Intersection of Polycystic Ovary Syndrome and the Gut Microbiome

Maryan G. Rizk; Varykina G. Thackray


J Endo Soc. 2021;5(2) 

In This Article

Metabolites Associated With Gut Dysbiosis and PCOS

Although association does not equal causation, examining metabolite profiles in women with PCOS compared with healthy controls may provide insight into host/microbe interactions mediated by metabolites that can influence PCOS pathology. An early study in women showed that elevated levels of serum lactate were associated with PCOS,[67] and host-produced lactate has been shown to enter the lumen of the gut and serve as a substrate for lactate-utilizing bacteria,[68–70] potentially exerting a selective pressure within the microenvironment of the gut (Figure 2). Moreover, 2 studies reported an association between increased serum levels of trimethylamine N-oxide (TMAO) and PCOS in women[71,72] (Figure 2). Trimethylamine N-oxid is a liver metabolite that originates from trimethylamine, which is produced by gut microbes from dietary precursors. Elevated levels of TMAO have been associated with an increased risk of cardiovascular disease.[73] While measuring microbiota-related metabolites in systemic circulation of women with PCOS may help identify mechanisms of regulation of host physiology by gut bacteria, investigating changes in metabolites in the gut or feces (as a proxy) may also highlight regulatory mechanisms. Along these lines, 1 study of the letrozole-induced PCOS rat model showed significant decreases in fecal SCFAs that are produced by gut bacterial fermentation of fiber and serve as signaling molecules in the host.[49]

The relationship among bile acids, gut microbiota, and metabolic diseases (extensively reviewed elsewhere[74–77]) highlights an emerging key role for bile acids in regulating metabolic diseases including, potentially, PCOS. Primary bile acids serve as substrates for gut microbial enzymes that result in secondary bile acids that are recycled between the gut and liver via enterohepatic circulation.[77] An examination of glyco- and tauro-conjugated primary bile acids in systemic circulation showed that they were at higher levels in women with PCOS than in healthy women and were positively associated with HA.[78] On the other hand, another study reported that serum glycocholic acid was lower in women with PCOS than in women without the disorder.[79] Additionally, targeted metabolomics showed that the secondary bile acids, glycodeoxycholic acid (GDCA) and tauroursodeoxycholic acid (TUDCA), were lower in the serum and feces of women with PCOS and normal weight compared with healthy women.[23] It is intriguing that TUDCA was reported to be decreased in mice that received an FMT from women with PCOS or transplantation with B. vulgatus,[23] suggesting that an altered gut microbiota was sufficient to cause changes in specific bile acid levels. Besides their functions in the absorption of lipids, bile acids act as signaling molecules by binding and activating receptors such as the farnesoid X receptor (FXR)[80–82] (Figure 2), Takeda G protein receptor 5,[83] vitamin D receptor,[84] pregnane X receptor,[85] sphingosine-1-phosphate receptor 2,[86] and muscarinic M2 receptor.[87] One study showed that FXR-knockout mice exhibited glucose intolerance and IR when challenged with glucose or insulin, respectively.[88] This suggests a role for bile acid signaling through FXR in regulating metabolism. However, the contributions of specific bile acids and gut bacteria that deconjugate bile acids (such as Bacteroides[89]) in PCOS remain unclear (Figure 2).

Caveats and Future Studies

Our understanding of how gut metabolites are altered in PCOS is extremely limited. Most of the studies have investigated metabolomic profiles associated with PCOS within systemic circulation, rather than the feces, and these studies have not been performed in a comprehensive manner due to the difficulty of identifying metabolites using untargeted metabolomics. Both liquid and gas chromatography coupled with mass spectrometry could be utilized to begin to comprehend the full array of gut microbial metabolites that are changed in the feces of women with PCOS, and these analyses should be complemented with quantitative, targeted metabolomics focused on specific metabolites such as bile acids and SCFAs (Figure 2A and 2B). Moreover, correlations between gut metabolites and microbial species/strains obtained with metagenomic sequencing will help provide a more comprehensive picture of the important interactions occurring in the gut of women with PCOS and potentially shed light on how steroid hormones can influence the gut microbiome.