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Articles

Wheat Bran and Soy Protein Feeding Do Not Alter Urinary Excretion of the Isoflavan Equol in Premenopausal Women¹

Johanna W. Lampe^*2, Heather E. Skor^*, Sue Li^*, Kristiina Wähälä, William N. Howald^** and Chu Chen

^* Cancer Prevention Research Program and Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109; Department of Chemistry, University of Helsinki, Finland and ^** Department of Medicinal Chemistry, University of Washington, Seattle, Washington 98195

²To whom correspondence should be addressed at Cancer Prevention Research Program, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, MP-900, Seattle, WA 98109. E-mail: jlampe{at}fhcrc.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
The capacity to convert the soy isoflavone daidzein to equol in vivo is presumably determined by an individual’s intestinal microfloral populations; however, diet may also influence this conversion. The objectives of the present study were to determine whether a 1-mo supplementation of dietary fiber as wheat bran increases urinary equol excretion in equol excreters and stimulates equol production in nonexcreters and whether longer-term soy isoflavone intake increases equol production or alters overall urinary isoflavone excretion. First, we screened 74 women, ages 20–40 y, and determined their equol-excreter status. In these women, health and lifestyle patterns and habitual dietary intake did not differ according to equol-excreter status. Next, 26 of the women (13 equol excreters and 13 nonexcreters) were assigned (blocked on equol-excreter status) to either longer-term (1 mo) or short-term (4 d) soy protein supplementation. Within each soy treatment group, women participated in two 1-mo intervention periods (the exact length was determined by each woman’s menstrual cycle) during which they consumed their usual diets supplemented daily with either 0 or 16 g dietary fiber in a randomized crossover design. A 1-mo washout period separated the two diet periods. Among the 19 women who completed both periods, fiber supplementation did not increase equol production in equol excreters or nonexcreters. In addition, isoflavonoid excretion did not differ by fiber dose or length of soy intervention. These results suggest that a daily 16 g-fiber dose as wheat bran and the addition of soy protein do not alter significantly the capacity of colonic microflora to produce equol.

KEY WORDS: • isoflavones • lignans • equol • daidzein • soy • wheat bran • dietary fiber • humans

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
Isoflavones are weakly estrogenic compounds that are present in high concentrations in soy. Their various biologic activities suggest that they offer potential alternative therapies for a range of conditions, including hypercholesterolemia and osteoporosis (1 ,2) ; however, wide variation in individual capacity to metabolize these compounds may influence exposure.

After ingestion, the major soy isoflavone glycosides daidzin and genistin are hydrolyzed to the aglycones daidzein and genistein, which can be absorbed or metabolized further by intestinal microflora to numerous other compounds before absorption (3) . Equol, one of the microfloral metabolites of daidzein, is produced in and appears in the urine of 30–40% of individuals when they are exposed to soy products containing isoflavones (4 ,5) .

The clinical relevance of equol production by intestinal microflora remains to be established; however, several observations support the rationale for further investigation. Equol is more estrogenic than daidzein and O-desmethylangolensin (ODMA) (6) , another daidzein metabolite (6 ,7) . Compared with daidzein and genistein, equol remains in circulation longer and remains elevated in urine longer after a soy challenge (8 ,9) . Thus, among individuals who regularly consume soy products, having the capacity to produce equol may prolong exposure to these bioactive agents. A recent report suggests that premenopausal women who excrete equol have plasma hormone profiles associated with a lower risk of breast cancer (10) . In addition, equol-excreter status may be a marker of a particular colonic microfloral profile, although what that profile is remains to be determined.

More than 15 y ago, Setchell et al. (4) proposed that the composition of intestinal microflora, intestinal transit time and variability in the redox potential of the colon, factors that can be influenced in part by diet, may contribute to variation in equol production in humans. Since then, several studies comparing the habitual diets of equol excreters and nonexcreters who consume Western diets have reported that equol excreters tend to have a higher intake of carbohydrate and dietary fiber, a higher percentage of energy as carbohydrate and a lower percentage of energy as fat (5 ,11) ; however, this has not been a consistent observation (10 ,12) .

