Intersection of Polycystic Ovary Syndrome and the Gut Microbiome

Maryan G. Rizk; Varykina G. Thackray

Disclosures

J Endo Soc. 2021;5(2) 

In This Article

Dysbiosis of the Gut Microbiome is Associated With Polycystic Ovary Syndrome (PCOS)

Alpha Diversity of the Gut Microbiota in Humans

The overall composition of gut microbiota can be represented by metrics of alpha diversity, which estimate the species richness and/or evenness of a community, sometimes taking phylogenetic relationships into account. Recent studies have shown that alpha diversity of gut microbiota is altered in women with PCOS compared with healthy women. By sampling the fecal microbial content and sequencing 16S ribosomal RNA (rRNA) genes amplified with universal bacterial primers, multiple studies demonstrated that alpha diversity of gut bacteria decreased in premenopausal women with PCOS as compared with age-matched, healthy women.[19,22,26–28,33] In contrast, 3 studies did not observe significant changes in alpha diversity between women with PCOS and healthy women, potentially due to small sample sizes.[21,24,34] Interestingly, studies that used shotgun metagenomic sequencing of the gut microbiome also did not report changes in alpha diversity.[20,23,25] All of the aforementioned studies included women diagnosed with PCOS using the Rotterdam criteria[35,36] from limited geographical locations in Asia and Europe, including China, Turkey, Austria, Poland, and Spain. A recent study on gut microbial changes (using 16S rRNA sequencing) in adolescent girls (14–16 years old) with PCOS and obesity and weight- and age-matched healthy controls from an ethnically diverse population in the United States reported that PCOS was also associated with a decrease in alpha diversity.[37] This study indicates that decreased biodiversity of gut microbes, like other features of PCOS,[38] manifests by adolescence. High alpha diversity was proposed as an indication of productivity and stability in an ecosystem, implying overall health of the community.[39] Decreases in alpha diversity have been observed in immune diseases such as Chron's disease, ulcerative colitis, type 1 diabetes mellitus, celiac disease, and allergies;[40–42] in cardiometabolic diseases such as obesity, T2D, and vascular stiffness;[42–44] colorectal cancer;[42] and autism.[42] Thus, loss of microbial diversity in the gut may serve as a biomarker of disease or as an indication of a functional problem, especially when correlated with changes in metabolites of the gut microbiome, as in T2D.[44]

Beta Diversity of the Gut Microbiota in Humans

In addition to alpha diversity, beta diversity (how similar or different the composition of 1 gut microbial community is compared to another community) can also be estimated using distance metrics that take or do not take phylogenetic relationships or abundance into account. Using 16S rRNA gene sequencing, multiple studies reported that beta diversity was altered in fecal samples obtained from women with PCOS compared with healthy women.[19,22,28] However, in other studies, no significant difference in beta diversity was detected in women with PCOS compared with healthy women,[21,26,33,34] potentially due to small sample sizes. Comparing adolescent girls with PCOS and obesity to BMI-matched controls, changes in beta diversity were also observed between the 2 groups.[37] Unlike alpha diversity, changes in beta diversity were observed in 2 studies where shotgun metagenomics were used to sequence gut microbiota in women with PCOS.[23,25] In contrast, 1 study using metagenomic sequencing did not observe differences in gut microbial beta diversity between women with and without PCOS.[20] Overall, these results indicate that differences in beta diversity also appear to be associated with PCOS.

Relative Abundance of Bacterial Taxa in Humans

In addition to looking at gut microbial diversity at the community level, various studies assessed differences in the relative abundance (RA) of specific bacterial taxa. In the healthy gut, the phyla Firmicutes, Bacteroidetes, Actinobacteria, and Verrucomicrobia are the most dominant, while Proteobacteria and Tenericutes exist at low abundance.[45]Table 1 summarizes cohort characteristics of women included in studies of PCOS and the gut microbiome, while Table 2 summarizes the different taxa that were significantly altered in women with PCOS from the studies reviewed herein and is organized by bacterial phyla. Of the genera within phylum Bacteroidetes, Bacteroides were positively associated with PCOS in 5/7 studies and Parabacteroides were positively associated with PCOS in 2 studies,[20,23–25,28,33] while the family S24-7 was negatively associated with PCOS in 2 studies.[19,33] Of the genera within phylum Firmicutes, family Clostridiaceae was positively associated with PCOS in 2 studies[22,25] and family Veillonellaceae in 2 other studies.[27,33] Of the genera within phylum Proteobacteria, Escherichia, and Shigella were positively associated with PCOS in 2 studies.[20,22]

