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Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN 55108 and * Department of Biostatistics, University of Minnesota, Minneapolis, MN 55407
3To whom correspondence should be addressed. E-mail: mkurzer{at}umn.edu.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • soy protein • isoflavones • probiotic bacteria • lipids • women
Coronary heart disease (CHD)4 is the leading cause of death in the United States, accounting for >502,000 deaths in 2001 (1). Considerable research has been devoted to the investigation of pharmaceutical and lifestyle interventions for primary and secondary prevention. Over the past 3 decades, soy-based foods and soy isoflavones have emerged as a viable adjunct for controlling plasma lipids and other CHD risk factors.
A 1995 meta-analysis of 38 trials (2) as well as numerous recent intervention studies (3–13) demonstrated a hypocholesterolemic effect of soy, although a few investigations (14–17) did not corroborate these results. Several components of soy were hypothesized to contribute to its effect on plasma lipid concentrations. These components include storage peptides (3,18), saponins (19), and isoflavones (5,20,21). If isoflavones are responsible for the effects of soy on HDL cholesterol (HDL-C) and LDL cholesterol (LDL-C), enhancing their absorption and metabolism to active forms may increase their therapeutic potential.
The isoflavone metabolite, equol, is of particular interest. Equol binds with greater affinity to the estrogen receptor than its precursor daidzein; therefore, it may have greater efficacy than other isoflavones in receptor-mediated effects of soy (22). It was suggested that the inconsistent clinical effectiveness of soy may be mediated by individual variation in the ability to produce equol (30–40% of humans produce large quantities of equol after soy consumption) and that in analyzing results, subjects should be stratified by equol production status (23–26). A recently published investigation reported significant reductions in total cholesterol (TC), LDL-C, and triglycerides (TG) for the subset of equol producers, but no significant differences for the group overall (27).
Intestinal bacteria perform critical roles in isoflavone metabolism (28). Provision of probiotic bacteria may modulate gut microflora, thereby augmenting isoflavone metabolism and increasing the effect on lipids. In addition, probiotic bacteria may independently affect plasma lipids. Studies incorporating probiotic bacteria into fermented food products (29–32) or capsules (33) reported a cholesterol-lowering effect, although not all investigations support this outcome (34–37).
The purpose of this study was to investigate the independent and interactive effects of soy protein isolate and probiotic bacteria on plasma lipids in normocholesterolemic and mildly hypercholesterolemic postmenopausal women. We hypothesized that the probiotic bacteria Lactobacillus acidophilus DDS+1 and Bifidobacterium longum would augment the effect of soy on plasma lipids as well as exert an independent hypocholesterolemic effect when administered in the absence of soy protein, and that the effect of soy on plasma lipids would be more pronounced in women who were equol producers.
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Study design and experimental diet. The study was conducted in a randomized crossover design. Subjects completed four 6-wk diet treatments separated by 2-wk washout periods; the entire study duration was 8 mo. The length of the washout period was considered sufficient for preventing residual effects of protein isolate or probiotic on subsequent diet periods. Participants were free-living and consumed their habitual diets (with restrictions as noted) supplemented by 1 of the following 4 treatment combinations during each of the 4 diet periods: 1) soy protein isolate, 2) soy protein isolate plus probiotic capsules, 3) milk protein isolate, and 4) milk protein isolate plus probiotic capsules. Protein isolates were obtained from the Solae Company. The soy powder was made with SUPROSOY (part of the Solae brand) isolated soy protein that had been water washed to retain the naturally occurring isoflavones. The isoflavone content of both powders was analyzed before and halfway through the study by HPLC (Dr. Pat Murphy, Department of Food Science and Human Nutrition, Iowa State University, Ames, IA). Expressed as aglycone equivalents, soy protein isolate contained 1.16 mg isoflavones/g powder (57% genistein, 34% daidzein, 9% glycitein); the milk protein isolate was devoid of isoflavones. The protein isolates were provided relative to body weight (wt) to supply 0.38 g protein/kg body wt (26 ± 5 g/d); soy protein provided 0.64 mg isoflavones/kg body wt (44 ± 8 mg isoflavones/d). The nutrient content of the protein isolates was similar but not identical (Table 1). To prevent weight gain and large macronutrient alterations from the habitual diet, women were encouraged to substitute the protein isolates for protein-containing foods. Subjects were instructed to consume the daily allotment of powder divided in 2 doses to minimize side effects and maximize potential biological effects.