Long-term exposure to isoflavones also may change usual plasma concentrations or urinary excretion of these compounds as a result of altered metabolism (13 ,14) . Although the capacity to produce equol appears to be a relatively stable phenotype (15) , there is at least one report of individuals who converted from being equol nonexcreters to excreters with long-term soy ingestion (14) . This suggests that microfloral populations may have the capacity to change in response to soy supplementation. Whether long-term intake of other dietary constituents can influence isoflavone excretion remains to be determined. In short-term trials, background diet (16) and the addition of wheat fiber (17) appear to have little effect on isoflavone bioavailability; however, these trials were extremely short (e.g., 1 d or single feedings) and would not have captured any changes mediated through altered intestinal microfloral populations.

To date, no intervention studies have examined the effect of dietary fiber supplementation on equol excretion or on equol-excreter status. The objectives of this study were 1) to determine whether a 1-mo intervention of dietary fiber as wheat bran increases urinary equol excretion in equol excreters and stimulates equol production in nonexcreters and 2) to determine whether longer-term soy isoflavone intake increases equol production or alters overall urinary isoflavone excretion.

	METHODS

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Study design.

We screened 74 women, ages 20–40 y, and determined their equol-excreter status. Women were excluded if they used oral contraceptives or other hormone treatments, used oral antibiotics in the 4 mo before the study or had irregular menstrual cycles (cycle lengths <25 or >30 d). Information on demographics, health and lifestyle patterns was obtained with a self-administered questionnaire, and habitual dietary intake within the past 2 mo was assessed with a food frequency questionnaire (FFQ).³ The women supplemented their habitual diets with 34 g soy protein powder (Altima HP-20; Protein Technologies International, St. Louis, MO) for 3 d and, on the morning of d 4, collected their first-void urine for isoflavonoid and creatinine analysis. A similar approach enabled us to distinguish between equol excreters and nonexcreters in previous work (5) . All activities were reviewed and approved by The Institutional Review Board at Fred Hutchinson Cancer Research Center.

After equol-excreter status was established, the women were contacted via written invitation to participate in the diet intervention. Twenty-six women (13 equol excreters and 13 nonexcreters) agreed to participate and were randomized to the diet treatments. Women were block randomized on the basis of equol-excreter status. Within each group, they were assigned randomly to either longer- or short-term soy protein supplementation. Women in the longer-term soy protein arm consumed a daily serving of soy protein powder (34 g chocolate-flavored Altima HP-20, Protein Technologies International, St. Louis, MO) during each 1-mo intervention period, whereas those in the short-term soy arm received the soy protein only during the last 4 d of each period. Within each soy treatment group, women participated in two 1-mo intervention periods (the exact length was determined by the length of a woman’s menstrual cycle), during which they consumed their usual diets supplemented daily with either 0 or 16 g dietary fiber in a randomized crossover design (Fig. 1 ). A 1-mo washout period (the length of the woman’s cycle) separated the two diet periods. Prepackaged, read-to-eat breakfast cereals were used for the 0-g (42 g Crispix; Kellogg Company, Battle Creek, MI) and 16-g (50 g All-Bran; Kellogg Company) dietary fiber treatments. The macronutrient content of the two cereals and the soy protein powder is presented in Table 1 .

View larger version (36K): [in this window] [in a new window]   Figure 1. Study design and diet treatments in the short- and longer-term soy protein treatment arms of the study.

Phytoestrogen analysis.

To establish equol-excreter status of the 74 women, we used the HPLC method of Franke and Custer (19) to measure daidzein and equol in the overnight urine collection. Samples were extracted, hydrolyzed and stored at -20°C in 100% methanol as described previously (19) . Before HPLC injection, the samples were equilibrated to room temperature, vortex-mixed, centrifuged at 850 x g for 5 min, decanted, dried by Speed-Vac at room temperature, reconstituted in 1 mL mobile phase [20% acetonitrile in acetic acid/water (10:90, v/v)], filtered through a 0.45-µm filter and transferred to HPLC vials. Analyses were conducted on an Hewlett Packard 1050 Series HPLC that included an autosampler, a quaternary pump, a diode array detector and Chemstation software (Agilent Technologies, Palo Alto, CA), with a NovaPak C18 (150 x 3.9 mm I.D.; 4 µm) reversed phase column (Waters, Milford, MA), at a flow rate of 0.8 mL/min with the following step gradient: 20% A in B for 10 min, then 30% A for 10 min, then 70% A for 10 min and again 20% A for 10 min, with A being acetonitrile and B being acetic acid/water (10:90, v/v). Daidzein and flavone (internal standard) were monitored at 260 nm, and equol was monitored at 280 nm. Women with urinary equol concentrations of >1 mg/mL were defined as equol excreters.

