Intersection of Polycystic Ovary Syndrome and the Gut Microbiome

Maryan G. Rizk; Varykina G. Thackray

J Endo Soc. 2021;5(2)

Abstract and Introduction

Abstract

The etiology of polycystic ovary syndrome (PCOS) remains unclear, although studies indicate that both genetic and environmental factors contribute to the syndrome. In 2012, Tremellen and Pearce proposed the idea that dysbiosis of the intestinal (gut) microbiome is a causative factor of metabolic and reproductive manifestations of PCOS. In the past 5 years, studies in both humans and rodent models have demonstrated that changes in the taxonomic composition of gut bacteria are associated with PCOS. Studies have also clearly shown that these changes in gut microbiota are associated with PCOS as opposed to obesity, since these changes are observed in women with PCOS that are both of a normal weight or obese, as well as in adolescent girls with PCOS and obesity compared with body mass index- and age-matched females without the disorder. Additionally, studies in both women with PCOS and rodent models of PCOS demonstrated that hyperandrogenism is associated with gut microbial dysbiosis, indicating that androgens may modulate the gut microbial community in females. One study reported that the fecal microbiome transplantation of stool from women with PCOS or exposure to certain bacteria resulted in a PCOS-like phenotype in mice, while other studies showed that exposure to a healthy gut microbiome, pre/probiotics, or specific gut metabolites resulted in protection from developing PCOS-like traits in mice. Altogether, these results suggest that dysbiosis of the gut microbiome may be sufficient to develop PCOS-like symptoms and that modulation of the gut microbiome may be a potential therapeutic target for PCOS.

Introduction

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders, affecting 5% to 10% of women of reproductive age worldwide.^[1,2] Diagnosis of PCOS includes 2/3 clinical presentations: (1) clinical or biochemical hyperandrogenism (HA), (2) oligomenorrhea or anovulation, and (3) polycystic ovaries.^[3] Women with PCOS are at a higher risk for infertility and pregnancy complications.^[4–7] In PCOS, metabolic dysregulation is correlated with HA, occurs independently of body mass index (BMI), and includes obesity, insulin resistance (IR), and dyslipidemia (Figure 1),^[8–10] which leads to an increased risk of developing type 2 diabetes (T2D), hypertension, and nonalcoholic fatty liver disease.^[6,11–14] Due to its prevalence and association with multiple chronic diseases, studying the mechanisms driving the etiology and pathogenesis of PCOS is of utmost importance in facilitating the development of novel therapies for PCOS.

(Enlarge Image)

Figure 1.

Correlations between hyperandrogenism (HA), dysbiosis of the gut microbiome, and metabolic dysfunction. A: Link between HA and dysbiosis of the gut microbiome. Recent studies in women and rodent models demonstrated that HA is correlated with dysbiosis of the gut microbiome, including changes in the overall biodiversity of gut bacteria as well as the relative abundance of certain bacteria. In addition, 1 study reported that introducing stool from women with PCOS or a bacterial species (B. vulgatus) in antibiotic-treated mice resulted in HA, suggesting that gut microbial dysbiosis or the overabundance of specific bacteria may be sufficient to induce PCOS-like symptoms. B: Link between HA and metabolic dysfunction. Metabolic dysfunction, including weight gain, insulin resistance (IR), and dyslipidemia, occurs predominantly in women with PCOS diagnosed with HA and ovulatory dysfunction, independent of body mass index. C: Link between dysbiosis of the gut microbiome and metabolic dysfunction. Gut dysbiosis has been associated with obesity, IR, and impaired lipid metabolism in metabolic diseases, including metabolic syndrome, type 2 diabetes, nonalcoholic fatty liver disease, and PCOS. Despite the tripartite set of correlations between HA, gut microbial dysbiosis, and metabolic dysfunction, the mechanisms of how each player affects the other 2 are still largely unknown. Future studies will be required to decipher how the gut microbiome communicates with the host and vice versa in order to alter or respond to varying levels of steroid and metabolic hormones.

