{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T02:17:17Z","timestamp":1777947437042,"version":"3.51.4"},"reference-count":85,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T00:00:00Z","timestamp":1625443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Health &amp; Welfare, Republic of Korea","award":["HI20C1496"],"award-info":[{"award-number":["HI20C1496"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Sj\u00f6gren\u2019s syndrome (SS), a chronic inflammatory disease involving the salivary and lacrimal glands, presents symptoms of sicca as well as systemic manifestations such as fatigue and musculoskeletal pain. Only a few treatments have been successful in management of SS; thus treatment of the disease is challenging. Metformin is the first-line agent for type 2 diabetes and has anti-inflammatory potential. Its immunomodulatory capacity is exerted via activation of 5\u2019 adenosine monophosphate-activated protein kinase (AMPK). Metformin inhibits mitochondrial respiratory chain complex I which leads to change in adenosine mono-phosphate (AMP) to adenosine tri-phosphate (ATP) ratio. This results in AMPK activation and causes inhibition of mammalian target of rapamycin (mTOR). mTOR plays an important role in T cell differentiation and mTOR deficient T cells differentiate into regulatory T cells. In this manner, metformin enhances immunoregulatory response in an individual. mTOR is responsible for B cell proliferation and germinal center (GC) differentiation. Thus, reduction of B cell differentiation into antibody-producing plasma cells occurs via downregulation of mTOR. Due to the lack of suggested treatment for SS, metformin has been considered as a treatment strategy and is expected to ameliorate salivary gland function.<\/jats:p>","DOI":"10.3390\/ijms22137231","type":"journal-article","created":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T22:02:04Z","timestamp":1625522524000},"page":"7231","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Metformin as a Treatment Strategy for Sj\u00f6gren\u2019s Syndrome"],"prefix":"10.3390","volume":"22","author":[{"given":"Joa","family":"Kim","sequence":"first","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine, Chosun University Hospital, Gwangju 61453, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yun-Sung","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine, Chosun University Hospital, Gwangju 61453, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sung-Hwan","family":"Park","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1007\/s00393-019-0625-8","article-title":"Sjogren\u2019s syndrome","volume":"78","author":"Witte","year":"2019","journal-title":"Z. Rheumatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1056\/NEJMcp1702514","article-title":"Primary Sjogren\u2019s Syndrome","volume":"378","author":"Mariette","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1038\/nrrheum.2013.110","article-title":"Advances in understanding the pathogenesis of primary Sjogren\u2019s syndrome","volume":"9","author":"Nocturne","year":"2013","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"196","DOI":"10.2174\/1871530315666150316124019","article-title":"Metformin and Inflammation: Its Potential Beyond Glucose-lowering Effect","volume":"15","author":"Saisho","year":"2015","journal-title":"Endocr. Metab. Immune Disord."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Salvatore, T., Pafundi, P.C., Galiero, R., Gjeloshi, K., Masini, F., Acierno, C., di Martino, A., Albanese, G., Alfano, M., and Rinaldi, L. (2020). Metformin: A Potential Therapeutic Tool for Rheumatologists. Pharmaceuticals, 13.","DOI":"10.3390\/ph13090234"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1172\/JCI13505","article-title":"Role of AMP-activated protein kinase in mechanism of metformin action","volume":"108","author":"Zhou","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1038\/nature13270","article-title":"Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase","volume":"510","author":"Madiraju","year":"2014","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"R97","DOI":"10.1530\/JOE-15-0447","article-title":"Current understanding of metformin effect on the control of hyperglycemia in diabetes","volume":"228","author":"An","year":"2016","journal-title":"J. Endocrinol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e224","DOI":"10.1038\/emm.2016.16","article-title":"AMPK activators: Mechanisms of action and physiological activities","volume":"48","author":"Kim","year":"2016","journal-title":"Exp. Mol. