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Description
Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder that affects 5-15% of reproductive age women. PCOS is the largest contributor to anovulatory infertility, and can also cause increased risk of pregnancy complications. PCOS is also a metabolic disorder and is a risk factor for later development of like hypertension and type 2 diabetes. The human gut microbiome (GM) is comprised of all microorganisms inhabiting the gastrointestinal tract, and includes bacteria, viruses, fungi and protozoa. In both mice and humans there is a link between the gut microbiome and metabolic disorders, including PCOS. Also, bacterial species richness is lower in women with PCOS compared to women without the disorder. Previous studies had shown, using a letrozole (LET)-induced mouse model of PCOS that cohousing was protective against development of metabolic and reproductive phenotypes likely because of the transfer of gut microbiome constituents from the placebo (P) to the LET animals via coprophagy. This work also showed via 16S amplicon sequencing that this protection correlated with time-dependent shifts in gut bacteria. In this study, we assessed the potential role gut metabolites might have played in the protective effects of cohousing. Gut metabolites were extracted from mouse feces from the same cohousing study and subject to high performance liquid chromatography and tandem mass spectrometry. A CAP analysis of the metabolites showed a clear, time dependent separation of treatment groups. A log2-fold analysis of the resulting metabolite data identified numerous metabolite features, particularly bile acids (BAs), to be highly differentiated between placebo and LET, as well as LET cohoused with placebo versus LET. Finally, random forest was used to determine the most important metabolite and metagenomic features which were then examined for strong positive or negative correlations between the metabolites and bacterial species. Our results indicate that changes in gut metabolites, particularly BAs, are associated with a PCOS-like phenotype as well as with the protective effect of cohousing. These insights into the GM and its relationship to hyperandrogenism in females suggest that small molecule control of gut microbial diversity and host physiology may provide new therapeutic options for the treatment of PCOS.