The intestinal (gut) microbiome is comprised of a community of diverse bacteria, archaea, fungi, protozoa, and viruses, along with their metabolites. This community plays an important role in host physiology, including immunity, the health of the gut epithelial barrier, production of vitamin B12, and production of short-chain fatty acids (SCFAs) via fermentation of fiber, metabolism, and neurological functions.^[15] Alterations in gut microbiota have been associated with metabolic diseases (Figure 1), autoimmune diseases, neurological disorders, and cardiovascular disease.^[16] In 2012, Tremellen and Pearce proposed that a connection might exist between dysbiosis of the gut microbiome and the metabolic and reproductive manifestations of PCOS.^[17] Two studies in 2016 and 2017 first reported evidence that changes in the gut microbiome were associated with PCOS in a mouse model of PCOS and in women with the disorder.^[18,19] Since then, multiple subsequent studies in humans^[20–28] and rodents^[29–32] provided further evidence that dysbiosis of the gut microbiome is associated with PCOS.

In this review, we highlight recent findings on the association between the gut microbiome and PCOS, the relationship between HA and the gut microbiome in PCOS, the relationship between substrates and metabolites of the gut microbiota and PCOS, and potential gut microbiota-altering treatments as therapies of PCOS. To do so, we used the following search terms in NCBI PubMed: "microbiome," "microbiota," and "polycystic ovary syndrome." We confined our search criteria to primary research articles of human and rodent studies on PCOS and the gut microbiome between 2016 and 2020.

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Table 1. Cohort characteristics of human studies on PCOS and the gut microbiome
Country	Cohort Groups	N	Diagnosis	Age (years)	T (nmol/L)	BMI (kg/m2)	HOMA-IR	Method	Ref
Austria	Controls	19	Rotterdam Criteria	32.0	1.1	22.3	0.8	16S rRNA (V1–V2)	[19]
Austria	PCOS	24	Rotterdam Criteria	27.0	1.3	24.9	1.7	16S rRNA (V1–V2)	[19]
China	Nonoverweight controls	7	Rotterdam Criteria	30.3	1.1	20.6	n/a	Metagenomics	[20]
	Overweight controls	7		28.6	0.7	27.1	n/a
	Nonoverweight PCOS	7		27.1	1.8	21.0	n/a
	Overweight PCOS	7		29.1	1.4	27.9	n/a
Spain	Nonobese controls	8	Rotterdam Criteria	27.3	1.6	23.4	1.6	16S rRNA (V4)	[21]
	Obese controls	8		27.3	2.0	35.9	3.3
	Nonobese PCOS	7		23.0	2.5	24.4	1.5
	Obese PCOS	8		29.9	2.4	37.0	2.6
China	Nonobese controls	12	Rotterdam Criteria	32.2	0.8	21.9	1.7	16S rRNA (V3–V4)	[22]
	Obese controls	6		33.0	1.0	27.5	3.5
	Nonobese PCOS	12		25.5	4.5	21.6	1.1
	Obese PCOS	21		29.3	5.4	30.0	3.3
China	Controls	43	Rotterdam Criteria	29.6	1.56^a	23.7	1.6	Metagenomics	[23]
China	PCOS	50		29.9	2.11^a	24.7	3.1	Metagenomics	[23]
China	Controls	8	Rotterdam Criteria	26.4	0.7	20.8	1.4	16S rRNA (V3–V4)	[24]
	NIR-PCOS	8		26.1	1.9	22.6	1.9
	IR-PCOS	9		25.1	2.1	22.6	4.1
China	Controls	26	B-ultrasound	26.7	0.8	n/a	n/a	16S rRNA (V3–V4)	[25]
	PCOS	38	Oligomenorrhea Hormones	27.6	6.0	n/a	n/a
	PCOS	38	Oligomenorrhea Hormones	27.6	6.0	n/a	n/a	Metagenomics
China	Nonobese controls	30	Rotterdam Criteria	22.1	1.66^a	n/a	n/a	16S rRNA (V3–V4)	[26]
	Obese controls	11		25.3	1.8^a	n/a	n/a
	Nonobese PCOS	30		25.1	2.67^a	n/a	2.4
	Obese PCOS	30		26.9	2.63^a	n/a	6.4
China	Controls	9	Rotterdam Criteria	27.9	1.3	20.9	1.7	16S rRNA (V3–V4)	[27]
	Nonobese PCOS	10		25.7	1.9	20.7	1.4
	Obese PCOS	8		27.1	2.2	29.5	3.8
Poland	Controls	48	Rotterdam Criteria	29.4	1.04^a	23.7	1.8	16S rRNA (V4)	[28]
	PCOM	42		29.8	1.04^a	22.6	1.7
	PCOS	73		27.4	0.56^a	25.6	2.3
Austria	Controls	20	Rotterdam Criteria	32.0	1.1	22.3	0.8	16S rRNA (V1–V2)	[33]
Austria	PCOS	24		27.0	1.3	24.9	1.7	16S rRNA (V1–V2)	[33]
Turkey	Controls	15	Rotterdam Criteria	22.0	0.97^a	31.5	2.1	16S rRNA (V3–V4)	[34]
Turkey	PCOS	17	Rotterdam Criteria	20.0	2.22^a	19.6	2.0	16S rRNA (V3–V4)	[34]
USA	Obese controls	21	NIH Criteria	14.5	0.69^a	35.0	4.1	16S rRNA (V3–V4)	[37]
USA	Obese PCOS	37	NIH Criteria	16.1	1.49^a	36.0	4.5	16S rRNA (V3–V4)	[37]

