The Gut–Hormone Connection: How Gut Microbes Influence Estrogen Levels

Emerging research indicates that the gut microbiome plays a central role in the regulation of estrogen levels within the body and thus influences the risk of developing estrogen-related diseases such as endometriosis, polycystic ovary syndrome, breast cancer, and prostate cancer. Read on to learn about the connection between gut microbes and estrogen levels and why correcting dysbiosis may be key for preventing and reversing estrogen-related conditions.

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Gut Microbes Regulate Estrogen

Scientific research has demonstrated that gut microbes regulate many aspects of human physiology, including intestinal permeability, the absorption of nutrients from food, and immunity. However, recent studies suggest that gut microbes play another crucial role in the human body by regulating circulating estrogen levels. 

The estrobolome is the collection of microbes capable of metabolizing estrogens. (1) The estrobolome modulates the enterohepatic circulation of estrogens and affects circulating and excreted estrogen levels. Microbes in the estrobolome produce beta-glucuronidase, an enzyme that deconjugates estrogens into their active forms. Beta-glucuronidase activity produces active, unbound estrogen that is capable of binding to estrogen receptors and influencing estrogen-dependent physiological processes.

Could balancing the microbiome be a new way to treat estrogen-related diseases?

When the gut microbiome is healthy, the estrobolome produces just the right amount of beta-glucuronidase to maintain estrogen homeostasis. However, when gut dysbiosis is present, beta-glucuronidase activity may be altered. This produces either a deficiency or an excess of free estrogen, thus promoting the development of estrogen-related pathologies. (2)

Gut Dysbiosis Is Linked to Estrogen-Related Diseases

Estrogen plays many vital roles in the human body. It regulates body fat deposition and adipocyte differentiation, female reproductive function, cardiovascular health, bone turnover, and cell replication. Gut dysbiosis has the potential to alter the estrobolome, disrupt estrogen homeostasis, and impair these processes, promoting the development of chronic diseases.

Obesity, Cardiovascular Disease, and Osteoporosis

In postmenopausal women, estrobolome disruption is associated with an increased risk of obesity, cardiovascular disease, and osteoporosis. Estrogens regulate glucose and lipid metabolism, adipocyte differentiation, bone formation, and the inflammatory response in atherosclerosis. Research indicates that the normal reductions in estrogen that occur at menopause impair these estrogen-dependent processes, triggering obesity, cardiovascular disease, and osteoporosis. (3, 4, 5, 6)

Gut dysbiosis resulting in decreased beta-glucuronidase activity may exacerbate the low-estrogen state in postmenopausal women, further increasing the risk of these chronic diseases. (7) Indeed, a high prevalence of gut dysbiosis has been observed in obese patients and those with cardiovascular disease and osteoporosis. (8, 9, 10) Taken together, this research suggests that an important relationship exists between the estrobolome, estrogen deficiency, and the incidence of obesity, cardiovascular disease, and osteoporosis.

Endometriosis

Endometriosis, an estrogen-driven condition characterized by the growth of endometrial tissue outside the uterus, has been associated with gut dysbiosis. (11) The estrobolome of women with endometriosis may have larger numbers of beta-glucuronidase-producing bacteria, leading to increased levels of circulating estrogen, which drives endometriosis. Dysbiosis of the vagina and endometrium, including a decrease in Lactobacilli and an increase in pathogenic gram-negative bacteria, has also been detected in women with endometriosis and may further contribute to hormonal imbalance. These findings indicate that perhaps the term “estrobolome” should be expanded to encompass microbes in both the gut and the female reproductive tract. (12, 13)

PCOS

Polycystic ovary syndrome (PCOS) may also be influenced by estrobolome disruption. Women with PCOS have an excess of androgens in relation to estrogen, as well as an altered gut microbiota. Researchers theorize that the altered gut microbiota in PCOS women may promote increased androgen biosynthesis and decreased estrogen levels through lowered beta-glucuronidase activity. (14, 15) Interestingly, modulation of the gut microbiota with fecal microbiota transplantation (FMT) has been found to improve estrous cycles and decrease androgen biosynthesis in an animal model of PCOS, indicating that modulation of the estrobolome may be beneficial in the treatment of PCOS. (16)

Breast, Endometrial, Cervical, and Ovarian Cancer

In recent years, an abundance of research has emerged linking dysbiosis of the gut microbiota to various forms of cancer. Researchers have discovered that cancer patients have a significantly altered gut microbiota compared to healthy controls, as well as imbalances in the microbiota of tissues such as the breast and endometrium. The altered gut microbiota of cancer patients may lead to increased beta-glucuronidase activity and increased levels of circulating estrogen, which binds to estrogen receptors and promotes cell proliferation in estrogen-sensitive tissues. (17) The microbial milieu of the gut may also affect the microbiome of distant estrogen-sensitive tissues, such as the breast, through direct transference of microbes; in one fascinating example of this phenomenon, probiotic Lactobacilli ingested by women were found to reach breast tissue, where they exert anticarcinogenic effects. (18) Clearly, an intricate relationship exists between the estrobolome, estrogen levels, estrogen-sensitive tissues, and cancer.

Prostate Cancer

Dysbiosis of the prostate gland has been associated with prostate cancer, and despite a current lack of studies on the topic, researchers hypothesize that the gastrointestinal microbiota may also be markedly different in men with this disease. (19, 20) Furthermore, elevated estrogen levels have been implicated in the development of prostate cancer, providing further support for the hypothesis that the estrobolome plays an important role in prostate cancer development. (21)

What Factors Disrupt the Estrobolome?

Diet and lifestyle factors that are commonly known to disrupt the gut microbiome also have the potential to disrupt the estrobolome. Antibiotics and hormonal contraceptives have been found to alter both the gut microbiota and estrogen levels within the body, suggesting that they may have an adverse impact on the estrobolome. (22, 23)

Diet is another important factor that may affect the estrobolome. A large body of research demonstrates that diet significantly impacts the gut microbiota; considering that the estrobolome is part of the overall microbiota, it is also likely to be affected by the foods we choose to consume. Notably, the consumption of phytoestrogens in foods has been found to significantly impact the gut microbiota and the risk of estrogen-related diseases. Phytoestrogens can be estrogenic or antiestrogenic and can, therefore, have either a protective or causative effect on the development of cancer and chronic diseases. (24) The estrobolome may be the key mediator determining the effects of phytoestrogens on endogenous estrogen levels. (25)

Could balancing the microbiome be a new way to treat estrogen-related diseases? #womenshealth #microbiome

Probiotics Can Restore a Healthy Estrogen Balance

Research indicates that it may be possible to modulate the estrobolome and reverse estrogen-related pathologies through probiotic supplementation.

• Supplementation with a broad-spectrum Lactobacillus probiotic has been found to normalize the estrous cycle and decrease testosterone biosynthesis in an animal model of PCOS. (26)
• In an animal model of endometriosis, Lactobacillus gasseri suppressed ectopic tissue growth, which is an estrogen-driven process. (27)
• In a menopausal mouse model of osteoporosis, Lactobacillus reuteri prevented bone loss resulting from low estrogen. (28)
• Lactobacilli have anticarcinogenic effects in breast tissue, suggesting that supplementation may be useful for the prevention of breast cancer. (29)

While research on the relationship between probiotic supplementation and the estrobolome is still in its infancy, this shouldn’t stop practitioners from recommending probiotics to their patients with estrogen-related conditions. Reversing dysbiosis appears to be key for modulating the estrobolome, and probiotic supplementation is a relatively simple and inexpensive way to accomplish this. Practitioners may just find that probiotics have been the missing tool in their toolbox for treating estrogen-related conditions!