UC San Diego

Polycystic Ovary Syndrome (PCOS) is a complex endocrine disorder characterized by reproductive and metabolic features, including hyperandrogenism, acyclicity, polycystic ovaries, weight gain, and insulin resistance. Previous research in mice using a letrozole (LET)-induced PCOS-like model indicated that alterations in the diversity and composition of gut microbiota may contribute to metabolic dysfunction observed in women with PCOS, but the role of the gut microbiome in metabolic dysregulation is not well understood. This thesis aims to determine whether the gut microbiome is required for metabolic and reproductive phenotypes in the dihydrotestosterone (DHT)-induced PCOS-like model which has elevated androgens but normal estrogen levels. As previously published, DHT-treated mice had acyclicity, abdominal adiposity, increased fasting blood glucose (FBG), and increased fasting blood insulin (FBI), recapitulating metabolic and reproductive phenotypes of PCOS. Treatment of mice with antibiotics (ABX) to deplete gut microbiota blunted the increase in abdominal adiposity, FBG and FBI after DHT treatment, indicating that the gut microbiome is required for these metabolic phenotypes in mice with elevated androgens. In contrast, ABX did not prevent acyclicity and increased body weight, suggesting that the gut microbiome is not required for the reproductive phenotype or weight gain observed in the DHT mouse model. In addition, exposure of DHT-treated mice to placebo mice also blunted the increase in abdominal adiposity, FBG and FBI typically observed after DHT treatment but did not affect cycling or weight gain. Thus, cohousing indicated that exposure to a health gut microbiome via coprophagy conveyed a protective effect against metabolic dysregulation in a PCOS mouse model and suggested that novel therapeutic options, such as next-generation probiotics, could be identified and developed to treat metabolic dysregulation in PCOS.