Endometriosis and the Microbiome: Insights and Emerging Research

Endometriosis is a multifaceted, heterogenous, inflammatory condition that impacts 10%-15% of women (XX) in their reproductive years, most commonly associated with chronic pelvic pain and infertility. 

Over the years, numerous theories have been proposed to explain its pathogenesis, but none have conclusively clarified its origins. Recently, however, researchers have begun investigating the complex interplay between endometriosis and the human microbiome. This article aims to provide an in-depth exploration of the current research into the relationship between endometriosis and the microbiome, with a particular focus on gut health, inflammation, and pathogenesis. 

Understanding Endometriosis

Endometriosis is marked by the growth of endometrial-like tissue found outside of the uterine cavity. This tissue is commonly found implanted over visceral and peritoneal surfaces within the abdominopelvic cavity, but can extend to the connective tissue and organs throughout the body. The condition can lead to severe dysmenorrhea, pelvic pain, and subfertility among a number of other symptoms and manifestations, significantly impairing a person’s quality of life.⁴

Read more: What causes endometriosis?

The Human Microbiome and Its Role in Health and Disease

The human microbiome comprises microorganisms that colonize our bodies and play crucial roles in nutrient metabolism and various physiological functions. The composition and balance of these microbial communities can significantly influence our health. For instance, the gut microbiota synthesizes vitamins B12 and K, maintains intestinal mucosal integrity, promotes angiogenesis and epithelial repair, and modulates immune functions.⁵ 

Disruptions in gut microbiota composition, a state known as dysbiosis, can contribute to the development and progression of numerous diseases, including inflammatory bowel diseases, arthritis, psoriasis, neuropsychiatric diseases, and even malignancies.⁴ Given that endometriosis is a chronic inflammatory disease potentially triggered by altered immune functions and increased angiogenesis, there is a growing interest in investigating the role of microbiota dysbiosis in the pathogenesis and pathophysiology of endometriosis.^1,4

The Microbiome-Endometriosis Connection: An Emerging Field of Research

Recent studies have commenced exploring whether microbiome composition is altered in women with endometriosis. For instance, one study identified significant differences in the microbial community structure between those with and without endometriosis.^1,5 This study found that the abundance of Acinetobacter, Pseudomonas, Streptococcus, and Enhydrobacter significantly increased, while the abundance of Propionibacterium, Actinomyces, and Rothia significantly decreased in the endometriosis group.⁵

Another study focused on the microbiota of extracellular vesicles in the peritoneal fluid.^4,5 These vesicles, small structures made of bilayered lipid membranes released by cells, carry proteins, nucleic acids, and lipids, and play a key role in immune function, inflammatory reactions, and disease development. Like other cells, bacteria can release extracellular vesicles that modulate host-cell immune responses and other health conditions. The study found significant differences in the microbial community of these vesicles between women with and without endometriosis.⁵

Highlighting the complex relationship between the microbiome and endometriosis, several studies have shown an increased bacterial colonization of menstrual blood and endometrial tissue in women with endometriosis compared to control subjects.⁵ A study on rhesus monkeys demonstrated that altered composition of the intestinal microflora and intestinal inflammation are associated with endometriosis. While we know animal comparison is not exactly like humans, the reproductive tract of rhesus monkeys closely resembles humans in both the form and function.⁷

Read more: Endo-Fighting Microbiome Optimization: Research-based Tips

Microbiome and the Inflammatory Response in Endometriosis

Endometriosis is known to trigger an inflammatory response within the body, characterized by increased production of pro-inflammatory cytokines, autoantibodies, growth factors, oxidative stress, and alterations in T-cell and natural killer cell reactivity.¹ This dysregulated immune response potentially creates an immunosuppressive environment that enables the growth of these endometriosis lesions.¹

Recent studies suggest that gut microbiome-derived extracellular vesicles could play a critical role in this process.⁵ These vesicles, ranging from 20 to 400 nm in diameter, can traverse the intestinal barrier, enter the systemic circulation, and potentially influence the peritoneal environment. They may carry a cargo of proteins, nucleic acids, and lipids that can influence immune function, inflammatory responses, and the development of diseases like endometriosis.

