Effects of dehydroepiandrosterone alone or in combination with a high-fat diet and antibiotic cocktail on the heterogeneous phenotypes of PCOS mouse models by regulating gut microbiota.

Objective: Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine and metabolic disease. The gut microbiota is highly correlated with androgen secretion and insulin resistance (IR), which are two potential major pathogenic mechanisms of PCOS. Currently, an antibiotic cocktail (ABX) is often used to construct pseudo germ-free mouse models for studies on the gut microbiota and PCOS. Our work aimed to study the effects of dehydroepiandrosterone (DHEA), a high-fat diet (HFD) and ABX on the heterogeneous phenotypes of PCOS mouse models by regulating the gut microbiota. Methods: PCOS mouse models were established by subcutaneous injection of DHEA alone or in combination with a HFD in wild-type and pseudo germ-free mice. The changes in ovary morphology and sex hormonal and glycolipid metabolic parameters were evaluated. Results: Wild-type mice treated with DHEA or DHEA+HFD showed a PCOS-like phenotype of hyperandrogenism, anovulation and polycystic ovaries. The former was combined with hyperinsulinemia and IR, while the latter was combined with glucolipid metabolic disorders, extremely heterogeneous hyperinsulinemia and IR. The phenotype of PCOS mice, especially the metabolic parameters, was correlated with the gut microbiota. The pseudo germ-free mice treated with DHEA or DHEA+HFD also showed a PCOS-like phenotype. However, DHEA could not induce hyperinsulinemia or IR in pseudo germ-free mice. Pseudo germ-free mice treated with DHEA+HFD exhibited decreased serum AMH level, glucolipid metabolic disorders and IR. Compared with the wild-type mice, the pseudo germ-free mice treated with DHEA showed significantly higher testosterone and lipid levels and lower blood glucose levels, and they did not present with hyperinsulinemia or IR. Conclusion: A better and stabilized mouse model simulating the pathophysiological defects of PCOS was induced by DHEA alone rather than by DHEA+HFD. The ABX intervention improved glucose metabolic disorders and hyperinsulinemia but aggravated the hyperandrogenism and lipid metabolic disorders of the PCOS mice. This study suggests that the gut microbiota plays an important role in the heterogeneous phenotypes of PCOS mouse models.