The Microbiome and Polycystic Ovary Syndrome (PCOS)

Version For Professionals

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder. Characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology, PCOS has significant metabolic, reproductive, and psychological implications. The pathogenesis of PCOS is multifactorial, involving genetic, hormonal, and environmental factors. Recently, the gut microbiome has emerged as a potential contributor to the development and progression of PCOS. 

The Gut Microbiome: An Overview

The gut microbiome refers to the trillions of microorganisms, including bacteria, viruses, fungi, and archaea, residing in the gastrointestinal tract. These microorganisms play crucial roles in maintaining host health by aiding in digestion, synthesizing vitamins, regulating the immune system, and protecting against pathogenic infections. The composition and function of the gut microbiome are influenced by various factors, such as diet, genetics, environment, and medication use. Dysbiosis, an imbalance in the gut microbiome, has been implicated in numerous diseases, including metabolic disorders, autoimmune conditions, and mental health issues.

The Microbiome-PCOS Connection

Recent studies have revealed significant differences in the gut microbiome composition between individuals with PCOS and healthy controls. These differences suggest that gut dysbiosis may contribute to the pathogenesis of PCOS through several mechanisms:

1. Metabolic Dysfunction:

Insulin Resistance: Insulin resistance is a hallmark of PCOS, affecting approximately 70% of individuals with the disorder. Gut microbiota can influence insulin sensitivity through the production of short-chain fatty acids (SCFAs) like butyrate, propionate, and acetate. SCFAs regulate glucose metabolism, lipid homeostasis, and inflammation. Dysbiosis in PCOS often results in reduced SCFA-producing bacteria, leading to impaired insulin sensitivity.

Research has shown that SCFAs play a crucial role in maintaining metabolic health. Butyrate, in particular, is known for its anti-inflammatory properties and its ability to enhance insulin sensitivity by activating G-protein-coupled receptors and inhibiting histone deacetylases. In people with PCOS, a decrease in butyrate-producing bacteria, such as Faecalibacterium prausnitzii, has been observed. This reduction may contribute to the chronic low-grade inflammation and insulin resistance characteristic of PCOS.

Obesity

The gut microbiome influences energy balance, adiposity and the host’s ability to extract and store energy from food. Dysbiosis can promote obesity by increasing energy harvest from the diet, altering bile acid metabolism, and modulating appetite-regulating hormones. 

For example, certain bacterial species can break down complex polysaccharides into simpler molecules that the host can absorb, thereby increasing caloric intake. Additionally, gut bacteria influence bile acid metabolism, which plays a key role in lipid digestion and energy expenditure. Alterations in the gut microbiome can lead to increased fat storage and obesity. Obesity exacerbates insulin resistance and hyperandrogenism, creating a vicious cycle.

In PCOS, this relationship is particularly concerning, as obesity is associated with worse metabolic and reproductive outcomes.

2. Hormonal Imbalance:

  • Androgen Excess

The gut microbiome can modulate sex hormone levels through the enterohepatic circulation. Dysbiosis may alter the metabolism and excretion of androgens, contributing to hyperandrogenism in PCOS.

The enterohepatic circulation involves the recycling of compounds such as bile acids, drugs, and hormones between the intestine and the liver. The gut microbiome can produce enzymes, such as β-glucuronidases, that deconjugate hormones, making them more readily reabsorbed into the bloodstream. In the context of PCOS, dysbiosis could increase the reabsorption of androgens, leading to elevated levels in the blood and exacerbating symptoms like hirsutism and acne.

  • Oestrogen Metabolism

The gut microbiome also affects oestrogen metabolism via the production of β-glucuronidase, an enzyme that deconjugates oestrogens, allowing them to be reabsorbed into the circulation. Dysbiosis may disrupt oestrogen homeostasis, further complicating the hormonal imbalance in PCOS.

