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

Treatments of Gut Dysbiosis in PCOS

Fecal Microbial Transplant

Since gut dysbiosis has been proposed as a driver of PCOS symptoms, treatment with an FMT from healthy donors or representative microbes from a healthy gut might serve as a useful therapy to re-diversify the gut microbiome, although there are limited studies to support this idea. One study showed that performing an FMT from healthy rats into a letrozole-induced PCOS rat model resulted in a reduction of androgen levels, improved estrous cycles, normalized ovarian morphology, and increased levels of Lactobacillus and Clostridium species and decreased Prevotella.[30] Additionally, a co-housing experiment showed improved reproductive and metabolic symptoms of PCOS in letrozole-treated mice that were co-housed with healthy, placebo-treated mice in addition to changing the RA of Coprobacillus and Lactobacillus.[31] Overall, these studies show promise that adjusting the gut microbial community in women with PCOS may alleviate some of the diet-independent, hyperandrogenic-induced symptoms.

Prebiotics: Wheat Dextrin and Inulin

Resistant dextrin, a glucose polysaccharide that is fermented in the colon by microbes rather than absorbed in the small intestine, was given to women with PCOS and women without the disorder for 3 months.[90] Resistant dextrin lowered levels of free testosterone, hirsutism, the interval between menstrual cycles, fasting blood glucose, and lipid profile,[90] but changes in alpha diversity or the RA of specific microbes was not assessed in this study. Additionally, the probiotic inulin was shown to improve gut dysbiosis, lower testosterone, and increase estradiol levels while improving ovarian morphology and weight gain in DHEA-treated mice fed an HFD.[64] However, alpha diversity was not assessed in this study, and thus, no conclusions can be specifically made about the role of inulin on the richness or evenness of the gut microbial community. In addition, it is unclear in mice whether inulin is targeting the effects of HFD or DHEA alone or in combination, so further studies investigating the effects of fermentable, dietary fiber on PCOS are warranted.

Probiotics: Bifidobacterium Lactis, Lactobacillus, and Lactic Acid Bacteria

Consuming probiotic (or beneficial) strains of bacteria has the potential to improve gut dysbiosis either directly through repopulation of the gut with healthy microbes or indirectly through the production of gut metabolites. Bifidobacterium lactis V9 given as a 10-week treatment for PCOS in 14 women with the disorder decreased LH and increased intestinal SCFAs.[25]Lactobacillus given to letrozole-treated rats reduced androgen levels, improved estrous cyclicity, normalized ovarian morphology, as well as increased Lactobacillus and Clostridium species and decreased Prevotella.[30]

Several studies also investigated the effects of probiotic combinations on PCOS phenotypes. A combination of Bifidobacterium, Lactobacillus acidophilus, and Enterococcus faecalis in a DHT-induced PCOS rat model improved reproductive and metabolic functions as well as alpha diversity of the gut microbiome.[50] In addition, certain strains of Lactobacillus and Bifidobacterium (HL2 and HB3) given to letrozole-treated rats protected against pathological changes in the ovaries and restored testosterone levels while upregulating levels of SCFAs.[48]

Small Molecules: Metformin and IL22

Previous studies have shown that metformin decreases total testosterone, hirsutism, acne, LH, BMI, waist-to-hip ratio, and fasting insulin, and increases SHBG, follicle-stimulating hormone, and progesterone, while it also improves menstrual cycles.[91,92] In addition to its role in the inhibition of androgen biosynthesis,[93,94] metformin treatment of individuals with T2D decreased the RA of Bacteroides fragilis and FXR signaling, while it increased levels of glycoursodeoxycholic acid in the gut in 1 study,[95] as well as the RA of Akkermansia muciniphila and SCFA-producing microbes in another study.[96] Although no studies have investigated the effect of metformin on the gut microbiome of women with PCOS, 1 study in DHEA-treated mice showed that it improved dysbiosis of the gut, including increased levels of Bacteroidetes and decreased levels of Helicobacter and Proteobacteria.[64] In this mouse model, metformin also decreased testosterone levels while also improving ovarian function, weight gain, and IR.[64]

IL22 is an anti-inflammatory cytokine produced by cells of the lymphoid lineage, including cells in the lamina propria of the intestinal wall called group 3 innate lymphoid cells (ILC3).[97] IL22 was used to treat symptoms of PCOS in mice that received an FMT from women with PCOS, a transplantation of B. vulgatus, or treated with DHEA.[23,98] In all of these models, IL22 improved reproductive and metabolic symptoms including a decrease in testosterone levels, increased insulin tolerance, and enhanced browning of adipose tissue.[23,98] However, it is unknown whether IL22 altered the composition or function of gut microbiome or if other mechanisms were responsible for the beneficial effect. Qi et al hypothesized that an increase in the abundance of B. vulgatus, and potentially other bacteria in the intestine of women with PCOS, results in increased deconjugation of secondary bile acids and lower levels of GDCA and TUDCA, which normally bind to receptors involved in the production of IL22.[23] Since there is no current evidence demonstrating that GDCA and TUDCA bind to receptors on ILC3 cells in vivo and that this binding leads to the production of IL22, future studies in PCOS rodent models will be useful to identify specific mechanisms by which changes in gut bacteria regulate secondary bile acids and IL22 production, as well as how IL22 signaling influences reproductive and metabolic phenotypes of PCOS.

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