OR02-08 Necessity of the Gut Microbiome for Aspects of Metabolic Dysregulation in a Polycystic Ovary Syndrome Mouse Model

Abstract Disclosure: J. Brown: None. K. Twigg: None. S. Dhanala: None. L. Le: None. P. Jayaram: None. K. Nanavati: None. S. Kelley: None. V.G. Thackray: None. Background: Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects 10-15% of women world-wide. PCOS is diagnosed using the Rotterdam Consensus with two out of three clinical features: hyperandrogenism, oligo- or anovulation, and cyst-like follicles in the ovary. Although it is a prevalent disease that increases the risk of infertility, pregnancy complications, type 2 diabetes, and cardiovascular disease, the etiology and pathophysiology of PCOS is not well understood. Numerous recent studies have demonstrated an association of the gut microbiome with PCOS in humans and rodent models of the disorder. Methods: To determine if the gut microbiome is required to develop PCOS reproductive and metabolic features, we used a PCOS-like mouse model in which four-week-old C57BL/6N female mice were given a 90-day treatment with dihydrotestosterone (DHT). The gut microbiome was depleted using an oral antibiotic cocktail of vancomycin, ampicillin, and neomycin. The four experimental groups included: 1. Placebo, 2. DHT, 3. Placebo + Antibiotic, and 4. DHT + Antibiotic, n=20/group. Reproductive dysregulation was assessed by measuring the estrous cycle for one week. Metabolic dysregulation was assessed by measuring weekly body weight, fasting blood glucose (FBG) and fasting blood insulin (FBI) at 11 weeks after treatment, and abdominal adiposity at the end of the study. Fecal samples were collected to determine depletion by the antibiotics and for future analyses of the gut microbiome. Results: Antibiotic treatment resulted in significant depletion of the gut microbiome. While antibiotic treatment decreased circulating DHT levels, it did not restore estrous cycling in DHT mice. On the other hand, antibiotic treatment completely prevented key aspects of DHT-induced metabolic dysregulation such as elevated FBG and FBI. In addition, antibiotic treatment had a partial effect on DHT-induced weight gain but did not alter DHT-induced abdominal adiposity. Conclusion: While the gut microbiome was not required for acyclicity in a PCOS-like mouse model, it was required for key aspects of metabolic dysregulation implicated in the development of insulin resistance and type 2 diabetes, suggesting that the gut microbiome plays a role in PCOS pathology. Presentation: Saturday, July 12, 2025