Oestrogens undergo conjugation in the liver, which makes them water-soluble and allows for their excretion via bile into the intestine. In the gut, β-glucuronidase produced by certain bacteria can deconjugate oestrogens, making them lipophilic again and facilitating their reabsorption into the bloodstream. Dysbiosis, characterized by an overabundance of β-glucuronidase-producing bacteria, can increase circulating oestrogen levels, potentially disrupting the delicate hormonal balance required for normal ovarian function.

3. Chronic Inflammation:

PCOS is associated with a state of low-grade chronic inflammation. Gut dysbiosis can contribute to systemic inflammation through increased intestinal permeability (“leaky gut”), allowing endotoxins such as lipopolysaccharides (LPS) to enter the bloodstream. Elevated LPS levels can trigger inflammatory pathways, exacerbating insulin resistance and hyperandrogenism.

Intestinal permeability is a critical factor in maintaining gut health. A “leaky gut” allows microbial products like LPS, a component of the outer membrane of Gram-negative bacteria, to translocate into the bloodstream. LPS is a potent endotoxin that can activate Toll-like receptors on immune cells, initiating inflammatory cascades. Chronic inflammation resulting from elevated LPS levels can worsen insulin resistance and hyperandrogenism, both of which are central features of PCOS.

4. The Gut-Brain Axis and Its Influence on PCOS: Neuroendocrine and Psychological Implications

The Gut-Brain Axis: A Complex Communication Network

The gut-brain axis refers to the intricate bidirectional communication system between the gastrointestinal tract and the central nervous system. This axis involves multiple pathways, including neural (vagus nerve), endocrine (hormones), immune (cytokines), and metabolic (short-chain fatty acids) routes. The gut microbiome plays a pivotal role in this communication, influencing brain function and behaviour through various mechanisms.

  1. Neurotransmitter Production Gut bacteria can produce and modulate several neurotransmitters, including serotonin, dopamine, and gamma-aminobutyric acid (GABA). Serotonin, often called the “feel-good” neurotransmitter, is significantly produced in the gut. Dysbiosis, or the imbalance of gut microbiota, can alter serotonin production, impacting mood and gastrointestinal function. Similarly, dopamine, crucial for reward and motivation pathways, and GABA, an inhibitory neurotransmitter, can be influenced by gut microbiota composition.
  2. Stress Response and Gut Permeability Stress can disrupt the gut microbiome, leading to increased gut permeability or “leaky gut.” This condition allows bacterial endotoxins to enter the bloodstream, triggering systemic inflammation and further influencing the brain through neuroinflammatory pathways. The feedback loop between stress and gut dysbiosis can exacerbate hormonal and metabolic dysregulation in PCOS, contributing to a cycle of stress and gut-brain axis disruption.
  3. Mood Disorders: Anxiety and Depression Individuals with PCOS have a higher prevalence of mood disorders such as anxiety and depression compared to the general population. The gut-brain axis may play a crucial role in this association. Dysbiosis can lead to altered levels of neurotransmitters and gut hormones, promoting neuroinflammation and affecting mood. For instance, a reduced abundance of butyrate-producing bacteria like Butyricicoccus has been linked to increased inflammation and decreased brain-derived neurotrophic factor (BDNF) expression, which supports neuroplasticity and has antidepressant effects.

The Gut Microbiome in PCOS and Mood Disorders

Research has shown that individuals with PCOS exhibit distinct gut microbiome profiles compared to healthy controls. These differences include reduced microbial diversity and altered abundance of specific bacterial taxa. For example, people with PCOS and mood disorders show a lower abundance of Butyricicoccus and higher levels of Sutterella, a genus associated with pro-inflammatory functions and metabolic disorders.

