Polycystic ovary syndrome (PCOS) is the leading cause of female infertility, affecting approximately 10% of reproductive-aged women. Moreover, women with the disorder often suffer from metabolic issues that can lead to type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease. Unfortunately, since PCOS is a complex genetic trait disorder, the cause is unknown, and current treatments center upon addressing symptoms, as there’s no cure for the condition.
However, research into the gut microbiome and its relationship to PCOS has provided promising threads of understanding. Women with PCOS often have both lower bacterial species richness and an altered relative abundance of certain bacterial taxa. Additionally, past studies have indicated a correlation between hyperandrogenism – a defining symptom of PCOS – and gut microbial diversity. But what are the nuances of these relationships? And more importantly, how can they be used to treat PCOS?
In an effort to further explore the links between PCOS and the gut microbiome, an inter-institutional team of researchers led by Dr. Varykina G Thackray of the Department of Obstetrics, Gynecology and Reproductive Sciences and the Center for Microbiome Innovation (CMI) at the University of California San Diego (UC San Diego) and Dr. Scott Kelley of the Department of Biology at San Diego State University collaborated on a study to evaluate whether exposure to a healthy gut microbiome was protective against developing PCOS metabolic or reproductive phenotypes. mSystems published their research in a recent article entitled “Gut Metabolites Are More Predictive of Disease and Cohoused States than Gut Bacterial Features in a Polycystic Ovary Syndrome-Like Mouse Model.”
To perform the study, the team implanted half of a group of mice with letrozole pellets, a nonsteroidal aromatase inhibitor, which recapitulates many of the reproductive and metabolic hallmarks of PCOS. The other half of the mice were implanted with placebo pellets, and they were cohoused in three configurations – two placebo mice per cage, two letrozole mice, and one of each type in a cage. Then, over the course of the experiment, fecal samples were collected weekly, and the team applied both untargeted metabolomics and shotgun metagenomics approaches to analyze the longitudinal samples.
As previous work in the area had implied, cohousing with healthy mice was protective against the development of both metabolic and reproductive dysregulation. However, there were some surprises in the results.
“In the current study, we showed that gut metabolite composition experienced earlier and more pronounced differentiation in both the PCOS model and letrozole mice cohoused with healthy mice compared with microbial composition, indicating that changes in metabolites were more predictive of the disease state as well the cohoused state,” according to Thackray. “In addition, our results demonstrating changes in bile acids in the PCOS mouse model and letrozole-treated mice cohoused with healthy mice suggest that focused research into small-molecule control of gut microbial diversity and host physiology may provide new therapeutic options for the treatment of PCOS.”
Building upon this study’s findings, Dr. Thackray and her team are planning further research into the role that specific bile acids play in modulating host-microbe interactions in relation to PCOS. “Since many women with PCOS have hyperandrogenism, we are interested in understanding how sex steroids regulate bile acid production in the liver, bile acid metabolism by gut microbes, and bile acid signaling to the host,” Thackray commented while discussing potential studies.
Additional co-authors include Bryan Ho, Daniel Ryback, Basilin Benson, Cayla N Mason, Pedro Torres at San Diego State University, and Robert A. Quinn at UC San Diego.
The Center for Microbiome Innovation is proud to include Varykina G Thackray as a faculty member.
FIG 1 For the cohousing study design, mice implanted with either placebo or 3-mg letrozole pellets were housed two per cage in three separate housing arrangements. This resulted in four treatment groups: placebo mice (P), letrozole mice (LET), placebo cohoused with letrozole (Pch), and letrozole cohoused with placebo (LETch) (n = 8 mice/group).