To measure the isoflavonoids genistein, daidzein, equol and ODMA in the two 24-h urine collections obtained at the end of each intervention period, we used a modified version of the gas chromatography-mass spectrometry method of Adlercreutz et al. (20) . Because whole wheat is a modest source of the enterolactone precursor secoisolariciresinol (2) , we also measured enterolactone. To monitor procedural loss and for positive identification of the compounds of interest, we added 4-methylumbelliferone glucuronide and deuterated internal standards of the unconjugated compounds to the urine (1/600 of the 24-h collection). The sample pH was adjusted with 1/10 the sample volume of 1.5 mol sodium acetate/L buffer, pH 3.0, and the sample was applied to a conditioned SepPak C18 cartridge (Waters) containing 500 mg sorbent. The C18 columns were then washed with 5 mL of 0.15 mol sodium acetate/L buffer, pH 3.0, and the adsorbed phytoestrogens were eluted with 4 mL methanol. The eluates were dried under nitrogen to evaporate all of the methanol and incubated overnight with 10 µL ß-glucuronidase (Helix pomatia extract; Sigma Chemical Co., St. Louis, MO) and 25 mg ascorbic acid in 5 mL of 0.15 mol sodium acetate/L buffer, pH 4.1, at 37°C. The next morning, each hydrolysate was applied to a conditioned SepPak C18 cartridge (Waters). The cartridge was then washed with 5 mL water and eluted with 4 mL methanol. The eluent was then applied to a 5-cm QAE-Sephadex A-25 (Sigma Chemical) anion-exchange column in the acetate form. Two separate fractions were collected: enterolactone and equol were eluted with 4 mL methanol, and ODMA, daidzein and genistein were eluted with 7 mL of 0.2 mol acetic acid/L in methanol. Fractions were dried under nitrogen and stored in 0.5 mL methanol at -20°C until derivatization. Trimethyl-silyl derivatives of the samples were analyzed on a Hewlett-Packard 5890 Series II gas chromatograph (Agilent Technologies, Palo Alto, CA) coupled to a Micromass 2000 quadrapole mass spectrometer (Micromass, Manchester, UK) in the selected ion monitoring mode. Each sample was run once. A quality control urine sample was included in duplicate in each run.

Statistical analysis.

Anthropometric and nutrient intake variables collected on participants during the screening were compared between equol excreters and nonexcreters using an unpaired, two-sided Student’s t test. We used ² analysis to test for differences in prevalence of self-reported diet and lifestyle behaviors. We analyzed the diet intervention data using a linear mixed regression model (PROC MIXED in SAS, Release 6.12) (21) and included the following effects in the model: study participant, equol-excreter status, feeding period, soy protein treatment and fiber treatment. Study participant was a random effect, and all other effects were fixed. We present least-squares means and standard errors for each diet and for diet x genotype combinations. The urinary isoflavonoid and enterolactone data from the intervention study, as well as the nutrient intake data from the cross-sectional study, were skewed, and we log-transformed (natural log) them before analysis. In these cases, we present back-transformed means and standard errors. Statistical significance was set at P = 0.05.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
Twenty-four (32%) of the 74 women were equol excreters. There were no differences between equol excreters and nonexcreters in any of the variables measured, including nutrient intakes as estimated by FFQ (Table 2 ).