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Subjects were instructed to abstain from soy or isoflavone food products (including foods containing soy protein, soy concentrate, soy hydrolysate but excluding soybean oil and soy lecithin), fermented dairy foods, flaxseed, alcoholic beverages, herbal or isoflavone supplements, and vitamin/mineral supplements containing >100% of the Daily Value for any nutrient. In addition, intake of legumes, sprouts, and nondairy pickled/fermented foods was limited to 1 serving/wk. Subjects recorded their powder and capsule consumption and compliance with study restrictions on individualized calendars. Capsules bottles were collected at the end of each diet period and the number of capsules remaining documented.
Data collection. As described previously (38), blood samples were obtained after a 12- to 14-h fast on d 1 of the first diet period (baseline) and on d 1 of the washout period after each diet period. All samples were drawn between 0600 and 1000 h; samples for an individual subject were obtained at the same time ± 30 min throughout the study. Blood was drawn into tubes containing EDTA, and plasma separated by centrifugation for 10 min at 5°C and 2000 x g. Aprotinin and sodium azide were added to final concentrations of 1 mg/L and 1 g/L, respectively. Plasma aliquots were frozen at –70°C until analysis.
Subjects kept detailed diet records for the 3 d preceding the first diet period (representing baseline) and for the final 3 d of each diet period. Food records were reviewed with each subject by study coordinators immediately upon submission and analyzed using Nutritionist V version 2.1 (First DataBank, Hearst Corporation). Anthropometric data collection included body composition [estimated by skinfolds at baseline (39)] and weight (measured at baseline, and at the midpoint and end of each diet period).
Sample Analysis. Plasma concentrations of TC and TG were determined using commercially available reagents (Cholesterol/HP and Triglyceride/GB; Roche Diagnostics) with an enzymatic colorimetric method previously adapted for microtiter plates (40). Cholesterol standards were prepared as dilutions of a stock solution (Cholesterol Calibrator 200 mg/dL; Sigma Chemical) and TG standards were created from a stock solution of oil with t-octylphenoxypolyethoxyethanol added for solubility (Triton X-100, Sigma Chemical). HDL-C was isolated by selective precipitation of apolipoprotein B–containing lipoproteins with phosphotungstic acid (6.1 mmol/L;Fischer Scientific) and magnesium chloride (20 mmol/L; Fischer Scientific). The resulting supernatant was analyzed for cholesterol content using the plasma cholesterol enzymatic assay. LDL-C was calculated using the Friedewald equation (41): LDL-C = TC – HDL-C – (TG/5). All samples from each subject were assayed in duplicate on the same day with a high and a low in-house plasma control and a standard curve on each plate. Plates were incubated at room temperature for 60 min before being read at 490 nm with an automated microplate reader (HTS-7000 Plus; Perkin Elmer). Interassay variability was 2% and intra-assay variability was <2% for TC, HDL-C, and TG. Plasma and urinary equol were analyzed by a competitive time-resolved fluoroimmunoassay as described previously (42); 8 of 37 subjects demonstrated equol production capacity in both tests (38).
