pISSN 1226-4407, eISSN 2234-7631
Introduction
Soy and soy-related foods have had an important dietary role in Asian countries, including Korea and Japan, for centuries, and in recent years have become increasingly popular in Western countries as well due to their reported potential health benefits. Recent epidemiologic studies indicate that a higher intake of soy and soy products is associated with a lower prevalence of cardiovascular disease1), osteoporosis2), hormone-dependent cancer3), and menopausal syndrome.4) In addition, a recent meta-analysis showed favorable effects of soy consumption on serum lipids.5) These beneficial effects of soy have led to studies of related effects in individuals at high risk for cardiovascular disease, such as those with obesity and metabolic syndrome.6) Isoflavonoids, the phytoestrogens present in soybeans, structurally and functionally resemble estradiol.6) Indeed, isoflavones such as genistein and daidzein bind weakly to estrogen receptor-α and more strongly to estrogen receptor-β, and might have organ-specific estrogenic and anti-estrogenic
effects.6)
The efficacy of isoflavones varies between individuals, however, possibly due to differences in the ability to produce equol.7,8) Recent studies demonstrated that the gut microbiome contributes to the obesity phenotype by affecting the energy harvest capability.9) Gut microflora not only affect various metabolic and immune states, but also the metabolism of ingested nutrients. Equol is an example of the contributions that gut bacteria make to the metabolism of ingested food. Here we review equol and the equol-producing bacteriotype on various human health issues, such as obesity.
Main 1. What is equol?
Equol (4', 7-isoflavandiol), first isolated from equine urine in 193210) and identified in human urine as a metabolite of soy isoflavones11), is a metabolite of daidzein, a major soybean isoflavone produced by gut microflora in the gastrointestinal tract.12) The ability to
What Equol Can Do for Human Health?
Takeshi Usui*
Clinical Research Institute, National Hospital Organization Kyoto Medical Center
ABSTRACT
Although soy is considered to be beneficial for various health problems, including postmenopausal symptoms, osteoporosis, lipid metabolism, and obesity based on several human studies, the effects of soy intake on human health remain controversial.
Soy contains isoflavones such as genistein and daidzein, which can act as weak estrogens, at least in vitro. Daidzein is metabolized into another isoflavonoid, called equol, by the intestinal bacteria in most animals and in some humans.
Equol-producing bacteriotypes in individual intestines may play an important role in the various effects of soy, including the endocrine effects. Recent studies indicate that the equol and equol-producing bacteriotypes are key factors in the soy-related health benefit. Equol could be useful as a nutritional supplement. Here we review the nature of equol and the effects of equol intervention on human health.
Key words: Soy, Equol, Bacteriotype
ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ
Corresponding author: Takeshi Usui, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 1-1 Mukaihata-cho Fukakusa Fushimi-ku, Kyoto 612-8555, Japan
Tel: 81-75-641-9161, Fax: 81-75-645-2781, E-mail: tusui@kuhp.kyoto-u.ac.jp
* In this manuscript, I reviewed my presentation on KSSO/JASSO joint symposium in October, 2014.
* This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/
by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
produce equol depends on the presence of certain intestinal microflora.13) The extent of metabolism of isoflavones into equol markedly differs among various species. Daidzin/daidzein is very efficiently converted to equol in rodents8), while this process is less efficient in pigs and humans.8,14) Equol is an isoflavone that belongs to the general class of compounds referred to as nonsteroidal estrogens. Due to the chiral carbon at position C-3 of the molecule, equol exists in two enantiomeric forms, R-(+) equol and S-(-) equol, and the latter is the natural diastereoisomer produced by intestinal bacteria in humans.15) Previous studies demonstrated high variations in the ability to synthesize equol, and evidence suggests that the responsiveness to isoflavones varies according to the individual equol-producing capacity.8,16) The variability in isoflavone metabolism might also be associated with the variability in the risk for various human diseases.
The chemical structures of genistein, daidzein, equol, and 17b-estradiol are shown in Fig. 1. The estrogenic activity of equol had been studied due to its structural similarity. Biochemical and pharmacologic studies revealed that equol has potent estrogenic activity, as do other soy isoflavones, at least in vitro.
Although it has been known for decades that intestinal bacteria are responsible for the production of S-(-)equol, specific bacteria capable of converting daidzin/daidzein to S-(-)equol have been only recently isolated and identified.
Table 1 shows the list of equol-producing bacteria identified to date.