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1007\/s00125-017-4342-z","article-title":"The mechanisms of action of metformin","volume":"60","author":"Rena","year":"2017","journal-title":"Diabetologia"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3985","DOI":"10.1038\/onc.2011.167","article-title":"Mitochondrial respiratory chain complexes: Apoptosis sensors mutated in cancer?","volume":"30","author":"Lemarie","year":"2011","journal-title":"Oncogene"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.cmet.2016.03.010","article-title":"Are Metformin Doses Used in Murine Cancer Models Clinically Relevant?","volume":"23","author":"Chandel","year":"2016","journal-title":"Cell Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1236","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":"ref_14","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1016\/j.immuni.2009.04.014","article-title":"The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment","volume":"30","author":"Delgoffe","year":"2009","journal-title":"Immunity"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/ni.2005","article-title":"The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2","volume":"12","author":"Delgoffe","year":"2011","journal-title":"Nat. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.intimp.2015.01.005","article-title":"Fibroblast growth factor 21 (FGF21) ameliorates collagen-induced arthritis through modulating oxidative stress and suppressing nuclear factor-kappa B pathway","volume":"25","author":"Yu","year":"2015","journal-title":"Int. Immunopharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/s10753-015-0251-9","article-title":"Treatment of CIA Mice with FGF21 Down-regulates TH17-IL-17 Axis","volume":"39","author":"Li","year":"2016","journal-title":"Inflammation"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e432","DOI":"10.1038\/emm.2017.245","article-title":"Metformin ameliorates experimental-obesity-associated autoimmune arthritis by inducing FGF21 expression and brown adipocyte differentiation","volume":"50","author":"Kim","year":"2018","journal-title":"Exp. Mol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1692","DOI":"10.4049\/jimmunol.1201767","article-title":"B cell-specific deficiencies in mTOR limit humoral immune responses","volume":"191","author":"Zhang","year":"2013","journal-title":"J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4805","DOI":"10.4049\/jimmunol.180.7.4805","article-title":"STAT3-mediated up-regulation of BLIMP1 Is coordinated with BCL6 down-regulation to control human plasma cell differentiation","volume":"180","author":"Diehl","year":"2008","journal-title":"J. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1016\/j.immuni.2009.10.008","article-title":"Analysis of interleukin-21-induced Prdm1 gene regulation reveals functional cooperation of STAT3 and IRF4 transcription factors","volume":"31","author":"Kwon","year":"2009","journal-title":"Immunity"},{"key":"ref_22","doi-asserted-by":"crossref","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":"ref_23","first-page":"491","article-title":"Macrophage cytokines: Involvement in immunity and infectious diseases","volume":"5","author":"Duque","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.mce.2017.09.025","article-title":"Metformin improves obesity-associated inflammation by altering macrophages polarization","volume":"461","author":"Jing","year":"2018","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/nature04516","article-title":"Gout-associated uric acid crystals activate the NALP3 inflammasome","volume":"440","author":"Martinon","year":"2006","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"34533","DOI":"10.1038\/srep34533","article-title":"Monosodium urate crystal-induced pro-interleukin-1 beta production is post-transcriptionally regulated via the p38 signaling pathway in human monocytes","volume":"6","author":"Chung","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5485","DOI":"10.1073\/pnas.1620910114","article-title":"Uric acid priming in human monocytes is driven by the AKT-PRAS40 autophagy pathway","volume":"114","author":"Cleophas","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1136\/annrheumdis-2018-214656","article-title":"mTOR inhibition by metformin impacts monosodium urate crystal-induced inflammation and cell death in gout: A prelude to a new add-on therapy?","volume":"78","author":"Vazirpanah","year":"2019","journal-title":"Ann. Rheum. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/nrmicro1710","article-title":"Beneficial suicide: Why neutrophils die to make NETs","volume":"5","author":"Brinkmann","year":"2007","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2981","DOI":"10.1172\/JCI67390","article-title":"Peptidylarginine deiminase inhibition is immunomodulatory and vasculoprotective in murine lupus","volume":"123","author":"Knight","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_31","doi-asserted-by":"crossref","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":"ref_32","doi-asserted-by":"crossref","first-page":"269","DOI":"10.4067\/S0716-97602012000300008","article-title":"Mesenchymal stem cell treatment for autoimmune diseases: A critical review","volume":"45","author":"Figueroa","year":"2012","journal-title":"Biol. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1634\/stemcells.2005-0342","article-title":"Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue","volume":"24","author":"Kern","year":"2006","journal-title":"Stem Cells"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2795","DOI":"10.1089\/ten.tea.2008.0630","article-title":"Requirement of IFN-gamma-Mediated Indoleamine 2,3-Dioxygenase Expression in the Modulation of Lymphocyte Proliferation by Human Adipose-Derived Stem Cells","volume":"15","author":"DelaRosa","year":"2009","journal-title":"Tissue Eng. Part A"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"182","DOI":"10.3389\/fimmu.2012.00182","article-title":"Toll-like receptors as modulators of mesenchymal stem cells","volume":"3","author":"DelaRosa","year":"2012","journal-title":"Front. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1892","DOI":"10.1002\/stem.1986","article-title":"PI3kalpha and STAT1 Interplay Regulates Human Mesenchymal Stem Cell Immune Polarization","volume":"33","author":"Mounayar","year":"2015","journal-title":"Stem Cells"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1016\/j.jaci.2016.09.004","article-title":"IFN-gamma orchestrates mesenchymal stem cell plasticity through the signal transducer and activator of transcription 1 and 3 and mammalian target of rapamycin pathways","volume":"139","author":"Vigo","year":"2017","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1093\/rheumatology\/kez631","article-title":"Metformin enhances the immunomodulatory potential of adipose-derived mesenchymal stem cells through STAT1 in an animal model of lupus","volume":"59","author":"Jang","year":"2020","journal-title":"Rheumatology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"127","DOI":"10.4049\/jimmunol.1800006","article-title":"Metformin Augments Anti-Inflammatory and Chondroprotective Properties of Mesenchymal Stem Cells in Experimental Osteoarthritis","volume":"203","author":"Park","year":"2019","journal-title":"J. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1002\/jcb.26275","article-title":"Effect of metformin on ossification and inflammation of fibroblasts in ankylosing spondylitis: An in vitro study","volume":"119","author":"Qin","year":"2018","journal-title":"J. Cell. Biochem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"274ra218","DOI":"10.1126\/scitranslmed.aaa0835","article-title":"Normalization of CD4+ T cell metabolism reverses lupus","volume":"7","author":"Yin","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e000429","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":"ref_43","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.intimp.2013.03.020","article-title":"Metformin downregulates Th17 cells differentiation and attenuates murine autoimmune arthritis","volume":"16","author":"Kang","year":"2013","journal-title":"Int. Immunopharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"973986","DOI":"10.1155\/2014\/973986","article-title":"Metformin Attenuates Experimental Autoimmune Arthritis through Reciprocal Regulation of Th17\/Treg Balance and Osteoclastogenesis","volume":"2014","author":"Son","year":"2014","journal-title":"Mediat. Inflamm."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"103","DOI":"10.3109\/08923973.2015.1122619","article-title":"Combination therapy with metformin and coenzyme Q10 in murine experimental autoimmune arthritis","volume":"38","author":"Jhun","year":"2016","journal-title":"Immunopharmacol. Immunotoxicol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"108875","DOI":"10.1016\/j.biopha.2019.108875","article-title":"Metformin inhibits the proliferation of rheumatoid arthritis fibroblast-like synoviocytes through IGF-IR\/PI3K\/AKT\/m-TOR pathway","volume":"115","author":"Chen","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1186\/s13075-020-02174-3","article-title":"Metformin rescues rapamycin-induced mitochondrial dysfunction and attenuates rheumatoid arthritis with metabolic syndrome","volume":"22","author":"Kim","year":"2020","journal-title":"Arthritis Res. Ther."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1002\/art.41190","article-title":"Insulin-Resistant Pathways Are Associated with Disease Activity in Rheumatoid Arthritis and Are Subject to Disease Modification Through Metabolic Reprogramming: A Potential Novel Therapeutic Approach","volume":"72","author":"Gallagher","year":"2020","journal-title":"Arthritis Rheumatol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1080\/03009742.2019.1695928","article-title":"Adherence to metformin and the onset of rheumatoid arthritis: A population-based cohort study","volume":"49","author":"Naffaa","year":"2020","journal-title":"Scand. J. Rheumatol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e17371","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"},{"key":"ref_51","unstructured":"Matsuoka, Y., Morimoto, S., Fujishiro, M., Hayakawa, K., Kataoka, Y., Suzuki, S., Ikeda, K., Takamori, K., Yamaji, K., and Tamura, N. (2020). Metformin repositioning in rheumatoid arthritis. Clin. Exp. Rheumatol., PMID: 32828146."