Interactions between estrogen and gut microbiota

Interactions between estrogen and gut microbiota

Estrogen dominance is the presence of too much estrogen in relation to progesterone. The term is controversial because outside of puberty and peri-menopause (when the body is trying to calibrate hormones to a new norm) it is very unlikely that the ovary itself produces too much estrogen. Therefore estrogen dominance does not necessarily mean that estrogen levels are too high, just that they are out of balance with progesterone. Estrogen dominance can take many forms including:

  1. no ovulation: some level of estrogen, but no progesterone
  2. high estrogen, normal progesterone
  3. high estrogen, low progesterone
  4. normal estrogen, low progesterone
  5. low estrogen, lower progesterone

In the cases when estrogen is high, estrogen dominance is usually caused by the compromised ability to clear out used up estrogen, leading to a build up of estrogen in the tissues. This leads to estrogenic symptoms like heavy and painful periods, fibroids, tender breasts, pms and increases risk for estrogen dependant breast cancer and other estrogenic cancers. (Read my understanding estrogen dominance article here). Estrogen metabolism and clearance happens all over the body but it occurs primarily at the liver, gall bladder and gut. The metabolism and clearance of estrogen happens through many different chemical pathways, one of the main pathways is called “glucaronidation.” This is when glucaronic acid is added to a molecule to make it water soluble, less reactive and easily transported through the body (1).  The liver is the main site for glucaronidation and it occurs in phase II liver detoxification. Many different toxins, drugs and endogenous chemicals go through the glucaronidation process to be safely excreted out of the body. In the case of estrogen, which is a steroid or “fat” based hormone, the purpose of glucaronidation is used to make estrogen water soluble and therefore easily removed through the urine and stool. Estrogen that is water soluble is inactive and does not contribute to estrogen dominance.

Working on liver health can help increase glucaronidation and decrease the activity of estrogen in the body. One of the best ways to do this is to reduce toxin exposure eg. alcohol and environmental toxins that contain xenoestrogens (synthetic chemicals that mimic estrogen) and increase the consumption of cruciferous vegetables that contain sulforphane like broccoli sprouts, brussel sprouts, broccoli, cauliflower, cabbage etc (2) and also incorporate bitter greens and citrus fruits (3). There are many other foods and herbs that may help increase glucaronidation.

What is beta-glucaronidase?

Helping enhance the glucoronidation process in the liver is just one step in the process to effective estrogen clearance and unfortunately there are a few factors that can interfere. This is where beta-glucaronidase comes in. Beta-glucaronidase is an enzyme produced by the bacteria in the gut. The large intestine is home to a subset of different bacterial species which together form the “estrobolome.” The estrobolome is by in large responsible for regulating the amount of estrogen that gets excreted out of the body and also determining how much estrogen should be allowed back into the bloodstream and how much estrogen should be manufactured from foods. In the case of bacterial overgrowth which occurs due to an overgrowth of opportunistic bacteria in either the large or small intestine (or both) an excess of beta-glucaronidase is produced. Beta-glucaronidase removes the glucaronic acid group from inactive (water soluble) estrogen that has been metabolised by the liver and makes estrogen active again (essentially reversing phase II liver detoxification). Once re-activated, estrogen is absorbed back into the blood stream and contributes to estrogen dominance (4). This process has been associated with an increased risk of estrogen cancers like breast cancer (5). The main bacterial species identified to produce beta-glucaronidase are Escherichia coli, Bacteroides species, and Clostridium perfringens (6). This is one of the many reasons “gut health” is foundational for hormone balance.

What increases beta-glucaronidase?

Factors that increase the opportunistic bacteria responsible for producing too much beta-glucaronidase include smoking, being overweight, increased age (post menopause when estrogen metabolism changes) and diets high in saturated fat (7). Certain drugs and medications also increase activity.

What decreases beta-glucaronidase?

Plant-rich diets that are high in fibre are associated with lower beta-glucaronidase activity (8) as are diets high in calcium, magnesium, iron and vitamin C (4).  Eating foods high in glucaronic acid such as broccoli, spinach, tomatoes, potatoes, cabbage, apples, lettuce and oranges is thought to help (9) Other helpful foods include pumpkin, zucchinis, pears, watermelon, cherries, strawberries, raspberries and plant protein sources from beans and other legumes (8).

Glucaronic acid is available as a supplement called “calcium d-glucarate” which is sometimes used for women with confirmed estrogen dominance and dealing with conditions like endometriosis or estrogen positive breast cancer, however most of the data analysing the effects of this supplement has been conducted on rats not humans. Animal studies do not always match up to human studies so caution should be used. While a supplement that reduces beta-glucoronidase activity sounds promising, a supplement alone can not restore balance to the microbiome and therefore is not a sustainable long-term solution for gut health or estrogen dominance.

Glucammon, a prebiotic fibre found mostly in the konjac root, is an evidenced based approach to lowering beta-glucaronidase activity in the gut (9). Supplementing the diet with 4.5 g of glucammon fibre can help to reduce beta-gucaronidase activity by up to 30%  in 4 weeks (9). Konjac root can be taken as a herbal medicine or can be incorporated into the diet in konjac noodles like “shirataki noodles.”