V1, V2, V3, and V4 are variable regions of the bacterial 16S ribosomal ribonucleic acid (rRNA) gene. Primers are designed to target these regions for 16S rRNA gene sequencing to identify specific bacterial genera.
Abbreviations: BMI, body mass index; B-ultrasound, brightness-mode ultrasound; HOMA-IR, homeostatic model assessment for insulin resistance; IR, insulin-resistant; n/a, not applicable; NIH, National Institutes of Health; NIR, non-insulin-resistant; PCOM, polycystic ovarian morphology; PCOS, polycystic ovary syndrome; Ref, reference number; rRNA, ribosomal ribonucleic acid.
^aConverted from ng/mL, ug/L, or ng/dL.

Table 2. Changes in bacterial taxa associated with PCOS in women
Phylum	Family	Genus	Change	Ref
Actinobacteria	Bifidobacteriaceae	Bifidobacterium	↓	[25]
Actinobacteria	Coriobacteriaceae	Collinsella	↑	[25]
Actinobacteria			↑	[37]
Bacteroidetes	Bacteroidaceae	Bacteroides	↑	[20]
Bacteroidetes	Bacteroidaceae	Bacteroides	↑	[23]
Bacteroidetes	Bacteroidaceae	Bacteroides	↑	[24]
Bacteroidetes	Bacteroidaceae	Bacteroides	↑	[28]
Bacteroidetes	Bacteroidaceae	Bacteroides	↑	[33]
Bacteroidetes	Bacteroidaceae	Bacteroides	↓	[22]
Bacteroidetes	Bacteroidaceae	Bacteroides	↓	[37]
Bacteroidetes	Porphyromonadaceae	Odoribacter	↓	[28]
Bacteroidetes	Porphyromonadaceae	Parabacteroides	↑	[20]
Bacteroidetes	Porphyromonadaceae	Parabacteroides	↑	[25]
Bacteroidetes	Porphyromonadaceae	Porphyromonas	↑	[28]
Bacteroidetes	Porphyromonadaceae		↓	[37]
Bacteroidetes	Prevotellaceae	Alloprevotella	↓	[26]
Bacteroidetes	Prevotellaceae	Prevotella	↑	[25]
Bacteroidetes	Prevotellaceae	Prevotella	↑	[37]
Bacteroidetes	Prevotellaceae	Prevotella	↓	[24]
Bacteroidetes	Prevotellaceae	Prevotella	↓	[33]
Bacteroidetes	S24–7		↓	[19]
Bacteroidetes	S24–7		↓	[33]
Bacteroidetes			↑	[27]
Firmicutes	Clostridiaceae	Clostridium	↑	[25]
Firmicutes	Clostridiaceae	ClostridiumIV	↑	[22]
Firmicutes	Erysipelotrichidae	Catenibacterium	↑	[21]
Firmicutes	Erysipelotrichidae	Kandleria	↑	[21]
Firmicutes	Lachnospiraceae	Blautia	↑	[28]
Firmicutes	Lachnospiraceae	Blautia	↓	[20]
Firmicutes	Lachnospiraceae	Blautia	↓	[25]
Firmicutes	Lachnospiraceae	Coprococcus	↑	[26]
Firmicutes	Lachnospiraceae	Oribacterium	↑	[21]
Firmicutes	Lachnospiraceae	Roseburia	↓	[28]
Firmicutes	Lachnospiraceae		↓	[27]
Firmicutes	Lactobacillaceae	Lactobacillus	↓	[22]
Firmicutes	Oscillospiraceae	Oscillibacter	↓	[22]
Firmicutes	Ruminococcaceae	Faecalibacterium	↑	[28]
Firmicutes	Ruminococcaceae	Faecalibacterium	↓	[20]
Firmicutes	Ruminococcaceae	Faecalibacterium	↓	[25]
Firmicutes	Ruminococcaceae	Ruminococcus	↓	[28]
Firmicutes	Ruminococcaceae	Subdoligranulum	↑	[27]
Firmicutes	Ruminococcaceae		↑	[34]
Firmicutes	Ruminococcaceae		↓	[22]
Firmicutes	Streptococcaceae	Lactococcus	↓	[26]
Firmicutes	Streptococcaceae	Streptococcus	↓	[22]
Firmicutes	Streptococcaceae		↑	[37]
Firmicutes	Veillonellaceae	Megamonas	↑	[27]
Firmicutes	Veillonellaceae	Megasphaera	↑	[33]
Firmicutes		Anaerococcus	↓	[28]
Proteobacteria	Comamonadaceae	Comamonas	↑	[20]
Proteobacteria	Enterobacteriaceae	Escherichia	↑	[20]
Proteobacteria	Enterobacteriaceae	Escherichia	↑	[22]
Proteobacteria	Enterobacteriaceae	Shigella	↑	[20]
Proteobacteria	Enterobacteriaceae	Shigella	↑	[22]
Synergistetes			↓	[26]
Tenericutes			↓	[19]
Tenericutes			↓	[26]
Verrucomicrobia	Akkermansiaceae	Akkermansia	↓	[22]

