Association of Bifidobacterium-regulated NIS expression with the CD40-NF-κB pathway in Graves' disease.

INTRODUCTION: Graves' disease (GD) represents a typical autoimmune thyroid disease triggered by thyroid-stimulating autoantibodies. Accumulating studies have verified the close correlation between intestinal microecology and GD progression, with Bifidobacterium prominently implicated, yet the specific molecular mechanisms underlying this association remain elusive. This study aimed to explore the regulatory effects of Bifidobacterium adolescentis on GD development via the CD40-NF-κB signaling cascade and sodium/iodide symporter (NIS) modulation.

METHODS: Clinically, fecal specimens from GD patients were recruited before and after iodine-131 (131I) therapy to characterize dynamic changes in intestinal Bifidobacterium abundance. In vitro cellular assays were conducted on human thyroid cells stimulated with Bifidobacterium adolescentis, followed by detection of cell proliferative activity, CD40-NF-κB pathway activity and NIS protein expression. In vivo GD mouse models were administered with Bifidobacterium adolescentis intervention, and subsequent assessments included thyroid and colonic histopathological changes and gut microbial profiling. The expression levels of key proteins associated with the CD40-NF-κB pathway and NIS were also quantified in thyroid and colon tissues.

RESULTS: Clinical results demonstrated that Bifidobacterium adolescentis abundance was significantly higher in GD patients prior to 131I treatment and markedly decreased after therapy. In vitro, Bifidobacterium adolescentis treatment facilitated thyroid cell proliferation, elevated NIS expression and activated the CD40-NF-κB signaling in a dose-dependent manner. In animal models, Bifidobacterium adolescentis supplementation aggravated hyperthyroidism, thyroid hyperplasia and intestinal inflammatory injuries.

DISCUSSION: Mechanistically, Bifidobacterium adolescentis drove CD40 and NIS upregulation through triggering NF-κB pathway activation. Collectively, Bifidobacterium adolescentis exacerbates GD pathogenesis by activating the CD40-NF-κB signaling axis and modulating thyroid NIS expression. This work reveals a novel microbial regulatory mechanism of GD, offering a promising theoretical basis for developing gut microbiota-targeted therapeutic strategies for GD treatment.