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Urinary O -desmethylangolensin (ODMA) concentrations provide a functional gut microbiome marker of dietary isoflavone daidzein metabolism to ODMA. Individuals who do not have gut microbial environments that produce ODMA have less favourable cardiometabolic and cancer risk profiles. Urinary metabolomics profiles were evaluated in relation to ODMA metabotypes within and between individuals over time. Secondary analysis of data was conducted from the BEAN2 trial, which was a cross-over study of premenopausal women consuming 6 months on a high and a low soya diet, each separated by a 1-month washout period. In all of the 672 samples in the study, sixty-six of the eighty-four women had the same ODMA metabotype at seven or all eight time points. Two or four urine samples per woman were selected based on temporal metabotypes in order to compare within and across individuals. Metabolomics assays for primary metabolism and biogenic amines were conducted in sixty urine samples from twenty women. Partial least-squares discriminant analysis was used to compare metabolomics profiles. For the same ODMA metabotype across different time points, no profile differences were detected. For changes in metabotype within individuals and across individuals with different metabotypes, distinct metabolomes emerged. Influential metabolites (variables importance in projection score > 2) included several phenolic compounds, carnitine and derivatives, fatty acid and amino acid metabolites and some medications. Based on the distinct metabolomes of producers v . non-producers, the ODMA metabotype may be a marker of gut microbiome functionality broadly involved in nutrient and bioactive metabolism and should be evaluated for relevance to precision nutrition initiatives.

Objective: Obesity can be a considerable health concern for peri- and post-menopausal women. Evidence suggests an association between the gut microbiome and obesity. The study objective was to evaluate the association between being overweight or obese and phenotypic markers of having an overall gut microbial environment not capable of metabolizing the isoflavone daidzein to equol or O-desmethylangolensin (ODMA)., Study Design: Cross-sectional study of 137 peri- and 218 post-menopausal women, aged 44-55 years, who consumed at least three servings per week of soy (source of daidzein). Equol and ODMA producers and non-producers were identified based on urinary concentrations of daidzein, equol and ODMA in a 24-h urine sample., Main Outcome Measures: Mean body mass index (BMI) and odds of obesity., Results: Fifty-one women were ODMA non-producers and 226 were equol non-producers. The ODMA non-producer phenotype was positively associated with obesity (OR: 3.33, 95% CI: 1.53, 7.23), and mean BMI was significantly higher in non-producers (28.9kg/m 2 ) than in producers (26.7kg/m 2 ), after adjusting for age, ethnicity, and menopausal status. Positive associations with being obese were observed in both peri-menopausal (OR=3.92, 95% CI: 0.90, 17.0) and post-menopausal (OR=3.00, 95% CI: 1.22, 7.70) women. The equol non-producer phenotype was not associated with obesity (OR=1.13, 95% CI: 0.64, 1.98), and mean BMI was not significantly different between equol producers (27.3kg/m 2 ) and non-producers (26.5kg/m 2 )., Conclusions: These results suggest that the ODMA non-producer phenotype is associated with obesity in peri- and post-menopausal women. Further work is needed to confirm these observations in additional populations and to evaluate possible mechanisms., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The objective for this paper was to review human studies of O-desmethylangolensin (O-DMA) concentrations and of O-DMA producers compared with nonproducers in the context of results from in vitro studies. O-DMA is an intestinal bacterial metabolite of daidzein, an isoflavone compound observed to have phytoestrogenic properties. Not all individuals harbor bacteria capable of metabolizing daidzein to O-DMA, and individuals can be classified as O-DMA producers and nonproducers. O-DMA is less structurally similar to 17β-estradiol than its parent compound, daidzein; thus, it may exhibit different biological actions than daidzein. Evidence from in vitro studies suggests that O-DMA has several cancer-related biological actions. However, results from human metabolic studies and observational studies of disease risk suggest that these actions may not be physiologically relevant in vivo due to the amount and form (primarily glucuronide) of circulating O-DMA. Apart from circulating O-DMA concentrations, the underlying bacteria may have a distinct physiological role. Urinary excretion of O-DMA in humans is a marker of harboring intestinal bacteria capable of C-ring cleavage. Bacterial C-ring cleavage reactions are relevant to other phytochemicals that may exert biological actions in vivo that are stronger than the actions of O-DMA; thus, the role of the phenotype may extend beyond daidzein metabolism. There are a limited number of studies that have evaluated disease risk factors in relation to being an O-DMA producer, with mixed results. Further research evaluating disease risk in relation to the O-DMA-producer phenotype from the perspective of intestinal microbial composition is recommended.