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.21037\/atm-20-3042","article-title":"Metformin inhibits inflammation and bone destruction in collagen-induced arthritis in rats","volume":"8","author":"Fan","year":"2020","journal-title":"Ann. Transl. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1159\/000507451","article-title":"Combination of LMT-28 and Metformin Improves Beneficial Anti-Inflammatory Effect in Collagen-Induced Arthritis","volume":"106","author":"Park","year":"2021","journal-title":"Pharmacology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1016\/j.omtm.2020.05.008","article-title":"Metformin, an AMPK Activator, Inhibits Activation of FLSs but Promotes HAPLN1 Secretion","volume":"17","author":"Chen","year":"2020","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.3389\/fphar.2020.01114","article-title":"Metformin Mitigates Cartilage Degradation by Activating AMPK\/SIRT1-Mediated Autophagy in a Mouse Osteoarthritis Model","volume":"11","author":"Wang","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_56","first-page":"632","article-title":"Metformin protects chondrocytes against IL-1beta induced injury by regulation of the AMPK\/NF-kappa B signaling pathway","volume":"75","author":"Zhang","year":"2020","journal-title":"Pharmazie"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1080\/01913123.2020.1762815","article-title":"Metformin pretreatment suppresses alterations to the articular cartilage ultrastructure and knee joint tissue damage secondary to type 2 diabetes mellitus in rats","volume":"44","author":"Dawood","year":"2020","journal-title":"Ultrastruct. Pathol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e119","DOI":"10.1136\/annrheumdis-2019-216713corr1","article-title":"Metformin limits osteoarthritis development and progression through activation of AMPK signalling","volume":"79","author":"Li","year":"2020","journal-title":"Ann. Rheum. Dis."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1186\/s13075-019-1915-x","article-title":"Association between metformin use and disease progression in obese people with knee osteoarthritis: Data from the Osteoarthritis Initiative-a prospective cohort study","volume":"21","author":"Wang","year":"2019","journal-title":"Arthritis Res. Ther."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Lu, C.H., Chung, C.H., Lee, C.H., Hsieh, C.H., Hung, Y.J., Lin, F.H., Tsao, C.H., Hsieh, P.S., and Chien, W.C. (2018). Combination COX-2 inhibitor and metformin attenuate rate of joint replacement in osteoarthritis with diabetes: A nationwide, retrospective, matched-cohort study in Taiwan. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0191242"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s13075-020-2129-y","article-title":"Exploration of metformin as novel therapy for osteoarthritis: Preventing cartilage degeneration and reducing pain behavior","volume":"22","author":"Li","year":"2020","journal-title":"Arthritis Res. Ther."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1186\/s13075-019-1904-0","article-title":"Metformin improves salivary gland inflammation and hypofunction in murine Sjogren\u2019s syndrome","volume":"21","author":"Kim","year":"2019","journal-title":"Arthritis Res. Ther."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/S0140-6736(03)12489-0","article-title":"Gut flora in health and disease","volume":"361","author":"Guarner","year":"2003","journal-title":"Lancet"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Al Bander, Z., Nitert, M.D., Mousa, A., and Naderpoor, N. (2020). The Gut Microbiota and Inflammation: An Overview. Int. J. Environ. Res. Public Health, 17.","DOI":"10.3390\/ijerph17207618"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1001\/jama.2016.20099","article-title":"The Microbiome and Risk for Obesity and Diabetes","volume":"317","author":"Komaroff","year":"2017","journal-title":"JAMA"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1038\/nature18646","article-title":"Human gut microbes impact host serum metabolome and insulin sensitivity","volume":"535","author":"Pedersen","year":"2016","journal-title":"Nature"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.cmet.2017.06.003","article-title":"A Specific Gut Microbiota Dysbiosis of Type 2 Diabetic Mice Induces GLP-1 Resistance through an Enteric NO-Dependent and Gut-Brain Axis Mechanism","volume":"26","author":"Grasset","year":"2017","journal-title":"Cell Metab."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"7546047","DOI":"10.1155\/2019\/7546047","article-title":"The Dynamic Interplay between the Gut Microbiota and Autoimmune Diseases","volume":"2019","author":"Xu","year":"2019","journal-title":"J. Immunol. Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1186\/s40168-018-0520-6","article-title":"A metagenomic study of the gut microbiome in Behcet\u2019s disease","volume":"6","author":"Ye","year":"2018","journal-title":"Microbiome"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"23561","DOI":"10.1038\/srep23561","article-title":"Altered Mucosal Microbiome Diversity and Disease Severity in Sjogren Syndrome","volume":"6","author":"Jones","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1038\/nature15766","article-title":"Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota","volume":"528","author":"Forslund","year":"2015","journal-title":"Nature"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1038\/nm.4345","article-title":"Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug","volume":"23","author":"Wu","year":"2017","journal-title":"Nat. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.cell.2013.02.035","article-title":"Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism","volume":"153","author":"Cabreiro","year":"2013","journal-title":"Cell"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"102611","DOI":"10.1016\/j.jaut.2021.102611","article-title":"Short-chain fatty acid butyrate induces IL-10-producing B cells by regulating circadian-clock-related genes to ameliorate Sjogren\u2019s syndrome","volume":"119","author":"Kim","year":"2021","journal-title":"J. Autoimmun."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1097\/BOR.0000000000000473","article-title":"Current views on the pathogenesis of Sjogren\u2019s syndrome","volume":"30","author":"Pontarini","year":"2018","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1111\/cei.12377","article-title":"Dysregulation of the suppressor of cytokine signalling 3-signal transducer and activator of transcription-3 pathway in the aetiopathogenesis of Sjogren\u2019s syndrome","volume":"177","author":"Vartoukian","year":"2014","journal-title":"Clin. Exp. Immunol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.jconrel.2013.07.016","article-title":"A rapamycin-binding protein polymer nanoparticle shows potent therapeutic activity in suppressing autoimmune dacryoadenitis in a mouse model of Sjogren\u2019s syndrome","volume":"171","author":"Shah","year":"2013","journal-title":"J. Control. Release"},{"key":"ref_78","first-page":"288","article-title":"Elevated MTORC1 Signature in B Cells from Sjogren\u2019s Syndrome Patients Correlates with B Cell Hyperactivity That Is Abrogated by MTOR Inhibition: A Novel Therapeutic Strategy to Halt B Cell Hyperactivity in PSS?","volume":"76","author":"Blokland","year":"2017","journal-title":"Ann. Rheum. Dis."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"3187","DOI":"10.1002\/art.11311","article-title":"Cellular basis of ectopic germinal center formation and autoantibody production in the target organ of patients with Sjogren\u2019s syndrome","volume":"48","author":"Salomonsson","year":"2003","journal-title":"Arthritis Rheum."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/j.semarthrit.2012.07.003","article-title":"The role of ectopic germinal centers in the immunopathology of primary Sjogren\u2019s syndrome: A systematic review","volume":"42","author":"Risselada","year":"2013","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/nrrheum.2016.217","article-title":"Ectopic lymphoid neogenesis in rheumatic autoimmune diseases","volume":"13","author":"Bombardieri","year":"2017","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.immuni.2014.02.005","article-title":"Transcription factor STAT3 and type I interferons are corepressive insulators for differentiation of follicular helper and T helper 1 cells","volume":"40","author":"Ray","year":"2014","journal-title":"Immunity"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.trsl.2016.03.006","article-title":"Metformin attenuates graft-versus-host disease via restricting mammalian target of rapamycin\/signal transducer and activator of transcription 3 and promoting adenosine monophosphate-activated protein kinase-autophagy for the balance between T helper 17 and Tregs","volume":"173","author":"Park","year":"2016","journal-title":"Transl. Res."},{"key":"ref_84","first-page":"165","article-title":"Anxiety and depression in patients with primary Sjogren\u2019s syndrome","volume":"27","author":"Valtysdottir","year":"2000","journal-title":"J. Rheumatol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/j.rdc.2016.03.010","article-title":"New Treatment Guidelines for Sjogren\u2019s Disease","volume":"42","author":"Vivino","year":"2016","journal-title":"Rheum. Dis. Clin. N. Am."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/13\/7231\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:26:20Z","timestamp":1760163980000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/13\/7231"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,5]]},"references-count":85,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["ijms22137231"],"URL":"https:\/\/doi.org\/10.3390\/ijms22137231","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,5]]}}}