Urinary isoflavonoid and enterolactone excretions were not significantly different between collection d 1 and 2, even among the women in the short-term soy protein treatment arm; therefore, the mean values of the 2 d were used to test the effect of soy and cereal treatment. There were no effects of equol-excreter status, length of soy protein treatment or wheat bran supplementation on 24-h excretion of any of the isoflavonoids or on enterolactone (Table 3 ). Although mean enterolactone excretion tended to be lower among the equol nonexcreters in the longer-term soy treatment group compared with the other groups, and mean ODMA excretion appeared to be higher in the equol nonexcreters in the longer-term soy treatment group compared with the other groups (Table 3) , there were no significant differences (P > 0.6).

	DISCUSSION

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Previously, in a group of 19 women and 5 men, compared with poor excreters, good equol excreters had a higher percentage of energy from carbohydrate and a lower percentage of energy from fat (11) . In another study, compared with 22 nonexcreting women, 8 equol-excreting women were reported to consume a diet higher in carbohydrate and dietary fiber, a difference that was not observed among the 30 men (5) . The addition of supplemental carbohydrate in an in vitro fermentation system also resulted in more rapid production of equol from daidzein (3) . These observations suggest that carbohydrate available to intestinal microflora may be important for equol-producing capacity. In contrast, Duncan et al. (10) found no difference in the dietary habits of five equol-excreting and nine nonexcreting women who consumed a Western diet, and in a study of individuals who consumed a traditional Japanese diet, equol excretion correlated positively with intake of fat and meat and the fat-to-fiber ratio (12) .

All of the previous reports that compared dietary intakes of equol excreters and nonexcreters used food intake records, not FFQ, to measure nutrient intakes; however, estimation of the usual diet has been shown to be similar whether assessed by FFQ or food record (23) . Typically, FFQ is a good reflection of the overall diet but may not as effectively reflect the recent diet (23) . Nevertheless, it is unlikely that the immediate diet is more important than the habitual diet in relation to equol-excreter status, a phenotype that seems to be relatively immune to perturbation. One possibility for the difference in findings among the various studies that compared the diets of equol excreters and nonexcreters is that carbohydrate, dietary fiber and fat intakes may be important only in a particular subset of individuals, a subset who met the inclusion criteria of the other studies.

The results of our dietary intervention indicate that changes in fiber content of the diet, as well as longer-term, daily soy protein intake, do not affect urinary isoflavone excretion in premenopausal women. Furthermore, these dietary modifications did not alter the capacity of colonic microflora to produce equol. Several small studies have suggested that long-term exposure to isoflavones may change the usual plasma concentrations and urinary excretion of these compounds as a result of altered metabolism. After an initial rise, plasma concentrations of daidzein and genistein decreased when individuals consumed soy daily over a 2-wk period (13) . Similarly, urinary isoflavone excretion decreased in women who consumed soy milk for 30 d (14) . In our study, there was no difference in isoflavone excretion between the women who received soy for 4 wk and those who consumed it for only 3 d.

The well-characterized metabolites of daidzein, equol and ODMA are routinely measured in urine. Urinary ratios of ODMA to daidzein appear to increase with increasing dose of isoflavones, and in a 3-mo soy-isoflavone intervention, daily ODMA excretion exceeded daidzein excretion (24) . Some (9 ,25) , but not all (26) , studies have reported an inverse relationship between the excretions of equol and ODMA. We found no overall difference in ODMA excretion between equol excreters and nonexcreters. The three equol nonexcreters who received the short-term soy protein treatment appeared to have a higher ODMA excretion compared with both equol excreters and the other nonexcreters; unfortunately, the small sample size in this subgroup precludes rigorous exploration of this observation.

The addition of 16 g dietary fiber as wheat bran approximately doubled the daily fiber intake of our study participants. Under controlled dietary conditions, supplementation of 20 g dietary fiber compared with 10 g dietary fiber as wheat bran in an otherwise fiber-free diet decreases intestinal transit and fecal pH and increases fecal weight and fecal water short-chain fatty acids (27) . Thus, the fiber dose we provided would have been sufficient to significantly alter the colonic environment. Although Rowland et al. (11) observed, among equol excreters compared with nonexcreters, a higher intake of energy as carbohydrate and a lower intake of energy, they found no significant difference in the intake of nonstarch polysaccharides. These data suggest that carbohydrate may be more important than dietary fiber per se, a hypothesis we were unable to test in this intervention given that we controlled for carbohydrate content of the two cereal treatments. Rowland et al. (11) also proposed that rather than carbohydrate and fiber stimulating gut microflora to produce equol, dietary fat may decrease the capacity of the microflora to produce equol. This remains to be investigated.