Background: Equol and O-desmethylangolensin (ODMA) are products of gut bacterial metabolism of daidzein, a phytochemical found predominantly in soy. Dietary sources of equol from animal products have been identified, which has raised the question of the relative contributions of daidzein intake and gut metabolism to equol and of equol intake from animal products in low-soy-consuming populations., Objective: The objective was to evaluate the contribution of dietary food groups to urinary isoflavone and daidzein metabolite concentrations in a representative sample of US adults., Design: A cross-sectional analysis of dietary and urinary isoflavonoid data from 3115 individuals in the 2001-2002 and 2003-2004 data cycles of the National Nutrition and Health Examination Survey (NHANES) was conducted., Results: Daidzein intake and consumption frequency of grain products and legumes, nuts, and seeds were significant correlates of daidzein, genistein, and ODMA concentrations; and soy legumes were a stronger correlate than were nonsoy legumes. Milk and milk product consumption and daidzein intake, but not legumes, were significant correlates of urinary equol concentrations; milk products were more strongly correlated (P for trend < 0.001) than was daidzein intake (P = 0.011)., Conclusions: These results suggest that dietary daidzein and legumes may contribute to urinary daidzein, genistein, and ODMA concentrations in this low-soy-consuming population. These results also suggest that equol concentrations in low-soy-consuming populations may reflect equol intakes from mammalian milk sources and may not reflect the endogenous production of equol from the microbial metabolism of daidzein-an observation not yet documented in the US population. These results support the careful design and interpretation of urinary isoflavonoid excretion studies, particularly bacterial metabolites, in low-soy-consuming populations.

Background: Proliferative benign breast conditions are associated with elevated risk of breast cancer, whereas nonproliferative conditions are not strongly associated with risk. Factors acting before onset of hyperplasia might be associated with both benign conditions and breast cancer, whereas those on the proliferative disease-to-cancer pathway would be associated only with cancer. Soy isoflavone exposure may influence breast cancer risk, but little is known of its association with benign conditions., Materials and Methods: We examined possible relationships between plasma genistein and daidzein concentrations and risk of breast disease in women, in a breast self-examination trial in Shanghai, China, diagnosed with breast cancer (n = 196) or a benign breast condition (n = 304), and 1,002 age-matched controls with no known breast disease. Benign conditions were classified as nonproliferative (n = 131) or proliferative with or without atypia (n = 173)., Results: Isoflavone concentrations were inversely associated with risk of nonproliferative and proliferative benign fibrocystic conditions, as well as with breast cancer, both with and without concomitant proliferative changes in ipsilateral noncancerous mammary epithelium (P(trend) < 0.01 for all comparisons with controls). Women in the highest quartile of plasma genistein (>76.95 ng/mL) were less likely to have breast cancer (odds ratio, 0.26; 95% confidence interval, 0.13-0.50) or benign conditions (odds ratio, 0.40; 95% confidence interval, 0.23-0.70) compared with women in the lowest quartile (<9.42 ng/mL). Observed risks for breast cancer with and without surrounding proliferative changes were not different, respectively, from observed risks for benign proliferative and nonproliferative conditions alone., Conclusion: Isoflavone exposure was inversely associated with fibrocystic breast conditions and breast cancer, and the results suggest that effects on cancer risk occur early in carcinogenesis.

Interindividual differences in metabolism of the soy isoflavone, daidzein, to equol and O-desmethylangolensin (ODMA) by human gut bacteria, have been associated with altered risk of cancer and other chronic diseases, according to some studies. Differences have been reported in the prevalence of the equol-producer phenotype among populations, with a higher prevalence in soy-consuming Asian populations than in Western populations. To date, prevalence of the daidzein-metabolizing phenotypes in Asians, compared with Caucasians, has not been evaluated in the context of a standardized phenotyping method. We assessed the prevalence of equol- and ODMA-producer phenotypes in 91 Korean American (KA) women and girls living in the Seattle, Washington area and compared this with previous similarly collected prevalence data in Caucasian American (CA) women and girls (n = 222). We also compared the dietary habits of the 2 groups. Isoflavonoid concentrations in first-void morning urines, collected after a 3-d soy challenge, were used to establish equol-, and ODMA-producer phenotypes (>44 microg/L). The prevalence of the equol-producer phenotype was higher (51 vs. 36%; P = 0.015) and the ODMA-producer phenotype was lower (84 vs. 92%, P = 0.03) in KA than in CA women and girls. KAs consumed approximately 3 times more soy foods than the CAs, but no significant associations were found between the consumption of soy foods and equol-producer phenotype. Our findings support the reports that, compared with Western populations, Asian populations have a higher equol-producer prevalence. The additional observation that the prevalence of the ODMA-producer phenotype is lower in KAs suggests that daidzein-metabolizing patterns in general may differ between KAs and CAs.

