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Healthy gut, healthy breast?

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Estrogens are a well-documented contributor in the etiology of breast cancer.[1] Consequently, the importance of proper estrogens metabolism and reducing exposure to xenoestrogens are increasingly recognised as effective ways to reduce breast and other estrogens-related cancer risk.[2]  Recent discoveries are unravelling the importance of gut bacteria and their DNA – collectively known as estrobolome – in the proper elimination of estrogens and endocrine-disrupting compounds (xenoestrogens). Could improving our gut health constitute the next step in maximizing hormonal balance and reducing our breast cancer risk?

Estrogens Metabolism

Estrogens must eventually be broken down into metabolites by the liver and excreted from the body through urine and feces.[3] In this process, estrogens metabolites of stronger or weaker estrogenic activity are produced, exerting estrogenic or anti-estrogenic effects.[4] Estrogens metabolism can be modulated through dietary modifications, which have the power to accelerate or slow-down our cytochrome P450 enzymes involved in estrogens metabolism.[5] One such example is the phytochemical sulforaphane found in cruciferous vegetables. Sulforaphane’s protective mechanism is associated to its ability to improve specific estrogen metabolites ratio.

One of the key detoxification pathways for estrogens and xenoestrogens in our liver is called glucoronidation. In the glucoronidation process, a glucuronic acid is combined with an estrogen molecule by an enzyme to form what is known as a glucuronide. Glucuronidated hormones are more water-soluble, which facilitates their transport and elimination from the body.12

Unfortunately, the chemical bond between the metabolised estrogen and glucuronic acid in the glucuronide compound can be severed by the β-glucuronidase enzyme secreted mostly by pathogenic intestinal bacteria in the colon.[6] When this cleavage occurs, it allows the free estrogens re-absorption from the lower intestine mucosa and uptake via the portal vein back into the liver. During this ‘recycling’ process, estrogens are re-conjugated as part of the enterohepatic circulation instead of being excreted, further increasing estrogenic activity in the body.[7] Clinical studies demonstrate a clear association between excess β-glucuronidase activity and increased risk of cancers, including breast cancer.[8]

 

Microbiome and Estrobolome

The human gastrointestinal (GI) tract constitutes a complex populous ecosystem, harboring up to 10(14) bacterial cells per gram of luminal content[9] and whose collective genome (or microbiome) contains a vastly greater number of individual genes than the human genome.[10] This huge community of residential microbe population living in our intestine and collectively known as the ‘microbiota’ is increasingly recognized as playing important roles in health and disease.[11] Studies of the human gut microbiota suggest that dysbiosis – alterations to the composition and dynamics of the microbiota – can be associated to a variety of chronic conditions.[12] In addition, our microbiome plays a key role in the detoxification of hormones and xenobiotics.[13]

Meet the Estrobolome

The estrobolome is a complete set of genes found in the microbiome – or a sub-biome – which code for enzymes that are capable of metabolising estrogens within the human intestine.[14] Certain bacterial species possess enzymes involving deconjugation and conjugation of estrogens, so they can impact their enterohepatic circulation. Simply put, the estrobolome is an aggregate of gut microbes whose DNA determines the detoxification of estrogens.

Professor Claudia Plottel and her team at New York University have been looking into how the estrobolome might affect women’s risk of developing postmenopausal estrogen receptor-positive breast cancer.[15] According to these researchers, the estrobolome composition is impacted by factors that modulate its functional activity such as delivery mode at birth and environmental influences including antibiotic use and dietary composition.

For example, vegetarians have increased fecal excretion of conjugated estrogens, and the use of pre-biotics or probiotics can change bacterial populations to modulate estrogens levels.[16]

Dietary modifications to improve estrogens metabolism

A diet high in saturated fats and low in fibers promotes the activity of β-glucuronidase. While it can be decreased by plant foods consumption and the addition of the probiotics Lactobacillus acidophilus and Bifidobacterium infantis.[17] Moreover, soluble fibers modulate estrogens ratio,[18] while insoluble fibers sequester endogenous estrogens within the gut, decreasing their enterohepatic circulation and improving their elimination via feces.[19]

Partially hydrolyzed guar gum (PHGG) constitutes an excellent way to increase soluble fibers in your diet, and a good alternative to other highly allergenic alternatives such as wheat fibers or corn-based products.  This tasteless, odourless supplement dissolves completely in water and it has been better tolerated and preferred by patients in clinical trials.

Oral supplementation with calcium-D-glucarate has been shown to inhibit β-glucuronidase activity and to support glucuronidation, resulting in increased estrogens metabolism and toxin elimination from the body.[20]  Calcium D-glucarate, by itself or in combination with other health-promoting substances, is an effective way to promote estrogens metabolism and excretion.

Another interesting way to promote gut health is by incorporating the chewable prebiotic fiber xylo-oligosaccharide (XOS). All other prebiotics such as fructooligosaccharides (FOS) and galactoarabinan promote the growth of all bacteria in the gut -good and bad – but XOS selectively promotes the growth of beneficial Bifidobacterium strains.

