Exposure to a Healthy Gut Microbiome Protects Against Reproductive and Metabolic Dysregulation in a PCOS Mouse Model

Abstract

AbstractPolycystic ovary syndrome (PCOS) is a common endocrine disorder affecting approximately 10% of reproductive-aged women worldwide. Diagnosis requires two of the following: hyperandrogenism, oligo/anovulation and polycystic ovaries. In addition to reproductive dysfunction, many women with PCOS display metabolic abnormalities associated with hyperandrogenism. Recent studies have reported that the gut microbiome is altered in women with PCOS and rodent models of the disorder. However, it is unknown whether the gut microbiome plays a causal role in the development and pathology of PCOS. Given its potential role, we hypothesized that exposure to a healthy gut microbiome would protect against development of PCOS. A co-housing study was performed using a letrozole-induced PCOS mouse model that recapitulates many reproductive and metabolic characteristics of PCOS. Since mice are coprophagic, co-housing results in repeated, non-invasive inoculation of gut microbes in co-housed mice via the fecal-oral route. In contrast to letrozole-treated mice housed together, letrozole-treated mice co-housed with placebo mice showed significant improvement in both reproductive and metabolic PCOS phenotypes. Using 16S rRNA gene sequencing, we observed that the gut microbial composition of letrozole-treated mice co-housed with placebo mice differed from letrozole mice housed together. In addition, our analyses identified several bacterial taxa including Coprobacillus, Dorea and Adlercreutzia associated with the improved PCOS phenotype in letrozole-treated mice co-housed with placebo mice. These results indicate that disruption of the gut microbiome may play a causal role in PCOS and that manipulation of the gut microbiome may be a potential treatment option for PCOS.SignificancePCOS is a common cause of female infertility and ~80% of women with PCOS have metabolic dysregulation that predisposes them to type 2 diabetes and cardiovascular disease. Since treatment options for the metabolic symptoms of PCOS are limited, there is a need to develop novel therapeutic options. The gut microbiome has emerged as an important player in human health and has been shown to play a causal role in obesity. In this study, we found that exposure to a healthy gut microbiome through co-housing protected against the development of reproductive and metabolic dysregulation in a PCOS mouse model. These results suggest that manipulation of the gut microbiome may be a potential treatment option for women with PCOS.