Physiol. Res. 67 (Suppl. 3): S401-S408, 2018 https://doi.org/10.33549/physiolres.934022 REVIEW Phytoestrogens and the Intestinal Microbiome L. KOLÁTOROVÁ1, O. LAPČÍK1,2, L. STÁRKA1 1Department of Steroids and Proteofactors, Institute of Endocrinology, Prague, Czech Republic, 2Department of Chemistry of Natural Compounds, University of Chemistry and Technology, Prague, Czech Republic Received August 8, 2018 Accepted September 11, 2018 Summary Introduction The microflora of the digestive tract is composed of a unique set of bacteria, yeasts, viruses and other microorganisms, generally The term microflora generally refers to the living known as the microbiome. The microbiome exhibits considerable exogenic component of the gastrointestinal tract inter-individual variability, with up to two-thirds of the microflora composed of bacteria, viruses, protozoans, and yeasts. differing between individuals. Because of this, the variable Currently, the term microbiome is becoming more intestinal microflora is responsible for many differences in popular, encompassing the summary of all microbiotic metabolic, hormonal and immunological processes in humans genetic information. and animals. Significant differences have been observed in the There is a relatively long history of medical metabolism of phytoestrogens, naturally occurring substances research on the influence of gastrointestinal microbiota that possess estrogenic or anti-estrogenic activity. These on the metabolic functioning of the host organism. substances occur predominately in legumes, especially in soy and Veterinary medicine has dealt with this issue since the many soy products. Because of their effects, phytoestrogens are 1950s, while human medicine concentrated mainly on the used as an alternative therapy for menopausal disorders and microbial composition and activities in the oral-nasal benign prostate hyperplasia. In connection with the worldwide cavities, and only later expanded interest to include the expansion of soy products as part of healthy lifestyles including entire gastrointestinal tract. vegetarianism and veganism, phytoestrogens have become The first important work that focused on a regular part of everyday life. The activity of phytoestrogens is metabolic processes in the intestines was a study on the strongly dependent on the microbiome. Their metabolites have microbial transformation of glucose to propionate in 1963 stronger estrogenic activity than the natural substances (Baldwin et al. 1963). A foundational study on the themselves, and because of the variability in microbiomes, there intestinal microbiota in the Czech Republic was the study are large differences in the effects of phytoestrogens among on the colonization of the Escherichia coli bacteria in individuals. children, with the aim of reducing nosocomial infections (Lodinová et al. 1991). Today, the term microbiome, Key words meaning the sum of microbiotic genetic information, has Phytoestrogens • Daidzein • Equol • Microbiota about 40,000 citations in biomedical databases. This increase in research on the intestinal Corresponding author microbiota makes clear that the microbiome plays L. Kolatorova-Sosvorova, Department of Steroids and Proteofactors, an important role in the health of the host. Knowledge of Institute of Endocrinology, Narodni 8, 116 94 Prague, Czech the metabolism and regulation mechanisms of humans Republic. E-mail: [email protected] must include information about the organism itself plus information about cells that are present but that do not PHYSIOLOGICAL RESEARCH • ISSN 0862-8408 (print) • ISSN 1802-9973 (online) 2018 Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic Fax +420 241 062 164, e-mail: [email protected], www.biomed.cas.cz/physiolres S402 Kolátorová et al. Vol. 67 come from the host’s body. The mass of the intestinal methylases, thiolases, lipases, nitroreductases, beta- microbiota ranges around 1-2 kg and current estimates glucuronidases, sulfatases and beta-lysases, as well as put the number of organisms at 1013, with 10 times the specific hydroxylases, oxidoreductases and lysases number of genes than the human genome (Sender et al. important in steroid metabolism. Some metabolic 2017). pathways, for instance steroid hormones in the microbiota, are similar or the same as in the host, while The development of the microbiota others are specific and determined by the microbial composition. The capabilities of these microorganisms The influence of the microbiota is determined have been richly used in the pharmaceutical industry to partly by its composition, which is the result of factors produce compounds that are much more difficult to both internal and external. The formation of the synthesize in other ways. microbiome begins