Effect of Human Intestinal Bacteria

On the Metabolism of Estrogen Hormones

Paul Faust, N.D.

Introduction

Estrogen hormones are modified to increase their water solubility by hydroxylation or conjugation in the liver and are excreted into bile for elimination. It has been observed that concentrations of steroids in the bile often exceed that of their precursors in the serum.1 A portion of the excreted hormones are reabsorbed just like bile acids, via the enterohepatic circulation. The reason for this is unknown, however, the circulating concentrations of hormones is determined in part, by the degree of reabsorption through the enterohepatic circulation. It has also been shown that bacteria present in the intestinal tract synthesize enzymes capable of metabolizing the modified steroid hormones excreted by the liver.

Metabolism of Estrogen by Gut Flora

The large intestine houses a complex microbial ecosystem – estimated at more than 500 different strains of anaerobic bacteria, with numbers exceeding 1011/g of fecal contents.2 More than three decades ago, researchers first provided evidence that the intestinal flora of animals synthesized steroid metabolizing enzymes not present in tissues.3,4 Several hydrolytic steroid enzymes such as 16α-dehydroxylase and 21-dehydroxylase are synthesized exclusively by bacteria.5 In the ensuing years, β-glucuronidase was identified as an important bacterial enzyme capable of hydrolysis of estrogen glucuronic acid conjugates in bile such as estradiol-3-glucuronide. In addition, the activity of β-glucuronidase in the intestinal lumen has been shown to be a factor of the concentration and type of bacteria present.6 It has also been shown that multiple estrogen conversions can occur in the large bowel, which upon subsequent reabsorption would result in changes in the circulating concentrations of estrogens.7

Substrate

Metabolites
Estrone Estradiol, 17α estradiol
Estradiol Estrone
Estriol Estrone
16α-hydroxyestrone Estriol, 16 epistriol, 17 epistriol

Lactobacillus Inhibition of β-Glucuronidase

Investigators have found that Americans consuming a mixed "Western" diet had higher levels of fecal bacterial β-glucuronidase than did American vegetarians, American Seventh Day Adventists (vegetarian), and Japanese or Chinese people.8 Since it had been reported that cells of Lactobacillus have low levels of β-glucuronidase 9, it was suspected that the difference observed in these diets might be due to different concentrations of lactobacillus.

Goldin and Gorbach subsequently demonstrated that feeding viable cultures of Lactobacillus acidophilus to rats consuming meat diets significantly lowered the activities of fecal β-glucuronidase.10 This led to them conducting a human intervention study in which Lactobacillus acidophilus supplements were given for 30 days to omnivores eating a "Western-type" diet, which resulted in treated β-glucuronidase levels comparable to vegans and lactovegetarians.11 They found that the mean levels of β-glucuronidase for omnivores decreased from a base-line value of 2.03 to a treated level of 1.11, which was comparable to baseline values for vegans (1.07) and lactovegetarians (0.93).

In another human study, Goldin and Gorbach studied the effect of Lactobacillus acidophilus supplements compared to milk on the activity of fecal β-glucuronidase levels.12 They found that there was no effect on the enzyme activity during the period of milk ingestion, but during milk plus Lactobacillus ingestion (109 per day), there was a significant decline in enzyme activity (avg 1.94 to 1.12) in all subjects. They also determined that it required at least 10 days for the effect of the Lactobacillus to be evident, and that the effect lasted for at least 10 days after supplementation.

Goldin and Gorbach clearly demonstrated that oral administration of viable L. acidophilus of human origin causes an alteration in the metabolic activity of the intestinal microflora of healthy individuals; however, the L. acidophilus they used was a composition of two strains isolated from human feces. The strains were not related to the species commonly used in most commercial yogurt production (i.e., Lactobacillus bulgaricus, Streptococcus thermophilus, Lactobacillus lactis, and Lactobacillus casei).