Wheat bran supplementation also did not affect urinary enterolactone excretion. We had hypothesized that the addition of the wheat bran cereal might influence enterolactone excretion by contributing additional secoisolariciresinol (a precursor of the lignans enterodiol and enterolactone) to the diet (2) or by altering colonic bacterial populations. The only difference observed was that equol nonexcreters in the long-term soy protein intervention tended to have a lower mean enterolactone excretion (30% that of the other study groups), but this occurred during both the 0- and 16-g fiber treatments. This suggests that either these 6 women were different from the other 13 women with regard to factors that influence enterolactone excretion or, possibly, long-term soy intake influences lignan metabolism in equol nonexcreters. A controlled feeding study might better address this question.

In summary, we showed that a daily 16-g dietary fiber dose as wheat bran and the addition of soy protein do not significantly modulate the capacity of colonic microflora to produce equol. Furthermore, in 74 premenopausal women, no differences in usual diet were detected between equol excreters and nonexcreters when diet was assessed using FFQ. These results suggest that equol-excreter status is a relatively stable phenotype that is not strongly associated with diet and not readily altered by diet. Consequently, the contribution to this phenotype of other environmental or possibly genetic factors should be explored.

	ACKNOWLEDGMENTS

 
The authors thank Lisa Szymura for her dedication to participant recruitment and retention and JoAnn Prunty for her assistance with the urinary isoflavone extractions for HPLC analysis. The ready-to-eat cereals and the soy protein powder were generous donations from the Kellogg Company (Battle Creek, MI) and Protein Technologies International (St. Louis, MO), respectively.

	FOOTNOTES

 
¹ Supported by National Cancer Institute grant R21-CA66186-02 and by the Fred Hutchinson Cancer Research Center.

³ Abbreviations used: FFQ, food frequency questionnaire; ODMA, O-demethylangolensin.

Manuscript received October 11, 2000. Initial review completed November 3, 2000. Revision accepted December 12, 2000.

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				C. Manach, G. Williamson, C. Morand, A. Scalbert, and C. Remesy Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies Am. J. Clinical Nutrition, January 1, 2005; 81(1): 230S - 242S. [Abstract] [Full Text] [PDF]

				C. L. Frankenfeld, C. Atkinson, W. K. Thomas, E. L. Goode, A. Gonzalez, T. Jokela, K. Wahala, S. M. Schwartz, S. S. Li, and J. W. Lampe Familial Correlations, Segregation Analysis, and Nongenetic Correlates of Soy Isoflavone-Metabolizing Phenotypes Experimental Biology and Medicine, October 1, 2004; 229(9): 902 - 913. [Abstract] [Full Text] [PDF]

				H. Wiseman, K. Casey, E. A Bowey, R. Duffy, M. Davies, I. R Rowland, A. S Lloyd, A. Murray, R. Thompson, and D. B Clarke Influence of 10 wk of soy consumption on plasma concentrations and excretion of isoflavonoids and on gut microflora metabolism in healthy adults Am. J. Clinical Nutrition, September 1, 2004; 80(3): 692 - 699. [Abstract] [Full Text] [PDF]

				J. A. Nettleton, K. A. Greany, W. Thomas, K. E. Wangen, H. Adlercreutz, and M. S. Kurzer Plasma Phytoestrogens Are Not Altered by Probiotic Consumption in Postmenopausal Women with and without a History of Breast Cancer J. Nutr., August 1, 2004; 134(8): 1998 - 2003. [Abstract] [Full Text] [PDF]

				S. Kreijkamp-Kaspers, L. Kok, D. E. Grobbee, E. H. F. de Haan, A. Aleman, J. W. Lampe, and Y. T. van der Schouw Effect of Soy Protein Containing Isoflavones on Cognitive Function, Bone Mineral Density, and Plasma Lipids in Postmenopausal Women: A Randomized Controlled Trial JAMA, July 7, 2004; 292(1): 65 - 74. [Abstract] [Full Text] [PDF]

