Oligofructose alleviates hyperandrogenism in polycystic ovary syndrome through gut microbiota-derived bile acids

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in reproductive-age women, characterized by hyperandrogenism and metabolic dysfunction. Dietary interventions are recommended as one of the first-line therapies. Oligofructose (OFS), a prebiotic fiber, has demonstrated clinical benefits in PCOS; however, its underlying mechanism remains unclear.

To determine whether OFS alleviates PCOS-like phenotypes through bile acid-dependent mechanisms and to identify downstream ovarian steroidogenic responses.

Letrozole-induced PCOS-like mice received OFS supplementation. Microbiota dependence was assessed using antibiotic depletion and fecal microbiota transplantation. Bile acid involvement was evaluated using cholestyramine. Gut microbial composition and function were profiled by 16S rRNA and metagenomic sequencing, and bile acids were quantified by UHPLC-MS/MS. Ovarian transcriptomics, ex vivo ovarian explants, and primary granulosa cells were used to examine steroidogenic changes, with pharmacological inhibition applied to assess TGR5-related signaling.

OFS improved reproductive and metabolic abnormalities in PCOS-like mice. These benefits were abolished by microbiota depletion and bile acid sequestration, indicating microbiota- and bile acid-dependent effects. OFS was associated with increased circulating hyodeoxycholic acid (HDCA), which negatively correlated with serum testosterone. HDCA supplementation partially reproduced endocrine improvements under microbiota-depleted conditions. Ovarian transcriptomic and functional analyses demonstrated enhanced aromatization following OFS treatment. In ex vivo ovarian explants and primary granulosa cells, HDCA increased estradiol production, reduced testosterone, and upregulated CYP19A1 (encoding aromatase). Under androgen stimulation, pharmacological inhibition of TGR5 attenuated HDCA-associated increases in estradiol and aromatase activity, supporting involvement of TGR5-related signaling.

OFS alleviates PCOS-like phenotypes in a microbiota- and bile acid-dependent manner and enhances ovarian aromatization. These findings move beyond descriptive bile acid alterations in PCOS by providing functional evidence that dietary fiber-induced bile acid remodeling is associated with modulation of ovarian steroidogenic regulation.