  1. Butyricicoccus and Inflammation Butyricicoccus is known for its butyrate production, a short-chain fatty acid with anti-inflammatory properties. Butyrate regulates immune function and maintains gut barrier integrity, preventing systemic inflammation. Its reduced abundance in PCOS patients with mood disorders may contribute to heightened inflammation and neuroinflammation, exacerbating anxiety and depression.
  2. Sutterella and Metabolic Dysfunction Sutterella’s increased abundance has been associated with metabolic disturbances such as insulin resistance, a common feature of PCOS. This genus adheres to the intestinal mucosa and may disrupt gut barrier function, promoting inflammation and influencing glucose metabolism. The link between Sutterella and mood disorders suggests a potential role in modulating the gut-brain axis through inflammatory pathways.

Implications for Treatment and Management

Understanding the role of the gut microbiome in PCOS opens new avenues for therapeutic interventions. Modulating the gut microbiome through dietary modifications, probiotics, prebiotics, and faecal microbiota transplantation (FMT) holds promise in managing PCOS symptoms and improving metabolic and reproductive outcomes.

Dietary Modifications

Diets rich in fibre and low in refined sugars can promote the growth of beneficial gut bacteria and enhance short-chain fatty acid (SCFA) production. SCFAs are crucial for maintaining gut health and have anti-inflammatory properties, which can help mitigate some of the chronic inflammation associated with PCOS​​.

Probiotics

Probiotic supplementation may help restore microbial balance and reduce inflammation in PCOS. Specific strains of probiotics, such as Lactobacillus and Bifidobacterium, have shown potential in improving insulin sensitivity and hormonal profiles in people with PCOS​​. For instance, studies have indicated that probiotics can lower androgen levels and improve menstrual regularity, contributing to better reproductive outcomes​​.

Prebiotics

Prebiotics, like inulin-type fructans (ITFs), can selectively promote the growth of beneficial bacteria. ITFs, found in foods such as chicory root, garlic, and onions, have been shown to improve insulin resistance, reduce androgen levels, and ameliorate menstrual irregularities in individuals with PCOS​​. ITFs with higher degrees of polymerization have demonstrated more significant effects on gut microbiota modulation, suggesting their superior efficacy in treating PCOS-related symptoms​​.

Faecal Microbiota Transplantation (FMT)

FMT is an emerging therapeutic approach that involves transplanting stool from a healthy donor to a recipient to restore healthy gut microbiota. Although still in the experimental stage for PCOS, FMT has shown promise in other conditions involving gut dysbiosis, such as Clostridium difficile infection and inflammatory bowel disease. Its potential in PCOS lies in its ability to reset the gut microbiota, thus possibly addressing the underlying dysbiosis and associated metabolic and inflammatory issues​​.

Polyphenols and Gut Microbiota

Polyphenols are plant-based compounds known for their antioxidant and anti-inflammatory properties. They can modify gut microbiota, fostering beneficial bacteria and suppressing harmful ones, which may alleviate PCOS symptoms.

  • Mechanisms of Action

Polyphenols act as prebiotics, altering the microbiome composition and producing metabolites that influence metabolic and ovarian functions in PCOS. These compounds enhance the growth of beneficial bacteria such as Lactobacillus and Bifidobacterium while inhibiting harmful bacteria like Clostridium​​. This modulation can lead to reduced inflammation and improved gut barrier function, thereby potentially reducing the severity of PCOS symptoms​​.

Specific Polyphenols and Their Effects

  1. Anthocyanins: Found in berries and other fruits, anthocyanins may improve ovarian function by reducing serum androgen levels and modulating gut microbiota. They also promote the growth of beneficial bacteria that support gut health​​.
  2. Catechins: Present in green tea, catechins have shown potential in reducing inflammation and improving hormone profiles in PCOS. They are known to enhance insulin sensitivity and reduce oxidative stress​​.

Resveratrol: Found in grapes and berries, resveratrol has anti-inflammatory and antioxidant effects. It may enhance ovarian function by altering gut microbiota and improving insulin sensitivity. Resveratrol has been demonstrated to increase beneficial bacteria like Lactobacillus and Bifidobacterium and decrease harmful bacteria, thereby supporting overall gut health​​.