Estrogen + Microbiome = Estrobolome
The function of the digestive tract is essential for proper function of almost every biological system in the body. Hormone metabolism and endocrinology is no exception to this rule. In fact, the connection is so strong with estrogen, that there is a term to describe it in the literature – the estrobolome.
The Estrobolome and Estrogen Metabolism
The insights leading to today’s understanding of the estrobolome date back to as early as 1985, when it was found that specific bacterial strains (in rats) could produce an enzyme called beta-glucuronidase, which would de-conjugate estrogens, making them available to be reabsorbed in the gut and back into circulation.
As a reminder, estrogens undergo several steps in order to be metabolized and excreted by the body. First, primary estrogens (estrone, estradiol and estriol) are hydroxylated by CYP 450 in the liver into the metabolites 2-OH, 4-OH, and 16-OH (and others). These metabolites undergo further metabolism with the actions of methylation, glucuronidation, and sulfonation into their conjugated form. At this point, the conjugated estrogens are “packaged up” and can then travel via the bile into the intestines for excretion.
Studies of injected, radioactively labeled estrogens in women showed that approximately 65% of injected estradiol, 48% of injected estrone, and 23% of injected estriol were recovered in bile (meaning they enter the intestines). However, only 10-15% of injected estrogens were found (in their conjugated forms) in the stool, suggesting that significant quantities of estrogens were deconjugated and reabsorbed in the intestinal tract.
This observation leads to the question of what happens to the remaining estrogens, and why? The answer lies in the estrobolome, the collection of microbes in the gut that are capable of metabolizing and modulating the amount of circulating estrogen in the body. One way that this occurs is through the production of beta-glucuronidase by microbes in the gut.
Beta-glucuronidase plays an important role in metabolism. In addition to estrogen, the substrate of note in this blog, beta-glucuronidase also hydrolyzes amino acid residues from other compounds, including medications like heparan sulfate and even the body’s own bilirubin, allowing it to be reabsorbed.
More than 60 genera of intestinal microbes have been observed to produce beta-glucuronidase, including key genera such as Lactobacillus, Bifidobacterium, Enterococcus, and others. It is also likely that the gut microbiome-hormonal connection goes beyond beta-glucuronidase, with evidence to show that intestinal flora can influence estrogen balance through other enzyme pathways. In the human GI tract, the most important genes that encode beta-glucuronidase are called the GUS genes. About 112 GUS genes have been identified and tend to be expressed in four main bacterial phyla including Bacteroidetes, Firmicutes, Verrucomicrobia, and Proteobacteria. Clinically appropriate levels of beta-glucuronidase have not yet been established.
The Estrobolome and Disease Risk
Through the estrobolome, the intestinal microbiome can directly impact a woman’s lifetime burden of estrogen and may also influence disease risk directly. Researchers have been evaluating the role of the estrobolome in several conditions with known estrogen influence, including estrogen-responsive cancers and endometriosis.
It has been postulated that the estrobolome may play a critical role in breast and other estrogen-responsive cancers through several mechanisms. Both endogenous and exogenous estrogens (such as xenoestrogens) require metabolism and excretion. If the estrobolome favors recirculation of estrogen and thus a higher total estrogen burden, this changes a women’s hormonal environment in a way that goes beyond the direct stimulation of estrogen receptors. Increased total estrogen can also cause changes in immune system function and can impact the gut microbiome even further.
The estrobolome (along with the genitourinary microbiome) is an area of interest in endometriosis as well. In women with pathologically confirmed endometriosis, there is a strong correlation between GI and urogenital bacterial species and concentrations of urinary estrogen and urinary estrogen metabolites, indicating a connection between microbial dysbiosis and endometriosis disease progression.
The estrobolome has even been acknowledged for its likely importance in protecting cardiovascular health in postmenopausal women. In a study published in June 2022, subjects participating in the Hispanic Community Health Study/Study of Latinos (a population with high cardiometabolic risk) underwent stool shotgun metagenomic sequencing. The results were interesting. The microbiome of postmenopausal women appeared more similar to men than premenopausal women and these gut microbiome changes were associated with adverse cardiometabolic risk in postmenopausal women.
There has been an association observed between phylogenic diversity in a woman’s gut microbiome and urinary estrogen metabolite-to-parent estrogen ratios. A 2014 study in healthy, postmenopausal women suggested that women with a more diverse gut microbiome exhibited a higher urinary ratio of hydroxylated estrogen metabolites to parent estrogen. Another study showed that elevated urinary estrone (but not other forms of estrogen) was associated with higher beta-glucuronidase activity, suggesting that recirculation of estrone may be higher than other forms of estrogen with increased beta-glucuronidase activity.
Improving the Estrobolome
When taking patient history for hormone-related concerns, evaluation of GI function and possible risk factors for dysbiosis should be included. These include use of (and history of use of) antibiotic therapies, history of or current obesity or type 2 diabetes, and the traditional “western diet” of low fiber, high fat, high carbohydrate foods (among many others).
Urinary indican, a new organic acid included on some DUTCH panels, has been shown to be a reliable marker for intestinal dysbiosis. Data from DUTCH Test samples in postmenopausal women and in men have shown a small, but statistically significant association between elevated urinary indican levels (suggesting dysbiosis) and estradiol levels, reinforcing the assertion that GI dysbiosis is an important factor in circulating estrogen levels.
The DUTCH test provides a uniquely useful insight into the estrobolome in this way. DUTCH Test panels show urinary indican to suggest whether dysbiosis is part of the patient picture in addition to total estrogen levels and estrogen metabolites, so practitioners can observe whether relative estrogen excess may be resulting from a sub-optimal gastrointestinal environment.
To address the estrobolome’s impact on hormone levels, it is imperative to address the root cause – the gut microbiome. Prebiotics, probiotics, and symbiotics have all been shown to balance beta-glucuronidase activity, along with a high fiber diet rich in diverse phytonutrients and fermented foods. There may also be a place for additional gut-supportive nutrients, though data showing direct correlation is lacking. Calcium-d-glucarate may also help to block beta-glucuronidase, reducing deconjugation of estrogens and supporting proper excretion of estrogen metabolites, and is a reasonable dietary supplement approach. Dosing typically ranges from 500 to 1000 mg daily.
The evidence clearly demonstrates a significant impact of the gut microbiome on a woman’s estrogen levels. It is critical to keep this in mind when working on a woman’s hormonal balance. While improving estrogen metabolism with lifestyle and supplementation, be sure to consider the potential impact of the estrobolome on recirculation. Only when the entire estrogen metabolism and excretion pathways are addressed can you restore optimal estrogen balance and function.
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By: Jaclyn Smeaton, ND
Dr. Jaclyn Smeaton, ND, is the Chief Medical Officer (CMO) at Precision Analytical and a naturopathic physician focused on infertility, reproductive, and genitourinary health. In addition to her private practice, Hello Fertility she is a prolific teacher in reproductive endocrinology and hormones. and has trained thousands of clinicians on her treatment methodology. Dr. Smeaton has extensive leadership experience in integrative medicine including President of the American Association of Naturopathic Physicians, an Ambassador for the Academy of Integrative Health and Medicine, and a board member of the Integrative Health Policy Consortium.