Role of the Gut Microbiome in Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-aged women worldwide. In addition to infertility, many women with PCOS have metabolic abnormalities that result in an increased risk of type 2 diabetes and cardiovascular disease. Although the etiology of PCOS is poorly understood, accumulating evidence suggests that androgen excess is an important contributor to the pathogenesis of PCOS. The human large intestine contains a complex community of microorganisms (the gut microbiome) important for human health and disease. Studies have shown that the gut microbiome is altered in humans with metabolic disorders such as obesity and type 2 diabetes, and that the gut microbiome may be a causal factor in the development of these disorders. Dysbiosis of the gut microbiome has been proposed to factor in the development of PCOS and studies have shown that changes in the gut microbiome are associated with PCOS in women and in rodent models. However, it is unknown if the gut microbiome plays a causal role in the PCOS phenotype. For this dissertation I used human fecal samples and a letrozole-induced PCOS mouse model together with 16S rRNA gene sequencing to further our understanding of the effects of androgen excess and the role of the gut microbiome in PCOS. Using human fecal samples and patient clinical parameters, the results in chapter 1 suggest that androgen excess may play a critical role in altering the gut microbiome in women with PCOS. Since there is considerable variation in the human gut microbiome due to differences in diet and ethnicity, chapters 2 and 3 used a PCOS mouse model to gain more insight into the pathophysiology of PCOS. The results from chapter 2 indicate that dysregulation of the metabolism and gut microbiome in PCOS may be influenced by the timing of androgen exposure. Lastly, the results from chapter 3 showed that exposure to a healthy gut microbiome improved the metabolic and reproductive phenotype in a PCOS mouse model. Overall, these results suggest that modulating the composition of the gut microbiome may be a potential treatment option for women with PCOS