Objectives: Intestinal bacterial metabolize the soy isoflavone daidzein to O-desmethylangolensin (O-DMA) or equol. Some individuals do not excrete O-DMA or equol after soy consumption, suggesting they do not harbor bacteria capable of producing these metabolites. The aim of this study was to evaluate bone mineral density (BMD) in relation to presence of these urinary metabolites., Methods: BMD, determined by whole-body dual X-ray absorptiometry scan, was age-adjusted and evaluated in relation to O-DMA-producer and equol-producer phenotypes in 92 postmenopausal women, aged 50-75 years. Women consumed supplemental soy foods (daidzein source) for 3 days and collected a first-void urine sample on the fourth day in order to determine metabolic phenotypes., Results: In O-DMA producers (n=76) compared to O-DMA non-producers (n=16), greater total, leg and head BMD (p<0.05) were observed. Total BMD among the O-DMA producers (geometric mean=1.04 g/cm2) was 6% greater than total BMD among the O-DMA non-producers (geometric mean=0.98 g/cm2). Total and site-specific BMD did not differ between equol producers (n=24) and non-producers (n=68) (p>0.05). In exploratory analyses, among regular soy consumers, spinal BMD was 20% lower among the equol producers than non-producers, whereas, among soy non-consumers, no such difference was observed (p-interaction<0.05). Among equol producers, circulating estrone and free estradiol concentrations were inversely or not associated with total BMD, whereas, among equol non-producers, these hormones were positively associated (p-interaction<0.05)., Conclusions: Our results provide evidence that intestinal bacterial composition may influence BMD in postmenopausal women. Further studies characterizing associations of intestinal bacterial profiles with BMD are warranted.

Particular intestinal bacteria are capable of metabolizing the soya isoflavone daidzein to equol and/or O-desmethylangolensin (O-DMA), and the presence of these metabolites in urine after soya consumption are markers of particular intestinal bacteria profiles. Prevalences of equol producers and O-DMA producers are approximately 30-50 % and 80-90 %, respectively, and limited observations have suggested that these daidzein-metabolizing phenotypes are stable within individuals over time. Characterizing stability of these phenotypes is important to understand their potential as markers of long-term exposure to particular intestinal bacteria and their associations with disease risk. We evaluated concordance within an individual for the equol-producer and O-DMA-producer phenotypes measured at two time points (T1, T2), 1-3 years apart. Phenotypes were ascertained by analysing equol and O-DMA using GC-MS in a spot urine sample collected after 3 d soya (source of daidzein) supplementation. In ninety-two individuals without recent (within 3 months before phenotyping) or current antibiotics use, 41 % were equol producers at T1 and 45 % were equol producers at T2, and 90 % were O-DMA producers at T1 and 95 % were O-DMA producers at T2. The percentage agreement for the equol-producer phenotype was 82 and for the O-DMA-producer phenotype was 89. These results indicate that these phenotypes are stable in most individuals over time, suggesting that they provide a useful biomarker for evaluating disease risk associated with harbouring particular intestinal bacteria responsible for, or associated with, the metabolism of the soya isoflavone daidzein.

The indigenous intestinal microflora are involved in a variety of processes within the human body, and are important for maintaining host health. As such, interindividual differences in the ability to harbor certain intestinal bacteria might be associated with interindividual differences in health and/or disease susceptibility. In the last decade there has been considerable interest in phytoestrogen intakes in relation to human health. Daidzein, an isoflavone phytoestrogen found in soy, is metabolized to equol and O-desmethylangolensin (O-DMA) by intestinal bacteria. The specific bacterium/bacteria responsible for equol and O-DMA production in humans have yet to be identified definitively, but in vitro and animal studies have suggested that equol and O-DMA are more biologically active than their precursor daidzein. Interestingly, substantial interindividual differences in daidzein metabolism exist; following soy or daidzein consumption, approximately 30%-50% of the human population produce equol, and approximately 80%-90% produce O-DMA. Observational and intervention studies in humans have suggested that the ability to produce equol and O-DMA may be associated with reduced risk of certain diseases including breast and prostate cancers. However, relatively few studies have been conducted to date. In this review, we discuss the available evidence for a relationship between daidzeinmetabolizing phenotypes and human health, and suggest potential mechanisms for some of the reported relationships.