 

Conclusion

New understandings emerging from the studies of the microbiome, and more specifically of the estrobolome, might provide a better understanding of the important link between gut health and hormonal balance. Improving our gut health may help modulate our lifetime burden of estrogens and xenoestrogens exposure and reduce our risk for certain diseases, including breast cancer. Adopting certain simple dietary changes like reducing our saturated fats intake and increasing our fiber intake combined with targeted nutritional supplements such as probiotics and calcium-D-glucarate can beneficially influence estrogens and protect our breast health.

 

References

[1] Estrogens, breast cancer, and intestinal flora. Gorbach SL. Rev Infect Dis. 1984 Mar-Apr;6 Suppl 1:S85-90. Review. PMID: 6326245

[2] Fucic A, Gamulin M, Ferencic Z, et al. Environmental exposure to xenoestrogens and oestrogen related cancers: reproductive system, breast, lung, kidney, pancreas, and brain. Environmental Health. 2012;11(Suppl 1):S8. doi:10.1186/1476-069X-11-S1-S8.

[3] Murray RK, Granner DK, Mayes PA, et al.

Harper’s Biochemistry. 24th ed. Stamford (CT): Appleton & Lange; 1996.

[4] Obi N, Vrieling A, Heinz J, Chang-Claude J. Estrogen metabolite ratio: Is the 2-hydroxyestrone to 16α-hydroxyestrone ratio predictive for breast cancer? International Journal of Women’s Health. 2011;3:37-51. doi:10.2147/IJWH.S7595. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3039007/

[5] Lukaczer D. Estrogen’s two-way street. Nutrition Sci News. November 2001 http://www.chiro.org/nutrition/FULL/Estrogens_Two-Way_Street.shtml visited on August 8th, 2013

[6] Fujisawa T, Mori M. Influence of bile salts on β-glucuronidase activity of intestinal bacteria. Lett Appl Microbiol 1996;22(4):271-74

[7] Jeffery E. Detoxification Basics in 13th International Symposium of The Institute for Functional Medicine. IFM 2006

[8] Severini G, Diana L, Di Giovannandrea R, et al. A study of serum glycosidases in cancer. J Cancer Res Clin Oncol 1995;121(1):61-63

[9] Plottel CS, Blaser MJ. Microbiome and Malignancy. Cell host & microbe. 2011;10(4):324-335. doi:10.1016/j.chom.2011.10.003. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3264051/

[10] The Intestinal Microbiome and Estrogen Receptor-Positive Female Breast Cancer. Kwa M, Plottel CS, Blaser MJ, Adams S. J Natl Cancer Inst. 2016 Apr 22;108(8). doi: 10.1093/jnci/djw029. Print 2016 Aug. Review. PMID: 27107051 https://www.ncbi.nlm.nih.gov/pubmed/27107051?report=docsum

[11] The Intestinal Microbiome and Estrogen Receptor-Positive Female Breast Cancer. Kwa M, Plottel CS, Blaser MJ, Adams S. J Natl Cancer Inst. 2016 Apr 22;108(8). doi: 10.1093/jnci/djw029. Print 2016 Aug. Review. PMID: 27107051 https://www.ncbi.nlm.nih.gov/pubmed/27107051?report=docsum

[12] Forum on Microbial Health; Board on Global Health; Institute of Medicine. Washington (DC): National Academies Press (US); 2014 Feb 18. https://www.ncbi.nlm.nih.gov/books/NBK189987/

[13] Forum on Microbial Health; Board on Global Health; Institute of Medicine. Washington (DC): National Academies Press (US); 2014 Feb 18. https://www.ncbi.nlm.nih.gov/books/NBK189987/

[14] Plottel CS, Blaser MJ. Microbiome and Malignancy. Cell host & microbe. 2011;10(4):324-335. doi:10.1016/j.chom.2011.10.003. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3264051/

[15] Plottel CS, Blaser MJ. Microbiome and Malignancy. Cell host & microbe. 2011;10(4):324-335. doi:10.1016/j.chom.2011.10.003. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3264051/

[16] Plottel CS, Blaser MJ. Microbiome and Malignancy. Cell host & microbe. 2011;10(4):324-335. doi:10.1016/j.chom.2011.10.003. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3264051/

[17] Hambly RJ, Rumney CJ, Fletcher JM, et al. Effects of high- and low-risk diets on gut microflora-associated biomarkers of colon cancer in human flora-associated rats. Nutr Cancer 1997;27(3):250-53

[18] Patel S, Hawkley LC, Cacioppo JT, Masi CM. Dietary fiber and serum 16a-hydroxyestrone, an estrogen metabolite associated with lower systolic blood pressure.Nutrition. 2011 Jul–Aug;27(7–8):778–781

[19] Haggans CJ, Travelli EJ, Thomas W, et al. The effect of flaxseed and wheat bran consumption on urinary estrogen metabolites in premenopausal women. Cancer Epidemiol Biomarkers Prev 2000;9:719-725.

[20] Minton JP, Walaszek Z, Schooley W, et al. b-Glucuronidase levels in patients with fibrocystic breast disease. Breast Cancer Res Treat 1986;8:217-22.

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