Abbreviations: PCOS, polycystic ovary syndrome; Ref, reference number.

Table 3. Cohort characteristics of rodent studies on PCOS and the gut microbiome
Animal	Treatment	Treatment Format	Start (week)	Duration (week)	N	Method	Ref
C57BL/6N mice	Letrozole	Pellet (50 ug/day)	4	5	10/group	16S rRNA (V4)	[18]
C57BL/6N mice	Letrozole	Pellet (50 ug/day)	4	5	10 placebo; 12 LET	16S rRNA (V4)	[29]
Sprague-Dawley rats	Letrozole	Oral gavage (1 mg/kg/day)	6	3	8/group	16S rRNA (V3)	[30]
C57BL/6N mice	Letrozole	Pellet (50 ug/day)	4	5	8/group	16S rRNA (V4)	[31]
Sprague-Dawley rats	DHT	Injection (83 ug/day)	3	6	5/group	16S rRNA (V3–V4)	[32]
Sprague-Dawley rats	Letrozole	Oral gavage (1 mg/kg/day)	6	11	8/group	16S rRNA (V3–V4)	[49]
Wistar rats	DHT	15 mg silicone tube	3	10	6/group	16S rRNA (V3–V4)	[50]

V1, V2, V3, and V4 are variable regions of the bacterial 16S ribosomal ribonucleic acid (rRNA) gene. Primers are designed to target these regions for 16S rRNA gene sequencing to identify specific bacterial genera.
Abbreviations: DHT, dihydrotestosterone; PCOS, polycystic ovary syndrome; Ref, reference number; rRNA, ribosomal ribonucleic acid.