One study demonstrated that extracellular vesicles from women with endometriosis carry unique cargo that can influence inflammation, angiogenesis, and proliferation.⁵ Another study identified specific proteins in the exosomes of peritoneal fluid samples from patients with endometriosis, suggesting a role of exosomes in the diagnosis and treatment of endometriosis.⁵

The Gut Microbiome and Estrogen Levels

The gut microbiome is a significant regulator of estrogen levels, influencing estrogen metabolism and hence potentially affecting estrogen-dependent diseases like endometriosis.³ In postmenopausal women, fecal microbiota richness and levels of fecal Clostridia taxa have been associated with systemic estrogen levels. Therefore, gut dysbiosis leading to abnormal circulating levels of estrogen could potentially play a role in the development of endometriosis or the associated symptoms.³

The Microbiome as a Diagnostic and Therapeutic Target

The alterations in microbiota composition associated with endometriosis may provide valuable diagnostic markers for the disease. For instance, one study has proposed a microbiota-based model that can distinguish infertile patients with and without endometriosis.¹ Another study has found that specific bacterial species are enriched in the endometrium and peritoneal fluid of patients with endometriosis.²

On the therapeutic front, the modulation of gut microbiota through dietary interventions, prebiotics, probiotics, or fecal microbiota transplantation could potentially represent a novel treatment approach for endometriosis.⁴ However, more research is needed to explore the potential of these strategies and to understand the precise mechanisms through which the microbiota influences endometriosis development and progression.

Read More: Integrative Therapies for Endometriosis

Conclusion

The complex relationship between the microbiome and endometriosis is still in its early stages of investigation. Recent studies indicate that alterations in microbiota composition may be associated with endometriosis. These insights not only enhance our understanding of endometriosis pathogenesis but also open up new possibilities for the diagnosis and treatment of this prevalent condition.

As our understanding of the microbiome continues to grow, so does the potential for novel, integrative health strategies that target this complex ecosystem. Further research is required to confirm the observed associations and to elucidate the mechanisms underlying the microbiome-endometriosis connection. Such research holds the promise of ushering in a new era in our approach to endometriosis, one that acknowledges the intricate interplay between our bodies and the microbes that inhabit them.

While there are limitations in the current usefulness of this research, we do know that the immune system is involved with regulating the disease. An important question remains: are the microbiota changes seen in those with endo the chicken or the egg?

References: 

1. Leonardi, M., Hicks, C., El-Assaad, F., El-Omar, E., & Condous, G. (2020). Endometriosis and the microbiome: a systematic review. BJOG, 127(2), 239-249. https://doi.org/10.1111/1471-0528.15916 
2. Oishi, S., Mekaru, K., Tanaka, S. E., Arai, W., Ashikawa, K., Sakuraba, Y., Nishioka, M., Nakamura, R., Miyagi, M., Akamine, K., & Aoki, Y. (2022). Microbiome analysis in women with endometriosis: Does a microbiome exist in peritoneal fluid and ovarian cystic fluid? Reprod Med Biol, 21(1), e12441. https://doi.org/10.1002/rmb2.12441 
3. Svensson, A., Brunkwall, L., Roth, B., Orho-Melander, M., & Ohlsson, B. (2021). Associations Between Endometriosis and Gut Microbiota. Reprod Sci, 28(8), 2367-2377. https://doi.org/10.1007/s43032-021-00506-5 
4. Jiang, I., Yong, P. J., Allaire, C., & Bedaiwy, M. A. (2021). Intricate Connections between the Microbiota and Endometriosis. Int J Mol Sci, 22(11). https://doi.org/10.3390/ijms22115644 
5. Lee, S. R., Lee, J. C., Kim, S. H., Oh, Y. S., Chae, H. D., Seo, H., Kang, C. S., & Shin, T. S. (2021). Altered Composition of Microbiota in Women with Ovarian Endometrioma: Microbiome Analyses of Extracellular Vesicles in the Peritoneal Fluid. Int J Mol Sci, 22(9). https://doi.org/10.3390/ijms22094608 
6. Wei, W., Zhang, X., Tang, H., Zeng, L., & Wu, R. (2020). Microbiota composition and distribution along the female reproductive tract of women with endometriosis. Ann Clin Microbiol Antimicrob, 19(1), 15. https://doi.org/10.1186/s12941-020-00356-0 
7. Burns, K. A., Pearson, A. M., Slack, J. L., Por, E. D., Scribner, A. N., Eti, N. A., & Burney, R. O. (2021). Endometriosis in the Mouse: Challenges and Progress Toward a ‘Best Fit’ Murine Model. Front Physiol, 12, 806574. https://doi.org/10.3389/fphys.2021.806574