Bacteroides fragilis and propionate synergize with low-dose methimazole to treat Graves’ disease

ABSTRACT Graves’ disease (GD) is a common autoimmune thyroid disease with limited treatment efficacy, high relapse rates, and severe adverse effects. Gut microbiota dysbiosis is thought to play a critical role in GD, with the potential for microbiota-based therapies in GD treatment. However, experimental evidence is needed to validate this hypothesis. In this study, we evaluated the therapeutic effects of the commensal bacterium B. fragilis and its metabolite, propionate, in a GD mouse model. We found that oral supplementation with B. fragilis or propionate significantly reduced serum levels of inflammatory cytokines, total thyroxine (TT4), and TSH receptor antibodies (TRAb). It also decreased the proportion of circulating Th17 cells while increasing the proportion of circulating regulatory T cells (Tregs), thus mitigating systemic inflammation, hyperthyroidism, and the autoimmune response against TSHR. In addition, B. fragilis and propionate significantly decreased the levels of inflammatory cytokines and the proportion of M1 macrophages in thyroid tissue, while increasing the proportions of Treg cells and M2 macrophages, thereby reducing thyroid inflammation and size. Notably, the combination of B. fragilis or propionate with methimazole (MMI) significantly ameliorated pathological changes in GD mice and markedly reduced MMI dosage requirements, demonstrating a synergistic therapeutic effect. Our findings suggest that B. fragilis and propionate could serve as effective adjuvant agents in combination with MMI, thereby enhancing therapeutic efficacy while reducing drug dosage and minimizing side effects. This study opens a new avenue for microbiota-based treatments in managing GD. IMPORTANCE This study explores a new approach to treat Graves’ disease (GD), a major type of hyperthyroidism. Traditional treatments for GD often come with significant side effects and high relapse rates. Researchers found that Bacteroides fragilis , a gut commensal bacterium, and its metabolite propionate can improve the condition of GD mice. When combined with methimazole, a conventional medication for GD treatment, these natural agents demonstrated enhanced therapeutic efficacy, enabling dose reduction of methimazole and consequently reducing adverse effects. This research suggests that combining gut microbiota-based treatments with standard therapies may offer a more effective and safer way to manage GD.