Table 4. Changes in bacterial taxa associated with rodent models of PCOS
Phylum	Family	Genus	Change	Ref
Actinobacteria	Bifidobacteriaceae	Bifidobacterium	↑	[29]
Actinobacteria	Bifidobacteriaceae	Bifidobacterium	↓	[18]
Actinobacteria	Bifidobacteriaceae	Bifidobacterium	↓	[49]
Actinobacteria	Coriobacteriaceae	Adlercreutzia	↑	[31]
Actinobacteria			↑	[32]
Actinobacteria			↑	[49]
Bacteroidetes	Bacteroidaceae	Bacteroides	↑	[32]
Bacteroidetes	Bacteroidaceae	Bacteroides	↑	[49]
Bacteroidetes	Bacteroidaceae	Bacteroides	↑	[50]
Bacteroidetes	Bacteroidaceae	Bacteroides	↓	[18]
Bacteroidetes	Odoribacteraceae	Odoribacter	↓	[29]
Bacteroidetes	Porphyromonadaceae	Parabacteroides	↑	[29]
Bacteroidetes	Porphyromonadaceae	Parabacteroides	↓	[18]
Bacteroidetes	Prevotellaceae	Ga6A1	↓	[50]
Bacteroidetes	Prevotellaceae	Prevotella	↑	[30]
Bacteroidetes	Prevotellaceae	Prevotella_9	↑	[50]
Bacteroidetes	Prevotellaceae		↓	[50]
Bacteroidetes	Rikenellaceae	Alistipes	↑	[32]
Bacteroidetes	Rikenellaceae	Alistipes	↓	[18]
Bacteroidetes	S24–7		↓	[18]
Bacteroidetes			↓	[32]
Cyanobacteria			↑	[32]
Firmicutes	Christensenellaceae	Christensenella	↓	[31]
Firmicutes	Clostridiaceae	Anaerotruncus	↑	[32]
Firmicutes	Clostridiaceae	Candidatus Arthromitus	↓	[31]
Firmicutes	Clostridiaceae	Clostridium	↑	[32]
Firmicutes	Clostridiaceae	Clostridium	↓	[30]
Firmicutes	Dehalobacteriaceae	Dehalobacterium	↓	[18]
Firmicutes	Erysipelotrichaceae	Allobaculum	↑	[18]
Firmicutes	Erysipelotrichaceae	Coprobacillus	↓	[31]
Firmicutes	Erysipelotrichaceae	Turicibacter	↑	[31]
Firmicutes	Eubacteriaceae	Eubacterium	↑	[32]
Firmicutes	Hungateiclostridiaceae	Ruminiclostridium	↓	[49]
Firmicutes	Lachnospiraceae	Blautia	↑	[18]
Firmicutes	Lachnospiraceae	Blautia	↑	[29]
Firmicutes	Lachnospiraceae	Butyrivibrio	↓	[49]
Firmicutes	Lachnospiraceae	Coprococcus	↑	[18]
Firmicutes	Lachnospiraceae	Dorea	↓	[29]
Firmicutes	Lachnospiraceae	Dorea	↓	[31]
Firmicutes	Lachnospiraceae	Roseburia	↑	[18]
Firmicutes	Lachnospiraceae	Roseburia	↑	[29]
Firmicutes	Lachnospiraceae	Roseburia	↓	[31]
Firmicutes	Lachnospiraceae	Tyzzerella	↑	[32]
Firmicutes	Lachnospiraceae		↓	[29]
Firmicutes	Lactobacillaceae	Lactobacillus	↑	[31]
Firmicutes	Lactobacillaceae	Lactobacillus	↓	[29]
Firmicutes	Lactobacillaceae	Lactobacillus	↓	[30]
Firmicutes	Ruminococcaceae	Ruminococcus	↑	[18]
Firmicutes	Ruminococcaceae	Ruminococcus	↑	[29]
Firmicutes	Ruminococcaceae	Ruminococcus	↓	[29]
Firmicutes	Ruminococcaceae	Ruminococcus	↓	[30]
Firmicutes	Ruminococcaceae	Ruminococcus_1	↑	[32]
Firmicutes	Ruminococcaceae		↓	[18]
Firmicutes			↑	[32]
Proteobacteria	Desulfovibrionaceae	Desulfovibrio	↓	[49]
Proteobacteria	Sutterellaceae	Sutterella	↑	[29]
Saccharibacteria			↑	[32]
Spirochaetes	Spirochaetaceae		↓	[50]
Verrucomicrobia	Akkermansiaceae	Akkermansia	↑	[31]

Abbreviations: PCOS, polycystic ovary syndrome; Ref, reference number.

