Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age and cannot currently be cured or prevented fundamentally. Prenatal androgen exposure is a key factor in PCOS development, and both PCOS patients and animal models exhibit gut microbiota alterations. We previously demonstrated that prenatally androgenized (PNA) model mice display changes of gut microbiota before the manifestation of PCOS phenotypes, suggesting that an intervention targeting gut microbiota from the early stage of life can prevent development of PCOS. Butyric acid, a short-chain fatty acid produced by bacteria in the intestines, has various physiological effects. We investigated whether butyric acid could prevent PCOS phenotypes in PNA mice when administered from the early stage of life as a nanoparticle-based donor. We have developed butyric acid-based self-assembling nanoparticles (BNP), which release butyric acid in a sustained manner when exposed to digestive enzymes so that butyrate is delivered to the intestines. Control and PNA offspring were administered water containing or lacking BNP from just after weaning until 20 weeks of age. Reproductive and metabolic phenotypes were compared among these offspring (n = 10-14 for each group). Administration of BNP normalized irregular estrus cyclicity and improved the polycystic ovarian morphology, as evidenced by smaller numbers of atretic follicles in PNA offspring. Regarding metabolic phenotypes, administration of BNP improved hypertrophy of adipocytes and insulin resistance. Furthermore, analysis of the gut microbiota suggested that these primary effects were caused by butyrate itself, with an increase in certain butyrate-producing bacteria supporting this mechanism. The present findings indicate that administration of butyric acid to PNA offspring, which are at high risk of developing PCOS, from the early stage of life effectively prevents development of PCOS phenotypes at reproductive ages. Further exploration is necessary to clarify the mechanism by which butyric acid prevents development of PCOS.
Sakaguchi et al. (Tue,) studied this question.