Cannabis and Endometriosis: The Roles of the Gut Microbiota and the Endocannabinoid System

Abstract

Endometriosis, a chronic condition affecting around 10-14% of women, is challenging to manage, due to its complex pathogenesis and limited treatment options. Research has suggested a potential role of the gut microbiota and the endocannabinoid system in the development and progression of endometriosis. This narrative review aims to explore the role of, and any potential interactions between, the endocannabinoid system (ECS) and the gut microbiota in endometriosis. This review found that both the ECS and microbiota influence endometriosis, with the former regulating inflammation and pain perception and the latter influencing immune responses and hormonal balance. There is evidence that a dysregulation of the endocannabinoid system and the gut microbiota influence endometriosis symptoms and progression via changes in CB1 receptor expression and increased circulating levels of endocannabinoids. Microbial imbalances in the gut, such as increases in Prevotella, have been directly correlated to increased bloating, a common endometriosis symptom, while increases in E. coli have supported the bacterial contamination hypothesis as a potential pathway for endometriosis pathogenesis. These microbial imbalances have been correlated with increases in inflammatory markers such as TNF-α and IL-6, both often raised in those with endometriosis. Protective effects of the ECS on the gut were observed by increases in endocannabinoids, including 2-AG, resulting in decreased inflammation and improved gut permeability. Given these findings, both the ECS and the gut microbiota may be targets for therapeutic interventions for endometriosis; however, clinical studies are required to determine effectiveness.

Keywords: CB1; CB2; endometriosis; gut microbiota; the endocannabinoid system.

Figure 1

The involvement of the ECS in endometriosis-associated pain. The impaired response to progesterone in endometriosis potentially occurs as a result of CB₁ regulation not occurring during menstruation. When present in endometriotic growths, the activation of CB1 decreases endometriosis-induced hyperalgesia while its blockage results in decreased pain. Increased levels of CB₁ receptors have been noted in the endometrial somata and nerve fibres. An endocannabinoid deficiency in endometriosis is demonstrated in plasma levels, where there is an increased level of TRPV1 (linked with hyperalgesia) and 2-AG and AEA (linked with abdominal pain). In contrast, decreased levels of CB₁ receptor expression and PEA (linked with dyspareunia) are also recognized as the defining features of an endocannabinoid deficiency. The decreased level of CB₁ receptors in endometrial stromal cells is suggested to cause a negative feedback loop, possibly impairing the ability of the ECS to control pain. Abbreviations: ECS = endocannabinoid system; CB₁ = cannabinoid receptor 1; 2-AG = 2-arachidonoyl glycerol; AEA = anandamide; PEA = palmitoylethanolamide.

Figure 2

The interplay between the gut microbiota and endometriosis. Dysbiosis in the gut and inflammation occurring both in the gut and in the peritoneal cavity results in endometriosis-associated symptoms including pain and fatigue. This figure was created using Canva.com (accessed on 27 September 2023).

Figure 3

Healthy gut homeostasis vs. inflamed gut microbial dysbiosis. The downregulation of inflammatory cytokines occurs under healthy conditions. However, under inflammatory conditions, proinflammatory cytokines are upregulated as a result of increases in pathogenic microorganisms. This image was created using Biorender.com (accessed 27 September 2023).