Mini But Mighty: How Microbes In The Uterine and Endometrial Microbiome Are Causing Endometriosis

Image Citation: [1]

Writer: Annabel Ovonlen ‘29

Editor: Morgan Rafferty ‘28

Bacteria. They’re everywhere from our scalps to the gut and even our lungs. In the various regions of our bodies, these microbes form powerful yet invisible colonies and kingdoms known as microbiomes. For women, the state of the uterine microbiome is particularly important because it affects other aspects of health. For the longest time, scientists have focused their efforts on understanding the composition of the lower reproductive tract (vaginal) microbiome. It wasn’t until recently that scientists began trying to uncover which microorganisms occupy the upper reproductive tract and how these microbes potentially play a role in fertility, pregnancy maintenance, and the pathogenesis of uterine diseases and disorders such as endometriosis. 

How are the compositions of the uterine and endometrial microbiomes found?

The uterus is a hollow pear-shaped organ that sits in the female pelvic cavity [2] and the endometrium is a mucous membrane that lines the inside of the uterus [3]. Before any microorganisms can be identified, a sample must be taken [4]. DNA is then extracted and sequenced. Typically, 16s rRNA sequencing is used [4]. This sequencing method identifies and classifies bacterial and archaeal species using the 16S rRNA gene as a marker [5]. This works well because the 16S rRNA gene is highly conserved across several different bacterial species but it also contains variable regions. This sequence diversity allows us to differentiate between different bacterial species within a sample. 

Microbiomes and endometriosis:

Researchers have found links between the compositions of the endometrial and uterine microbiomes and several endometrial diseases and disorders such as endometrial polyposis, uterine fibroids and endometrial cancer [6]. However, there’s a particular focus on endometriosis because it affects approximately 10% of women and its pathogenesis remains unclear. It is a chronic inflammatory condition which results in endometrial tissue developing in abnormal locations outside of the uterine cavity such as the ovaries, fallopian tubes, and abdominal cavity [7]. Endometriosis seems to be a multi-etiological (caused by multiple factors) disease that is influenced by genetics, immunological and endocrine factors. Researchers suspect that bacteria also play a role by influencing inflammatory responses in the endometrium. For example, Fusobacterium nucleatum has been found to activate the immune response using lipopolysaccharide (LPS) [8]. LPS is a component of the cell wall of gram-negative bacteria, and its concentration in menstrual fluid is significantly higher in women with endometriosis than in women without endometriosis [9]. It has been shown that (LPS) interacts with toll-like receptor 4 in endometrial and endometriotic cells and activates the immune response by increasing the production of pro-inflammatory cytokines (chemical signalling molecules) such as interleukin-6 (IL-6) [10]. F. nucleatum infiltration leads to a similar result. Firstly, increased numbers of macrophages infiltrate endometrial tissues, particularly M2 macrophages which are anti-inflammatory. Once the receptors on these macrophages have identified F. nucleatum, they release transforming growth factor beta 1 (TGF-β1) - a profibrotic cytokine that induces the proliferation, migration and matrix production of fibroblasts and myofibroblasts. A systematic review and meta-analysis found that there is increased expression of TGF- β in endometrial tissues affected by endometriosis. It is thought that TGF-β plays an important role in the development of endometriosis lesions because it induces the expression of the protein transgelin (TAGLN) which is up-regulated in fibroblasts in the ectopic endometrium of patients with endometriosis [11]. TAGLN allows for increased cell motility, migration, proliferation and adhesion, all of which are required for the formation and maintenance of endometriosis lesions [12]. All in all, F. nucleatum infection triggers a signaling cascade that results in the development of endometriosis lesions.

What’s next?

Currently, treatment pertaining to endometriosis focuses on managing pain by reducing or removing lesions using gonadotropin-releasing hormone agonists or surgical intervention [7]. The latter is highly invasive, and the former has a negative effect on fertility which makes them unattractive options. Consequently, scientists are looking for alternative treatments that aim to treat endometriosis rather than simply manage symptoms, and immunotherapy is bidding to be one of them. As we have established, the role of microbes in the pathogenesis of endometriosis is highly connected to the body’s immune system. Therefore, researchers are exploring whether endometriosis can be treated by inhibiting and modulating aspects of the immune system that are involved in the various signalling pathways connected to the development of endometriosis [13]. Bacille Calmette-Guérin vaccine is a possible contender as it may increase the ratio of M1/M2 macrophages which could make it harder for the signalling pathway triggered by F. nucleatum to occur [14]. Thereby inhibiting or slowing the development of endometrial lesions.

To conclude, bacteria may be an important factor for scientists to continue investigating in the context of endometriosis due to their dysregulatory effect on the immune system which ultimately triggers the development of endometriosis. There are a wide variety of ways in which scientists can try to control and inhibit these effects, particularly when it comes to immunotherapy, and it will be interesting to see what new therapies and treatments are developed over the next coming years. 

References:

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