Some probiotic strands like The probiotic L. helveticus L. casei and B. breve decreased beta-glucuronidase activity in some studies (10). These might be a viable option alongside necessary dietary changes to assist the gut microbiome. Professional guidance may be necessary.

Is it always necessary to lower beta-glucaronidase?

While it can be tempting to attempt to lower all beta- glucoronidase activity, it is important to remember that the enzyme is not purely negative, and actually serves a vital role in the body. Many compounds that undergo glucaronidation in the liver NEED reactivating in the gut. Beta-glucaronidase is needed to reactive important compounds like vitamin D, serotonin and thyroid hormones (12). It may be unwise to take any supplements or probiotics to purposefully lower beta-glucoronidase unless there has been faecal testing to confirm elevated levels. Some people have low gut microbial diversity, meaning that they have too little of the bacteria to produce beta-glucaronidase, which is also not ideal. The aim is not to eradicate all bacteria that produce beta-glucaronidase but rather keep the bacteria in check within the gut microbiome. The only way to do this is to work on sustainable gut health by slowly and carefully increasing the diversity of plant foods in the diet and limiting factors that negatively impact that gut microbiome like alcohol, antibiotics, unnecessary drugs and stress etc. (read my gut health article here)

It is also important to remember that the science on this topic is relatively new and we do not yet have adequate human data on the effects of lowering beta-glucaronidase or the best methods to do so. Personally I think the data we do have is fairly compelling, but as always, there is more to learn and until we know more, a slow, gentle, sustainable food first approach to healing the gut is best.

References

1. Yang, G., Ge, S., Singh, R., Basu, S., Shatzer, K., Zen, M., Liu, J., Tu, Y., Zhang, C., Wei, J., Shi, J., Zhu, L., Liu, Z., Wang, Y., Gao, S., & Hu, M. (2017). Glucuronidation: driving factors and their impact on glucuronide disposition. Drug metabolism reviews49(2), 105–138. https://doi.org/10.1080/03602532.2017.1293682

2.Basten, G. P., Bao, Y., & Williamson, G. (2002). Sulforaphane and its glutathione conjugate but not sulforaphane nitrile induce UDP-glucuronosyl transferase (UGT1A1) and glutathione transferase (GSTA1) in cultured cells. Carcinogenesis23(8), 1399–1404. https://doi.org/10.1093/carcin/23.8.1399

3.Saracino, M. R., Bigler, J., Schwarz, Y., Chang, J. L., Li, S., Li, L., White, E., Potter, J. D., & Lampe, J. W. (2009). Citrus fruit intake is associated with lower serum bilirubin concentration among women with the UGT1A1*28 polymorphism. The Journal of nutrition139(3), 555–560. https://doi.org/10.3945/jn.108.097279

4.Ervin, S. M., Li, H., Lim, L., Roberts, L. R., Liang, X., Mani, S., & Redinbo, M. R. (2019). Gut microbial β-glucuronidases reactivate estrogens as components of the estrobolome that reactivate estrogens. The Journal of biological chemistry294(49), 18586–18599. https://doi.org/10.1074/jbc.RA119.010950

5.Sui, Y., Wu, J., & Chen, J. (2021). The Role of Gut Microbial β-Glucuronidase in Estrogen Reactivation and Breast Cancer. Frontiers in cell and developmental biology9, 631552. https://doi.org/10.3389/fcell.2021.631552

6.Skar, V., Skar, A. G., & Strømme, J. H. (1988). Beta-glucuronidase activity related to bacterial growth in common bile duct bile in gallstone patients. Scandinavian journal of gastroenterology23(1), 83–90. https://doi.org/10.3109/00365528809093853

7.Maruti, S. S., Li, L., Chang, J. L., Prunty, J., Schwarz, Y., Li, S. S., King, I. B., Potter, J. D., & Lampe, J. W. (2010). Dietary and demographic correlates of serum beta-glucuronidase activity. Nutrition and cancer62(2), 208–219. https://doi.org/10.1080/0163558090330537

8.Lampe, J. W., Li, S. S., Potter, J. D., & King, I. B. (2002). Serum beta-glucuronidase activity is inversely associated with plant-food intakes in humans. The Journal of nutrition132(6), 1341–1344. https://doi.org/10.1093/jn/132.6.1341

9.Wu, W. T., Cheng, H. C., & Chen, H. L. (2011). Ameliorative effects of konjac glucomannan on human faecal β-glucuronidase activity, secondary bile acid levels and faecal water toxicity towards Caco-2 cells. The British journal of nutrition105(4), 593–600. https://doi.org/10.1017/S0007114510004009

10.De Preter, V., Raemen, H., Cloetens, L., Houben, E., Rutgeerts, P., & Verbeke, K. (2008). Effect of dietary intervention with different pre- and probiotics on intestinal bacterial enzyme activities. European journal of clinical nutrition62(2), 225–231. https://doi.org/10.1038/sj.ejcn.1602706

11.Walsh, J., Olavarria-Ramirez, L., Lach, G., Boehme, M., Dinan, T. G., Cryan, J. F., Griffin, B. T., Hyland, N. P., & Clarke, G. (2020). Impact of host and environmental factors on β-glucuronidase enzymatic activity: implications for gastrointestinal serotonin. American journal of physiology. Gastrointestinal and liver physiology318(4), G816–G826. https://doi.org/10.1152/ajpgi.00026.2020

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