				C. Manach, A. Scalbert, C. Morand, C. Remesy, and L. Jimenez Polyphenols: food sources and bioavailability Am. J. Clinical Nutrition, May 1, 2004; 79(5): 727 - 747. [Abstract] [Full Text] [PDF]

				P. A. Newcomb, A. C. Bush, G. L. Stoner, J. W. Lampe, J. D. Potter, and J. Bigler No Evidence of an Association of JC Virus and Colon Neoplasia Cancer Epidemiol. Biomarkers Prev., April 1, 2004; 13(4): 662 - 666. [Abstract] [Full Text] [PDF]

				C. Atkinson, S. Berman, O. Humbert, and J. W. Lampe In Vitro Incubation of Human Feces with Daidzein and Antibiotics Suggests Interindividual Differences in the Bacteria Responsible for Equol Production J. Nutr., March 1, 2004; 134(3): 596 - 599. [Abstract] [Full Text] [PDF]

				E. J. Frische, A. M. Hutchins, M. C. Martini, W. Thomas, and J. L. Slavin Effect of Flaxseed and Wheat Bran on Serum Hormones and Lignan Excretion in Premenopausal Women J. Am. Coll. Nutr., December 1, 2003; 22(6): 550 - 554. [Abstract] [Full Text] [PDF]

				R. M. Blair, S. E. Appt, A. A. Franke, and T. B. Clarkson Treatment with Antibiotics Reduces Plasma Equol Concentration in Cynomolgus Monkeys (Macaca fascicularis) J. Nutr., July 1, 2003; 133(7): 2262 - 2267. [Abstract] [Full Text] [PDF]

				L. Zubik and M. Meydani Bioavailability of soybean isoflavones from aglycone and glucoside forms in American women Am. J. Clinical Nutrition, June 1, 2003; 77(6): 1459 - 1465. [Abstract] [Full Text] [PDF]

				K. D. R. Setchell, N. M. Brown, P. B. Desai, L. Zimmer-Nechimias, B. Wolfe, A. S. Jakate, V. Creutzinger, and J. E. Heubi Bioavailability, Disposition, and Dose-Response Effects of Soy Isoflavones When Consumed by Healthy Women at Physiologically Typical Dietary Intakes J. Nutr., April 1, 2003; 133(4): 1027 - 1035. [Abstract] [Full Text] [PDF]

				K. D. R. Setchell, N. M. Brown, and E. Lydeking-Olsen The Clinical Importance of the Metabolite Equol--A Clue to the Effectiveness of Soy and Its Isoflavones J. Nutr., December 1, 2002; 132(12): 3577 - 3584. [Abstract] [Full Text] [PDF]

				R. M. Blair, S. E. Appt, C. Bennetau-Pelissero, T. B. Clarkson, M. S. Anthony, V. Lamothe, and S. M. Potter Dietary Soy and Soy Isoflavones Have Gender-Specific Effects on Plasma Lipids and Isoflavones in Golden Syrian F1B Hybrid Hamsters J. Nutr., December 1, 2002; 132(12): 3585 - 3591. [Abstract] [Full Text] [PDF]

				C. Atkinson, H. E. Skor, E. D. Fitzgibbons, D. Scholes, C. Chen, K. Wahala, S. M. Schwartz, and J. W. Lampe Overnight Urinary Isoflavone Excretion in a Population of Women Living in the United States, and Its Relationship to Isoflavone Intake Cancer Epidemiol. Biomarkers Prev., March 1, 2002; 11(3): 253 - 260. [Abstract] [Full Text] [PDF]

				M. Messina, C. Gardner, and S. Barnes Gaining Insight into the Health Effects of Soy but a Long Way Still to Go: Commentary on the Fourth International Symposium on the Role of Soy in Preventing and Treating Chronic Disease J. Nutr., March 1, 2002; 132(3): 547S - 551. [Abstract] [Full Text] [PDF]

				M. J. Messina and C. L. Loprinzi Soy for Breast Cancer Survivors: A Critical Review of the Literature J. Nutr., November 1, 2001; 131(11): 3095S - 3108. [Abstract] [Full Text] [PDF]

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