Metformin Reverses Hashimoto's Thyroiditis by Regulating Key Immune Events

Background: Hashimoto's 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. Methods: This study systematically explored the therapeutic effect of metformin on HT and its underlying mechanism by comprehensively utilizing methods including animal model, in vitro cell culture and differentiation, mRNA sequencing and 16S rRNA gene sequencing. Findings: We found that metformin indeed has a therapeutic effect on mice with HT mainly by reducing TgAb and lymphocyte infiltration in thyroid tissue. In addition, metformin also significantly inhibits the formation of Th17 cells and M1 macrophages in vivo. Furthermore, metformin can inhibit the differentiation and function of Th17 in vitro. The results of mRNA sequencing of thyroid tissue showed that the therapeutic effect of metformin on HT is mainly achieved by regulating immune disorders. 16S RNA sequencing of the intestinal flora found that the intestinal flora of HT mice differ significantly from that of the normal mice and also are altered by metformin treatment. Interpretation: This experiments provide a preliminary theoretical basis for the clinical application of metformin in the treatment of HT. Funding Statement: The present work was supported by grants from the National Natural Science Foundation of China (No.81873636 and No.81900710), Shanghai Natural Science Foundation (No.18ZR1433800). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: All patients and healthy controls have signed informed consent. The study was approved by the ethical committees of Zhoupu Hospital and performed in accordance with relevant guidelines and regulations. All animal experiment procedures were approved by the Animal Ethics Committee of Fudan University.