"Next-generation sequencing of 16S ribosomal RNA gene amplicons.","volume":"19","author":"Sanschagrin","year":"2014","journal-title":"J. Vis. Exp."},{"key":"B26","doi-asserted-by":"publisher","first-page":"945","DOI":"10.2174\/1389450118666170613081730","article-title":"Metformin, a new era for an old drug in the treatment of immune mediated disease?","volume":"19","author":"Schuiveling","year":"2018","journal-title":"Curr. Drug Targets"},{"key":"B27","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1016\/j.autrev.2016.07.012","article-title":"Microbiota at the crossroads of autoimmunity.","volume":"15","author":"Shamriz","year":"2016","journal-title":"Autoimmun. Rev."},{"key":"B28","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1016\/j.tem.2019.07.015","article-title":"Metformin as anti-aging therapy: is it for everyone?","volume":"30","author":"Soukas","year":"2019","journal-title":"Trends Endocrinol. Metab."},{"key":"B29","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1590\/S0004-28032016000300012","article-title":"SEQUENCE SIMILARITY BETWEEN THYROID SELF-PROTEIN AND HEPATITIS C VIRUS POLYPROTEIN: possible triggering mechanism of autoimmune thyroiditis.","volume":"53","author":"Sousa Mde","year":"2016","journal-title":"Arq. Gastroenterol."},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1136\/lupus-2020-000429","article-title":"Effects of metformin on disease flares in patients with systemic lupus erythematosus: post hoc analyses from two randomised trials.","volume":"7","author":"Sun","year":"2020","journal-title":"Lupus Sci. Med."},{"key":"B31","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.jneuroim.2016.01.014","article-title":"Metformin ameliorates the development of experimental autoimmune encephalomyelitis by regulating T helper 17 and regulatory T cells in mice.","volume":"292","author":"Sun","year":"2016","journal-title":"J. Neuroimmunol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1038\/nrendo.2018.18","article-title":"Global epidemiology of hyperthyroidism and hypothyroidism.","volume":"14","author":"Taylor","year":"2018","journal-title":"Nat. Rev. Endocrinol."},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01236","article-title":"Metformin and autoimmunity: a \u201cnew deal\u201d of an old drug.","volume":"9","author":"Ursini","year":"2018","journal-title":"Front. Immunol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1016\/j.tips.2018.07.006","article-title":"Metformin as an anticancer agent.","volume":"39","author":"Vancura","year":"2018","journal-title":"Trends Pharmacol. Sci."},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07911-6","article-title":"RORgammat inhibition selectively targets IL-17 producing iNKT and gammadelta-T cells enriched in Spondyloarthritis patients.","volume":"10","author":"Venken","year":"2019","journal-title":"Nat. Commun."},{"key":"B36","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1056\/NEJMc1614624","article-title":"Graves\u2019 disease.","volume":"376","author":"Viard","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2018.01397","article-title":"Sex differences in the associations of obesity with hypothyroidism and thyroid autoimmunity among chinese adults.","volume":"9","author":"Wang","year":"2018","journal-title":"Front. Physiol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"3190","DOI":"10.1002\/art.39296","article-title":"Neutrophil extracellular trap mitochondrial DNA and its autoantibody in systemic lupus erythematosus and a proof-of-concept trial of metformin.","volume":"67","author":"Wang","year":"2015","journal-title":"Arthritis Rheumatol."},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1007\/s11926-012-0314-y","article-title":"The role of the microbiome in rheumatic diseases.","volume":"15","author":"Yeoh","year":"2013","journal-title":"Curr. Rheumatol. Rep."},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2019.112330","article-title":"BuZangTongLuo decoction improved hindlimb ischemia by activating angiogenesis and regulating gut microbiota in diabetic mice.","volume":"248","author":"Zheng","year":"2020","journal-title":"J. Ethnopharmacol."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.685522\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,28]],"date-time":"2021-05-28T08:21:50Z","timestamp":1622190110000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.685522\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,28]]},"references-count":40,"alternative-id":["10.3389\/fcell.2021.685522"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2021.685522","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,28]]},"article-number":"685522"}}