The Microbiome and Endometriosis-Associated GI Symptoms

Key Takeaways:

• The gut microbiome (estrobolome) regulates estrogen metabolism; dysbiosis leads to higher circulating estrogen, which drives lesion growth.
• Compromised gut barriers ("leaky gut") allow bacterial toxins to escape, causing systemic inflammation that impairs the immune clearance of ectopic tissue.
• Bloating and pain are frequently caused by visceral hypersensitivity via the gut-brain axis.

Endometriosis is a complex disorder affecting approximately 10 percent of reproductive-aged women. While classically characterized by pelvic pain and infertility, a significant proportion of patients report gastrointestinal (GI) symptoms.¹

These GI symptoms can include bloating, nausea, constipation, and diarrhea. They frequently overlap with irritable bowel syndrome (IBS), leading to diagnostic delays and management challenges.^1-3

Recent research has identified the gut microbiome as a critical factor in the pathophysiology of endometriosis. The "gut-endometriosis axis" describes a bidirectional relationship where gut dysbiosis influences estrogen metabolism, systemic inflammation, and immune regulation, thereby exacerbating both endometriotic lesion growth and associated GI symptomatology.^1-3

Pathophysiology: dysbiosis and the estrobolome

The human gut microbiome plays a pivotal role in regulating circulating estrogen levels through a cluster of bacterial genes known as the "estrobolome." These bacteria produce beta-glucuronidase, an enzyme that deconjugates estrogen, allowing it to be reabsorbed into the bloodstream rather than excreted.⁴

In patients with endometriosis, studies have observed a distinct dysbiosis characterized by:^1-5

• Altered bacterial ratios – A higher firmicutes/bacteroidetes ratio and reduced gut bacteria species diversity. One study showed a higher ratio was associated with endometriosis, while another study showed a lower ratio was associated with endometriosis. Regardless, both bacteria, as well as Bifidobacterium, have genes related to glucuronidase activity.
• Bacterial changes – A reduced number of beneficial bacteria, such as Lactobacillus and Ruminococcus (which promote gut barrier integrity), alongside an increase of potentially pathogenic bacteria like E. coli, Pseudomonas, and Prevotella (which are pro-inflammatory). However, this research is observational, and there is no current research proving causality.

This dysbiotic state promotes elevated beta-glucuronidase activity, leading to increased levels of circulating active estrogen. Given that endometriosis is estrogen-dependent, this "estrogen dominance" drives the proliferation of ectopic endometrial tissue.^2,4

Furthermore, the local inflammatory environment created by dysbiosis contributes to the cyclical hemorrhage and fibrosis of these lesions, perpetuating the disease process.¹

Immune dysregulation and intestinal permeability

The integrity of the intestinal barrier is crucial in stopping harmful substances inside the intestines from leaking into the bloodstream. In endometriosis, dysbiosis is frequently associated with compromised barrier function, often referred to as "leaky gut."²

This increased permeability allows bacterial endotoxins, specifically lipopolysaccharides (LPS) from gram-negative bacteria, to translocate into the peritoneal cavity. LPS activates Toll-like receptor 4 (TLR4), triggering a cascade of pro-inflammatory cytokines, including IL-6, IL-8, and TNF-alpha.⁵

At baseline, people living with endometriosis have higher levels of circulating proinflammatory cytokines. This, combined with chronic low-grade inflammation from intestinal permeability, not only facilitates the adhesion and invasion of endometrial cells but also creates a toxic environment that impairs cellular function. Consequently, the immune system fails to clear ectopic tissue effectively, allowing lesions to establish and grow.^1,2,6

The gut-brain axis and visceral hypersensitivity

The high prevalence of GI symptoms in endometriosis cannot be explained solely by the presence of bowel lesions, which occur in a minority of cases. Instead, central sensitization and the gut-brain axis play significant roles.⁶

The gut-brain axis is a communication network linking the enteric nervous system to the central nervous system. Dysbiosis can disrupt this signaling, influencing pain perception and mood. The chronic release of inflammatory mediators sensitizes visceral nociceptors, leading to visceral hypersensitivity – a hallmark of both IBS and endometriosis.⁶

This phenomenon explains why patients often experience severe GI distress and pain in response to normal gut distension, independent of direct bowel infiltration. In addition, neuroinflammation driven by dysbiosis may contribute to the fatigue, anxiety, and depression commonly observed in people living with endometriosis.⁶

Clinical implications

Understanding the gut-endometriosis axis opens new avenues for non-invasive management strategies. While standard treatments (hormonal suppression, surgery) address the lesions, they often fail to resolve functional GI symptoms.1-3
Some non-invasive strategies to help with GI symptoms can include:^1-3,6

• Probiotics and prebiotics – Emerging evidence suggests that restoring gut eubiosis through Lactobacillus-containing probiotics may reduce pain and lesion size in animal models, though human trials are still ongoing.
• Dietary changes – Diets high in fiber, fruits, vegetables, and fermented foods can improve the gut microbiome by promoting more bacterial diversity and reducing inflammation. Processed foods, sugar, and red meat can be highly inflammatory. Anti-inflammatory diets or the low-FODMAP diet may help manage visceral hypersensitivity and reduce bloating.
• Healthy lifestyle habits – Focusing on lifestyle habits like daily exercise and improved sleep may also help reduce inflammation throughout the body.
• Antibiotic caution – Given the role of dysbiosis, the use of antibiotics should be done so with caution, to avoid further disrupting the microbial ecosystem.

Contributing to the disease burden

The gut microbiome is not merely a bystander but an active participant in the pathophysiology of endometriosis. Through the modulation of estrogen via the estrobolome, the induction of systemic inflammation via intestinal permeability, and the sensitization of pain pathways via the gut-brain axis, dysbiosis significantly contributes to the disease burden.^1-3

It is likely that the treatments for endometriosis, such as GnRH agonists and antagonists, may cause further dysbiosis by altering the microbiome. Encouraging diet and lifestyle changes may still be relevant for patients undergoing treatment.²

For healthcare providers, recognizing the gut-endometriosis axis emphasizes the need for a holistic approach. Addressing gut health through diet and potential microbial modulation may offer symptomatic relief and improve the quality of life for patients struggling with the complex GI manifestations of endometriosis.^1-3