Alpha and Beta Diversity in Rodent Models of PCOS

In addition to human studies, changes in overall gut microbial diversity were also observed in PCOS-like rodent models compared with placebo controls using 16S rRNA gene sequencing. As recently reviewed,[46] hyperandrogenic rodent models of PCOS have been created using treatment with dihydrotestosterone (DHT) or the nonsteroidal aromatase inhibitor, letrozole. In a letrozole-induced pubertal PCOS mouse model, alpha diversity of the gut microbiome was lower in letrozole-treated mice than placebo controls, while beta diversity was also changed between the 2 groups.[18] In contrast, letrozole-induced PCOS in adult mice and rats showed no change in alpha diversity.[47,48] Although adult mice treated with letrozole showed a shift in beta diversity, changes in specific bacterial taxa were distinct between the pubertal and the adult PCOS mouse models,[47] and there were no changes in beta diversity observed in adult rats treated with letrozole.[48] In a cohort of 6-week old rats treated with letrozole, changes in beta diversity were observed when compared with placebo-treated rats, while alpha diversity was not different between the 2 groups.[49] These results suggest that the age at which PCOS is induced in rodent models may be critical in order to recapitulate the metabolic dysregulation and gut microbial changes that resemble those found in women with PCOS.

RA of Bacterial Taxa in Rodents

In addition to looking at changes in the overall gut microbial community in rodents, various studies assessed differences in the RA of specific bacterial taxa in PCOS rat and mouse models. Table 3 summarizes cohort characteristics of rodent models of PCOS where gut microbiota was assessed. Table 4 summarizes the different taxa that were altered in the PCOS models and is organized by bacterial phyla. Of the genera within phylum Actinobacteria, Bifidobacterium was negatively associated with PCOS in 2/3 studies.[18,49] Of the genera within phylum Bacteroidetes, Bacteroides were positively associated with PCOS in 3/4 studies, while Prevotella were positively associated with PCOS in 2 studies.[30,32,49,50] Of the genera within the phylum Firmicutes, Blautia and Roseburia were positively associated with PCOS in 2 studies,[18,29] while Lactobacillus was negatively associated with PCOS in 2/3 studies.[29,30]

Caveats and Future Directions

The diversity in the clinical presentation of PCOS presents a challenge for studies attempting to decipher consistent patterns in the dysbiosis of the gut microbiome in women with PCOS since not all women diagnosed with PCOS have the same pathological phenotypes. Other challenges of studying dysbiosis of the gut microbiome, in general, are geographical and diet-based differences between study populations, which, in turn, can affect the composition of the gut microbiota. Moreover, the use of different methods for the collection and storage of fecal samples, sequencing, and data analysis probably contribute to inconsistent findings in human gut microbiome studies.[51] For instance, 2 factors that may influence the results obtained from the studies outlined herein is the use of different primers for the sequencing of the hypervariable regions (V1-4) of 16S rRNA gene and the use of different bioinformatics programs for data analysis[51] (Table 1 and Table 3). In addition, we note that there is considerable variability in the characteristics of the human cohorts with regards to HA, BMI, and IR, which may also explain some of the inconsistencies with regards to alpha diversity, beta diversity, and the RA of specific bacterial taxa.

Moving forward, consensus methods for studying the gut microbiome in women with PCOS may be required to clearly differentiate differences in the gut microbiome that are due to factors such as geography and diet with those that are related to PCOS. Additionally, since most of the previous studies have relied on 16S rRNA gene sequencing, metagenomic approaches in future studies will be beneficial to investigate whether other gut microbes such as archaea, fungi, and viruses are altered in PCOS and dissect gut microbial gene functions that are associated with PCOS phenotypes. Specifically, metagenomic sequencing of the gut microbiome of adolescent and premenopausal age- and BMI-matched women from diverse ethnic and geographical backgrounds with and without PCOS will be needed to further understand the relationship of PCOS with dysbiosis of the gut microbiome. Mechanistic studies using rodent models of PCOS will also be required to understand how these microbes influence the development and pathogenesis of PCOS.

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