Objective: The food-frequency questionnaire (FFQ) can be an efficient tool to evaluate dietary intake in large, population-based studies, especially for specific foods. The objective of this study was to validate the assessment of soy and isoflavone (daidzein and genistein) intakes, measured by an FFQ, by comparing intakes with serum isoflavone concentrations., Design and Setting: Soy and isoflavone intakes and serum isoflavone concentrations were determined as part of a case-control study of dietary factors and risks of benign breast disease and breast cancer. The FFQ, administered during an in-person interview, included six soy-specific line items. Blood was drawn within one week of FFQ completion., Subjects: In total, 1823 women living in Shanghai, People's Republic of China., Results: In this population, soybean milk, fresh bean curd and other bean foods were eaten once per week, and fermented bean curd, fried bean curd puff and soybeans were eaten less than once per week. A significant linear trend (P<0.01) in serum isoflavone concentrations across increasing categories of soy and isoflavone intakes was observed, indicating that soy and isoflavone intakes, measured by the FFQ, well distinguished serum isoflavone concentrations. Linear trends were also observed in both case and control groups in stratified analyses, suggesting little differential bias by case-control status., Conclusions: The results suggest that the FFQ provides a useful marker of soy food consumption and isoflavone exposure in this population.

Circulating hormones are associated with mammographic density, an intermediate marker of breast cancer risk. Differences in circulating hormones, including estrone and testosterone, have been observed in premenopausal women based on their capacity to metabolize daidzein, an isoflavone found predominantly in soybeans. Equol and O-desmethylangolensin (O-DMA) are products of intestinal bacterial metabolism of daidzein. There is interindividual variability in the capacity to produce daidzein metabolites; individuals can be equol producers or non-producers and O-DMA producers or non-producers. We tested the hypothesis that daidzein-metabolizing phenotypes are associated with mammographic density. Participants were recruited from among 92 sedentary, postmenopausal women, ages 50 to 75 years, who participated in a 1-year physical activity intervention. Pre-intervention mammographic density was determined using a computer-assisted, gray-scale thresholding technique. Fifty-five of these women consumed supplemental soy protein (>10 mg daidzein/d) for 3 days and collected a first-void urine sample on the fourth day to determine daidzein-metabolizing phenotypes. Equol and O-DMA concentrations were measured using gas chromatography-mass spectrometry. Associations between daidzein-metabolizing phenotypes and percent mammographic density were adjusted for age, maximum adult weight, gravidity, family history of breast cancer, and serum follicle-stimulating hormone and free testosterone concentrations. Mammographic density was 39% lower in equol producers compared with non-producers (P = 0.04). O-DMA producers had mammographic density 69% greater than non-producers (P = 0.05). These results suggest that particular intestinal bacterial profiles are associated with postmenopausal mammographic density, and these associations are not entirely explained by differences in reproductive or anthropometric characteristics or circulating hormones.

Equol and O-desmethylangolensin (O-DMA) are products of bacterial metabolism of daidzein, an isoflavone in soybeans; thus, the presence or absence of equol and/or O-DMA in urine is a marker of particular intestinal bacteria profiles. Plasma hormone concentrations may be lower in pre-menopausal women who harbor the bacteria capable of producing equol (equol producers) compared to women who do not (equol non-producers). We evaluated concentrations of serum hormones, sex hormone-binding globulin (SHBG), and urinary 2-hydroxyestrone (2-OH E(1)) and 16alpha-hydroxyestrone (16alpha-OH E(1)) in relation to equol-producer and O-DMA-producer phenotypes in 89 post-menopausal women. Follicle stimulating hormone (FSH) was 23% greater in O-DMA-producers compared to non-producers (P = 0.04). No significant differences in serum estrogens, androgens, metabolic hormones, or SHBG were observed in relation to either daidzein-metabolizing phenotype. Compared with non-producers within each phenotype, age-adjusted 2-OH E(1):16alpha-OH E(1) was 27% greater (P = 0.06) in equol-producers and 9% greater (P > 0.10) in O-DMA-producers, and 2-OH E(1) concentrations were 24% greater in equol producers (P = 0.07) and 42% greater in O-DMA producers (P = 0.02). No significant differences in 16alpha-OH E(1) were observed in relation to either phenotype. These results suggest that interindividual variability in intestinal bacteria may be related to differences in products of hormone metabolism in post-menopausal women.