2. Equol producers
Previous studies demonstrated high variation amongst individuals in the ability to synthesize equol, and evidence suggests that the responsiveness to isoflavones varies according to equol-producing capacity.8,17) The prevalence of individuals who carry equol-producing intestinal bacteria varies from 30% to 60% among humans and is higher among Asians and vegetarians.18) Recent evidence suggests that equol has even stronger estrogen-like activity than daidzein.19) Therefore, the clinical effectiveness of isoflavones might be due to their ability to induce the production of equol in the intestine.16) Individuals who can metabolize daidzein to equol are designated ‘equol producers’, whereas those who cannot convert daidzein to
prevalence of equol producers is estimated to be 30% to 35% in Western populations7,20,21) and up to 60% in vegetarians18) and Asians.22) However, whether the ability to produce equol is stable over time or necessarily results in favorable health outcomes is widely debated.16,18,23,24)
Previous studies indicated that equol production is stable
“in most individuals over 1~3 years”25), or only “over one year”26,27), or “in 85% of individuals over 1.5 years”.22) A recent study demonstrated that the equol-producing capability changed in 16% of subjects over a one year period28), while another report indicated that the equol-producing capability remained unchanged in 100%
of equol non-producers and 80% of equol producers over a two year period.17)
Another topic of debate is whether diet can influence an individual's ability to produce equol, and the results of observational and feeding studies have been inconsistent.
Some studies have observed relationships between equol production and soy, animal products, and green tea.7,18,20,22,29-32)
Two studies reported that consumption of a high-fiber, low-fat diet may contribute to equol production, but this observation was not consistent with other reports.7,20,29,33,34)
At least one study reported that long-term soy ingestion could convert equol nonproducers to equol producers35); in contrast, another study involving premenopausal women proposed that “once an equol producer, always an equol producer”.36) Thus, we do not know which factors support equol-producing bacteria in the intestine. Understanding this issue will provide a novel therapeutic target against obesity.
Fig. 1. Chemical structures of genistein, daidzein, equol, and 17β -estradiol.
3. The effect of equol on postmenopausal women
Considering the potential estrogenic effect of equol, it is expected to be beneficial for postmenopausal women as an alternative estrogen therapy. In a study of the effects of equol on perimenopausal/postmenopausal women, Ishiwata et al37) reported that 12 weeks of 30 mg/day S-equol supplement improved mood-related symptoms without any adverse effects in perimenopausal/
postmenopausal equol non-producers. Furthermore, according to Aso et al38) study, 10 mg/day of equol consumption for 12 weeks significantly reduced the symptoms of postmenopause (hot flashes and other menopausal symptoms) in postmenopausal Japanese women who were equol non-producers. These two reports suggest that equol could improve both physical and mental symptoms related to perimenopausal/
postmenopausal women.
Bone health is a major issue in the health of postmenopausal women. Tousen et al2) studied the effect of 6 mg/day and 10 mg/day of equol on bone markers and concluded that 10 mg/day equol contributes to bone health in equol non-producing postmenopausal women.
Ishimi et al39) reviewed the significance of equol on bone health, and concluded that equol may contribute to prevent bone loss in early postmenopausal women.
Furthermore, Oyama et al40) reported that S-equol supplementation may have beneficial effects on skin aging in postmenopausal women.
Based on the accumulating evidence, equol may act as a selective estrogen receptor modulator to improve peri- or postmenopausal health disorders and to prevent bone loss in postmenopausal women. In these equol intervention studies, no adverse effects were reported. Although long-term intervention studies are needed, equol might be helpful in promoting postmenopausal health.
4. The effect of equol on obesity
Currently, no reports are available regarding the prevalence of equol producers and the effect of equol supplements on overweight or obesity and metabolic syndrome. We previously reported that the frequency of equol-producers among obese or overweight patients is 32.1%, which is lower than the previously reported
frequency of equol-producers in the Japanese population.41) In addition, we have preliminary data showing that a potential beneficial clinical parameter of metabolic syndrome in equol producers is high-sensitivity C-reactive protein (unpublished data). These findings led us to study the effect of equol intervention on obese and overweight patients. The study was a randomized, double-blind, placebo-controlled crossover design. The subjects were considered overweight or obese if they had a body mass index greater than 25 kg/m2. Placebo or natural S-equol tablets, containing 10 mg of S-equol, were orally ingested daily for 12 weeks. Equol non-producers comprised 67.9%
of the overweight or obese subjects. The ratio of equol non-producers in this overweight or obese subject group was higher than the previously reported ratio of equol non-producers (approximately 50%) in the general population. Compared with the placebo group, intervention with natural S-equol led to a significant decrease in HbA1c, serum low-density lipoprotein-cholesterol levels, and cardiovascular index score. Furthermore, the effect was more prominent in the subgroup of female equol non-producers.41) Although body weight did not change, these findings suggest that natural S-equol has a role in the prevention of diabetes and cardiovascular disease through the suppression of HbA1c, low-density lipoprotein- cholesterol, and cardiovascular index in overweight or obese individuals, based on sex and equol-producing capability.
Conclusion 1. Future prospects
Gut micro-flora is now a hot field of study in various human disorders. The equol-producing bacteriotype is a unique bacteriotype that influences nutrient metabolism.
Equol status is now known to have a key role in the beneficial effects of soy intake. Both equol itself and probiotics of equol-producing bacteria are new targets for the treatment of various human disorders, including obesity.
Disclosure summary
The author has no conflicts of interest.
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