When the balance of good and bad microbes in your microbiome is disrupted (dysbiosis) can contribute to endometriosis by causing immune system dysregulation and altered estrogen metabolism [1].

Here we dive into the latest research and explain how this microbiome link could be utilized for better management of endometriosis. If you need to learn more about the basics of endometriosis first, check out the information available from the Office on Women’s Health.

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What causes endometriosis?

Endometriosis is a condition affecting 1 in 10 women, where tissue similar to the lining of the womb (endometrium) builds in places where it shouldn’t, such as the ovaries and fallopian tubes. It can cause chronic pain, difficulty getting pregnant [2] and an increased risk of developing depression and anxiety disorders [3]. 

The cause of endometriosis is not completely understood but it is thought to be due to a combination of factors, including genetics, retrograde menstruation, inflammation, and your microbiome. 

1. Retrograde menstruation

Retrograde menstruation is when tissue shed from the endometrium during the menstrual period flows upwards out of the uterus into the peritoneal cavity (the space between your abdomen and your internal organs), rather than flowing out of your body via the cervix and vagina [4]. These endometrial fragments can implant in the peritoneal cavity and seed endometrial growths [4].

The idea that retrograde menstruation is involved in endometriosis is almost 100 years old and still stands as the leading theory for disease onset and progression. However, 90% of menstruators experience retrograde menstruation [5] but only 10% will develop endometriosis. So what is different in endometriosis sufferers that causes the endometrial tissue to adhere outside of the uterus and grow into lesions? The answer lies, at least in part, in inflammation. 

2. Inflammation

Inflammation is part of your immune system’s natural response to an injury or infection, there to protect you from harm. In some cases, the inflammatory response can be too much and can make things worse. 

The peritoneal cavity of women with endometriosis exists in a constant state of inflammation (chronic). The progression of endometriosis involves a vicious cycle of inflammation and endometrial growth, so it is not clear if the inflammation is a cause or effect of endometriosis [1].

1. Chronic inflammation helps endometrial tissue to stick and grow in places it shouldn’t. 
2. The increase in endometrial debris could overload the immune system, causing chronic immune dysregulation and more inflammation. 
3. Poor immune regulation means more misplaced endometrial tissue can escape immune defenses.
4. Inflammation helps this tissue develop into endometrial lesions and the cycle starts again.

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3. The human microbiome

Your microbiome is the community of bacteria and microbes living in and on you, including many good bacteria which play an important role in protecting your health. Studies have shown that there is a bidirectional relationship between your microbiome and the progression of endometriosis [1]. That means that endometriosis can cause disruption to your microbiome, but also that a disruption in your microbiome can contribute to endometriosis. The research into this link is still in its infancy, but these are some of the most interesting findings [1].

• The microbiomes of women with endometriosis have lower levels of protective Lactobacillus species and higher levels of bacterial vaginosis associated bacteria.
• The endometrial microbiome of women with endometriosis is more diverse than healthy women.
• A study with over 140 thousand participants showed that patients with pelvic inflammatory disease (PID)— an ascending infection of vaginal bacteria to the upper reproductive tract— have a three times greater risk of developing endometriosis. 
• Antimicrobial and probiotic treatment has been effective in treating endometriosis in humans and animals.
• Vaginal dysbiosis is associated with adverse pregnancy outcomes (e.g. preterm birth and ART failure) and this is thought to be due to inflammation of the endometrium.

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How does the microbiome influence endometriosis?

So, what are some of the possible explanations for this link? There is a large amount of preliminary research into this relationship but much remains unclear. Some of the most interesting evidence points towards a relationship with the hallmark of endometriosis: inflammation.

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1. Bacterial contamination hypothesis

The microbiomes of women with endometriosis have elevated levels of Gram-negative bacteria. These Gram-negative bacteria shed a toxin called lipopolysaccharide (LPS). The bacterial contamination hypothesis suggests that retrograde mensuration transports LPS from the uterus into the peritoneal cavity, triggering the immune system and promoting the onset and progression of endometriosis lesions [6]. 

This is supported by studies in animals that show LPS promotes the development of endometrial lesions and that antibiotic treatment can reduce peritoneal inflammation and the size of lesions [1].

2. Immune regulation

Your microbiome can influence endometriosis by up or down-regulating your immune system, for example by increasing the concentration of circulating inflammatory proteins or reducing immunosurveillance. Over time, this dysregulation can lead to chronic inflammation, creating the perfect environment to drive endometriosis onset and progression [1].

In return, endometriosis can make the environment in your gut less favorable to good bacteria and more favorable to bad bacteria, by releasing inflammatory proteins called cytokines which travel from the peritoneal cavity to the gut and suppress gastric acid secretion and gut motility.

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3. Other theories

There could be many factors influencing this relationship. Some other possible contributors to this association include [1]:

• Estrogen metabolism: In women with endometriosis, estrogen stimulates inflammatory activity and the growth of endometrial lesions. Estrogen metabolism is regulated by the gut microbiome. Dysbiosis can impair this regulation, resulting in excess estrogen which could then drive endometriosis.
• Stem cell regulation: Endometrial tissue regenerates with the help of stem cells, but stem cell regulation appears to be altered in endometriosis patients. Microbiome composition correlates with stem cell proportions in the bone marrow so could be involved in stem-cell regulation and therefore endometriosis progression.

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How can the microbiome be utilized in endometriosis care?

It takes 8-10 years to get a diagnosis of endometriosis after the onset of symptoms and surgery remains the gold standard for diagnosis and treatment [7]. Unlocking the microbiome could be key to earlier, less invasive and more reliable endometriosis care. 

1. Diagnosis of endometriosis with the microbiome

The gut microbiome is already used as a diagnostic for colorectal cancer and has potential for other gastrointestinal disorders. The vaginal microbiome has had less research behind it but could be key to a better diagnostic for endometriosis. 

• One study suggests that analysis of the gut microbiome could be used as an early diagnosis of endometriosis [8]. 
• Early research suggests the vaginal microbiota could be useful for the diagnosis of diseases of the upper reproductive tract [9].
• Another study found that vaginal microbiome testing performed better than gut microbiome analysis to predict the stage of disease in women with endometriosis  [7]. 

2. Treatment of endometriosis with the microbiome

There is promising research that treatment targeting the microbiome could be effective for endometriosis [1]:

• Antibiotic treatments effectively treated endometriosis in animals by inhibiting the growth of lesions, decreasing inflammation and reducing the size of lesions.
• Lactobacillus probiotic treatment treated and prevented endometriosis in animals.
• Lactobacillus probiotics reduced endometriosis-associated pain in human women.
• Two existing treatments known to prevent endometriosis progression were shown to exert their effect via the restoration of healthy microbiota.

3. Powering up research with the microbiome

It’s clear that the microbiome of the reproductive tract is closely linked to endometriosis onset and progression, but it’s too soon to know how to use this information. More research is needed. That’s why Juno Bio exists, to power up research into women’s health conditions and the vaginal microbiome. We hope that in the future, vaginal microbiome testing can be used to detect disease and guide treatment plans. 

Until then, the Juno Vaginal Microbiome Test can give you a picture of the microbiome of your reproductive tract and can be used as a simple, non-invasive screen to rule out vaginal dysbiosis as a factor in disease progression.