Commercial Yogurt Ineffective

This would prove to be an important distinction, because in a later human study, a commercial yogurt (Yoplait®) containing active Lactobacillus acidophilus cultures was shown to be ineffective at reducing fecal β-glucuronidase levels after 3 weeks of supplementation.13

Goldin and Gorbach realized that Lactobacillus from human origin was crucial to the health benefits they had observed so they named the strain they had been using Lactobacillus GG.14 To clarify this point, researchers showed in a double-blind, placebo-controlled study that 4 weeks supplementation of yogurt containing active cultures of Lactobacillus GG decreased fecal β-glucuronidase levels by 30% as compared to the same yogurt that had been pasteurized.15

Conclusion

It has been shown that conjugated estrogens are excreted in the bile for elimination, that they undergo conversion and deconjugation by enzymes (especially β-glucuronidase) secreted by intestinal bacteria, and that some of these estrogen metabolites are subsequently reabsorbed via enterohepatic circulation. It has also been shown supplementation of Lactobacillus acidophilus of human origin significantly reduces the fecal activity of β-glucuronidase.

Although it has not yet been confirmed clinically, these previous studies suggest that supplementation with Lactobacillus acidophilus of human origin can significantly effect the circulating levels and types of estrogen hormones. It is also interesting to note that a vegan or lactovegetarian diet might achieve the same therapeutic effect without Lactobacillus supplementation. This could have profound implications in the treatment of female endocrine conditions including breast and endometrial cancer, polycystic ovaries syndrome, dysmenorrhea, and menopause to name a few.

References:

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  2. Gossling J, et al. Predominant gram-positive bacteria in human feces: numbers, variety, and persistence. Infect Immun 1974;9:719-29.
  3. Gustafsson, J.  Steroids in germfree and conventional rats. Identification of C19 and C21 steroids in feces from conventional rats. European J Biochem 1968;6:248
  4. Gustafsson, B. et al. Steroids in germfree and conventional rats. Identification of 3α, 16α-dihydroxy-5α-prengan-20-one and related compounds in feces from germfree rats. European J. Biochem 1968;4:568
  5. Bokkenheuser VD. Biotransformation of steroid hormones by gut bacteria. Am J Clin Nutr 1980;33:2502-6.
  6. McBain AJ, et al. Ecological and physiological studies on large intestinal bacteria in relation to production of hydrolytic and reductive enzymes involved in formation of genotoxic metabolites. J Med Microbiol 1998;47:407-16.
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  8. Reddy BS, et al. Large bowel carcinogenesis: Fecal constituents of populations with diverse incidence rates of colon cancer. J Natl Cancer Inst 1973;50:1437-42.
  9. Hawksworth G, et al. Intestinal bacteria and the hydrolysis of glycosidic bonds. J Med Microbiol 1971;4:451-9.
  10. Goldin BR, Gorbach SL. Alterations in fecal microflora enzymes related to diet, age, Lactobacillus supplements, and dimethylhydrazine. Cancer 1977;40:2421-6.
  11. Goldin BR, Gorbach SL, et al. Effect of diet and Lactobacillus acidophilus supplements on human fecal bacterial enzymes. JNCI 1980;64(2):255-61.
  12. Goldin BR, Gorbach SL. The effect of milk and Lactobacillus feeding on human intestinal bacterial enzyme activity. Am J Clin Nutr 1984;39:756-61.
  13. Marteau P, et al. Effect of chronic ingestion of a fermented dairy product containing Lactobacillus acidiophilus and Bifidobacterium bifidum on metabolic activities of the colonics flora in humans. Am J Clin Nutr 1990;52:685-8.
  14. Goldin BR, Gorbach SL, et al. Survival of Lactobacillus species (strain GG) in human intestinal tract. Dig Dis Sci 1992;37:121-8.
  15. Ling WH, et al. Lactobacillus Strain GG supplementation decreases colonics hydrolytic and reductive enzyme activities in healthy female adults. J Nutr 1994;124:18-23.

Copyright © 2008  Paul Faust, N.D. Chesapeake Natural Health Center