Background: Soy foods may have various health benefits, but little is known about the patterns and correlates of soy consumption among postmenopausal women in the United States., Objective: We assessed the reliability and validity of a soy food-frequency questionnaire (FFQ) and examined demographic, lifestyle, and dietary correlates of plasma isoflavone concentrations in postmenopausal women., Design: In this cross-sectional study, soy isoflavone intake and plasma isoflavone concentration were analyzed in 96 postmenopausal women aged 50-79 y; the data were obtained at 2 visits that were 1 wk apart. Intake was determined with a 20-item soy FFQ and a comprehensive FFQ that included questions about tofu and soymilk. Fasting plasma daidzein and genistein concentrations were determined with liquid chromatography-mass spectrometry., Results: Intraclass correlations between week 1 and week 2 values were >0.98 for both the soy and comprehensive FFQs. Median reported isoflavone intake was <2 mg/d. Pearson's product-moment correlation coefficients relating isoflavone intakes with plasma isoflavone concentrations ranged from 0.35 to 0.43. Plasma isoflavone concentrations were positively associated with age, fiber consumption, servings of fruit and vegetables, and dietary supplement use and were inversely associated with caffeine consumption; no associations with body mass index, education, dietary beliefs, activity level, alcohol intake, or fat intake were observed., Conclusions: Within a population with low soy consumption, the soy FFQ and comprehensive FFQ showed good reliability and moderate validity. Associations of plasma isoflavone concentrations with other dietary behaviors suggest that these compounds may serve as biomarkers of health behaviors in populations with low soy consumption.

Objective: To validate assessment of soy intake using food frequency questionnaires (FFQs) compared with plasma isoflavone (genistein and daidzein) concentrations., Design: Cross-sectional analysis of soy isoflavone intake and plasma analysis of isoflavones., Subjects: 77 men and women, age range 20 to 40 years, recruited from the Seattle metropolitan area., Main Outcome Measures: Isoflavone intake was determined from responses to a 40-item soy FFQ and from tofu and soymilk intake assessed as part of a comprehensive FFQ used for the Women's Health Initiative (WHI FFQ). Isoflavone concentrations in fasting blood samples were determined by liquid chromatography-mass spectrometry., Statistical Analyses: Correlation coefficients were calculated for: a) isoflavone intake assessed by the soy FFQ and the WHI FFQ, b) intake assessed by the soy FFQ and plasma isoflavone concentrations, and c) intake assessed by the WHI FFQ and plasma isoflavone concentrations., Results: Isoflavone intake was highly correlated between the soy FFQ and the WHI FFQ (r = 0.84). Genistein and daidzein intakes determined by the soy FFQ were significantly correlated with plasma concentrations (r = 0.53 and 0.45, respectively). Isoflavone intake assessed from the WHI FFQ was also correlated with plasma concentration (r = 0.46 and 0.45). Soymilk and tofu were the two major contributors to isoflavone intake (38.6%)., Conclusions: A soy-specific, 40-item FFQ assessed isoflavone intake with good validity. Isoflavone intake assessed by the WHI FFQ (tofu and soymilk) had lower correlations with plasma concentrations compared with the soy FFQ. Nonetheless, assessment of the two foods is a reasonably good marker for soy food consumption in this sample.

Interindividual differences in metabolism of the soy isoflavone, daidzein, to equol and O-desmethylangolensin (ODMA) by human gut bacteria, have been associated with altered risk of cancer and other chronic diseases, according to some studies. Differences have been reported in the prevalence of the equol-producer phenotype among populations, with a higher prevalence in soy-consuming Asian populations than in Western populations. To date, prevalence of the daidzein-metabolizing phenotypes in Asians, compared with Caucasians, has not been evaluated in the context of a standardized phenotyping method. We assessed the prevalence of equol- and ODMA-producer phenotypes in 91 Korean American (KA) women and girls living in the Seattle, Washington area and compared this with previous similarly collected prevalence data in Caucasian American (CA) women and girls (n = 222). We also compared the dietary habits of the 2 groups. Isoflavonoid concentrations in first-void morning urines, collected after a 3-d soy challenge, were used to establish equol-, and ODMA-producer phenotypes (<44 μg/L). The prevalence of the equol-producer phenotype was higher (51 vs. 36%; P = 0.015) and the ODMA-producer phenotype was lower (84 vs. 92%, P = 0.03) in KA than in CA women and girls. KAs consumed approximately 3 times more soy foods than the CAs, but no significant associations were found between the consumption of soy foods and equol-producer phenotype. Our findings support the reports that, compared with Western populations, Asian populations have a higher equol-producer prevalence. The additional observation that the prevalence of the ODMA-producer phenotype is lower in KAs suggests that daidzein-metabolizing patterns in general may differ between KAs and CAs. [ABSTRACT FROM AUTHOR]