Haizao Yuhu Decoction alleviates goiter via the gut-thyroid axis: Microbiota-derived SCFAs promote hormone synthesis...

Haizao Yuhu Decoction (HYD) is a classic Traditional Chinese Medicine for goiter, but its mechanism related to the "gut-thyroid axis" remains unknown. This study investigates whether HYD treats goiter via this axis and elucidates the underlying mechanisms.

A rat goiter model was induced with propylthiouracil (PTU), followed by two weeks of HYD treatment. Gut microbiota was analyzed by metagenomic sequencing; fecal and serum short-chain fatty acids (SCFAs) were quantified by targeted LC-MS/MS analysis. Thyroid function was assessed via iodine content and hormone levels. Key proteins in hormone synthesis and apoptosis were evaluated by Western blot and immunohistochemistry. Fecal microbiota transplantation (FMT) supported microbiota causality.

HYD alleviated goiter and hypothyroidism. It restored gut microbiota diversity and enriched SCFA-producing bacteria (e.g., Bifidobacterium pseudolongum), coincident with increased SCFAs including butyrate. These SCFA changes correlated with reduced HDAC1/2/3/8 in thyroid tissue, consistent with enhanced histone acetylation, and were accompanied by upregulation of NIS, TG, TPO, and DUOX2. Concurrently, elevated SCFAs were associated with AKT/Mdm2 pathway inhibition, p53 stabilization, downstream activation of P21 and Caspase-3, and suppression of Bcl-2, supporting a model of promoted thyroid cell apoptosis. FMT supported that HYD-modulated microbiota alone reproduced these effects.

HYD alleviates PTU-induced goiter in rats in a manner associated with gut microbiota remodeling and increased SCFA production, which correlate with enhanced thyroid hormone synthesis and restored apoptosis-a relationship supported by FMT experiments. However, direct interactions between HYD and PTU cannot be fully excluded. These findings are consistent with a model in which HYD acts through the gut-thyroid axis, providing mechanistic insights into its therapeutic effects.