Table 5. Changes in gut bacteria correlated with testosterone levels in women and PCOS rodent models
Phylum	Family	Genus	Correlation	Host	Ref
Actinobacteria	Bifidobacteriaceae	Bifidobacterium	Negative	Human	[25]
Actinobacteria	Bifidobacteriaceae	Bifidobacterium	Negative	Rodent	[49]
Actinobacteria	Coriobacteriaceae	Collinsella	Positive	Human	[25]
Actinobacteria	Coriobacteriaceae	Collinsella	Positive	Human	[26]
Actinobacteria			Positive	Rodent	[49]
Bacteroidetes	Bacteroidaceae	Bacteroides	Positive	Human	[20]
Bacteroidetes	Bacteroidaceae	Bacteroides	Positive	Human	[22]
Bacteroidetes	Bacteroidaceae	Bacteroides	Positive	Human	[24]
Bacteroidetes	Bacteroidaceae	Bacteroides	Positive	Human	[25]
Bacteroidetes	Bacteroidaceae	Bacteroides	Positive	Rodent	[49]
Bacteroidetes	Bacteroidaceae		Positive	Human	[24]
Bacteroidetes	Porphyromonadaceae	Parabacteroides	Positive	Human	[20]
Bacteroidetes	Porphyromonadaceae		Negative	Human	[37]
Bacteroidetes	Prevotellaceae	Prevotella	Negative	Human	[24]
Bacteroidetes	Prevotellaceae	Prevotella	Positive	Human	[25]
Bacteroidetes	Prevotellaceae	Prevotella	Positive	Human	[26]
Bacteroidetes	Prevotellaceae	Prevotella	Positive	Human	[27]
Bacteroidetes	Prevotellaceae	Prevotella	Positive	Rodent	[30]
Bacteroidetes	Prevotellaceae		Negative	Human	[24]
Bacteroidetes	S24–7		Negative	Human	[19]
Firmicutes	Clostridiaceae	Anaerotruncus	Positive	Rodent	[32]
Firmicutes	Clostridiaceae	Clostridium	Positive	Rodent	[32]
Firmicutes	Hungateiclostridiaceae	Ruminiclostridium	Negative	Human	[27]
Firmicutes	Lachnospiraceae	Butyrivibrio	Negative	Rodent	[49]
Firmicutes	Lachnospiraceae	Coprococcus	Positive	Human	[25]
Firmicutes	Lachnospiraceae	Fusicatenibacter	Negative	Human	[27]
Firmicutes	Lachnospiraceae	Tyzzerella	Negative	Human	[27]
Firmicutes	Lachnospiraceae	Tyzzerella	Positive	Rodent	[32]
Firmicutes	Lachnospiraceae-ND3007		Negative	Human	[27]
Firmicutes	Lactobacillaceae	Lactobacillus	Negative	Rodent	[49]
Firmicutes	Rumiacoccaceae-UCG-003		Negative	Human	[27]
Firmicutes	Ruminococcaceae	Faecalibacterium	Negative	Human	[25]
Firmicutes	Ruminococcaceae	Ruminococcus	Positive	Human	[26]
Firmicutes	Ruminococcaceae	Ruminococcus	Positive	Rodent	[32]
Firmicutes	Ruminococcaceae	Subdoligranulum	Negative	Human	[27]
Firmicutes	Ruminococcaceae		Negative	Human	[22]
Firmicutes	Ruminococcaceae		Positive	Human	[34]
Firmicutes	Streptococcaceae	Streptococcus	Positive	Human	[22]
Firmicutes	Streptococcaceae	Streptococcus	Positive	Rodent	[49]
Firmicutes	Veillonellaceae	Megasphaera	Positive	Human	[26]
Firmicutes			Negative	Rodent	[49]
Proteobacteria	Desulfovibrionaceae	Desulfovibrio	Negative	Rodent	[32]
Proteobacteria	Desulfovibrionaceae	Desulfovibrio	Negative	Rodent	[49]
Proteobacteria	Enterobacteriaceae	Escherichia	Positive	Human	[22]
Proteobacteria	Enterobacteriaceae	Raoultella	Positive	Human	[21]
Proteobacteria	Enterobacteriaceae	Shigella	Positive	Human	[22]
Proteobacteria	Enterobacteriaceae		Positive	Human	[20]
Tenericutes			Negative	Human	[19]
Verrucomicrobia	Akkermansiaceae	Akkermansia	Negative	Human	[22]