already during embryonic Microorganisms influence digestion, cleave development, and a critical time is the period after birth, complex saccharides, produce short-chain fatty acids, when the mother’s milk plays an important protective support detoxification, and synthesize various vitamins. role in the child. The microbiome is generally stabilized They affect immunity and are part of the defense around the 2nd to 3rd year of life. Different people have mechanism against pathogens. They regulate epithelial greatly varied microbiotic compositions, but within an cell differentiation, and influence the development and individual the composition is quite stable. However, physiology of various systems as well as the appearance changes do appear under the influence of various factors. and progression of some diseases. They have indirect Antibiotic treatment has a marked impact on the effects on the central nervous system, influencing microbiota. Disruption of the intestinal equilibrium by perceptions such as taste (Podzimek et al. 2018), mood, antibiotics can lead to changes in up to 90 % of analyzed and behavior. metabolites such as bile acids, eicosanoids and steroid Just as the intestinal microbiota influence hormones. Subsequent disruption of metabolic pathways immunity, hormonal and nerve functions, so can the can be critically important to the host. immune and endocrine system in the mucus of the gastrointestinal tract influence the microbial composition The influence of the microbiota on metabolic and regulate “intestinal health” (Šefčíková et al. 2010, processes Šefčíková and Bujňáková 2017). The host thus gains possible defenses against invasive pathogens by the The microbiota has a diverse composition production of antimicrobial peptides in the epithelial including bacteria, protozoans, and viruses, and plays layer, such as defensin and cathelicidin. The microbiota a key role in metabolizing compounds traversing the and host influence each other in both directions. gastrointestinal tract, including food particles, medicines and toxins from the external environment, as well as Phytoestrogens compounds excreted into the gastrointestinal tract such as bile acids. From a chemical point-of-view, phytoestrogens Bacteria, the most frequent members of are a variable group of compounds. In contrast to the microbiota, can be taxonomically divided into the estrogens themselves, they are not steroids, but rather phyla Firmicultes, Bacteriodates, Protobacteria and products of several of the metabolic pathways of Actinobacteria. Microbial fermentation breaks down phenylpropanoids. This large group of compounds is dietary compounds and xenobiotics, and products can common in multicellular plants, but do not occur in include compounds with hormonal character. On the animals. Common characteristics of phytoestrogens other hand, hormones produced by humans are include the presence of at least one benzene ring (usually metabolically transformed by the microflora and can thus two), a relatively stable and flat molecule, and two or have different activity than the original hormone. The three hydroxyl groups with distances similar to the intestinal microbiota has even been called a new distances between C3 and C17 in 17β-estradiol (Mazur endocrine organ (Brown and Hazen 2015). and Adlercreutz 2000). The molecular weights are also The microbiota produces a wide range of similar to those of natural estrogens. Active compounds common enzymes, such as azoreductases, esterases, of this type are thought to act through the estrogen 2018 Phytoestrogens and Microbiome S403 receptors ERβ and ERα (Plišáková et al. 2010). 17β-hydroxysteroids, 3β-hydroxysteroids, and aromatase. Isoflavanoids, which are numerous in legumes, are the This lowers the production of the most biologically active most important, followed by flavonoids, lignans, sex hormones, testosterone and estradiol. Genistein, coumestans, ellagitannins, and stilbenes (Mazur and biochanin A and S-equol are inhibitors of 5α-reductases, Adlercreutz 2000). and lower the local concentrations of dihydrotestosterone, Direct estrogenic or anti-estrogenic activities are the main androgen in the prostate. Phytoestrogens also shown by only a fraction of the total number of known influence the biological availability of sex hormones compounds in this group. Of practical significance are through the inhibition of sulfatase and sulfotransferase. mainly genistein, daidzein and its metabolite S-equol, and Another important impact is the lowered activity of to a degree also coumestrol – which while being actively CYP24, an enzyme that plays a role in the degradation of estrogenic only occurs at very low concentrations. In calcitriol. Some isoflavones, genistein in particular, addition it