Statistical analysis. Data were analyzed using SAS version 8.2 (SAS Institute). Results are expressed as least-squares mean ± SEM. Significance was set at P < 0.05. Two-sample t tests were employed to compare groups at baseline (normocholesterolemic vs. hypercholesterolemic, equol producers vs. nonproducers) and to compare plasma isoflavone concentrations in the women when they consumed the soy diet and the soy + probiotic diet to evaluate the effect of probiotic. Spearman correlation coefficients were used to determine associations among plasma isoflavones and lipids during the diets. Repeated-measures ANOVA with F-tests based on between-subject variability was used to compare groups within the study. The effects of diet order on lipids, interactions between diet treatments, and differences in plasma lipids and nutrition intake between the diet treatments and between diet treatments and baseline were also evaluated with repeated-measures ANOVA with F-tests based on within-subject variability. Plasma lipids did not change significantly over sequential diet periods; thus, time was not included as an adjusting variable in primary endpoint analyses.
Data from 37 subjects were included in the analyses: 33 completed all diet periods, 3 completed 3 periods, and 1 completed 2 diet periods. There was no interaction between the soy and probiotic treatments. To evaluate the effect of protein isolate treatment, the 4 diets were consolidated into 2 on the basis of the protein isolate consumed (soy diets: soy and soy + probiotic; milk diets: milk and milk + probiotic). For probiotic treatment comparisons, the diets were collapsed into 2 on the basis of the use of probiotic capsules (probiotic diets: soy + probiotic and milk + probiotic; diets without probiotic: soy and milk).
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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There were no significant correlations between individual plasma isoflavones and any lipid endpoints. Differences in plasma TC, LDL-C, HDL-C, and TG between soy and milk diet periods were not correlated with plasma concentrations of any individual isoflavone or total isoflavones. In addition, plasma isoflavone concentrations were not correlated with any lipid endpoints during either soy diet period. Furthermore, the effects of soy consumption on lipids in all subjects, hypercholesterolemic subjects alone, or normocholesterolemic subjects alone, did not differ between equol producers and nonproducers (data not shown).
In addition to differences between soy and milk treatments, changes in lipid variables occurred between baseline and intervention diet periods in the entire group (Fig. 1). Plasma TC (–5.0%; P = 0.003) and LDL-C (–6.1%; P = 0.002) differed between baseline and soy diet periods. HDL-C did not change from baseline; consequently, the TC:HDL-C and the LDL-C:HDL-C ratios were lower during soy diet periods than at baseline (TC:HDL-C, –3.6%; P = 0.02, LDL-C:HDL-C, –4.6%; P = 0.009). In contrast, plasma TC decreased 2.6% (P = 0.03), LDL-C tended to decrease (–2.4%; P = 0.06) and HDL-C did not change from baseline after consumption of the milk diets, resulting in unchanged TC:HDL-C and LDL-C:HDL-C ratios. Plasma TG concentrations did not differ between baseline and either the soy of milk diet periods.
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The majority of recently published soy interventions including mildly or moderately hypercholesterolemic postmenopausal women (3,5,10–13) support the hypocholesterolemic role of soy found in this study, although a few investigations did not report decreases in TC and/or LDL-C after soy consumption (16,17). The effect of soy on HDL-C and TG has been less consistent. Although several studies in postmenopausal women (3,11,13) showed an increase in HDL-C as found in this study, others (10,12,16,17) have not reported a significant change in HDL-C. Similarly, the reported effect of soy on TG varied from a decrease (11,43), consistent with our results, to no effect (10,12,16,17).
Our results suggest that the cholesterol-lowering effect of soy is limited to hypercholesterolemic subjects. When examined separately, normocholesterolemic women in this study showed no response to soy treatment. This observation is in agreement with the majority of results reported for subsets or samples of normocholesterolemic subjects (5,14) but contradicts isolated reports of a hypocholesterolemic effect in normocholesterolemic men (4) and women (8).
When the results of this study were stratified according to equol producer status, equol producers and nonproducers did not differ in baseline lipid values or the effects of soy consumption. Although the small number of equol producers (8 of 37) may have limited the power to detect differences, Meyer et al. (27) did find lipid-lowering effects in a small subset of equol producers (8 of 23 subjects). These inconsistent results may be due to different soy products (soy protein isolate vs. whole bean soy milk), a lower isoflavone dose in this study, or different definitions of an equol producer.
This investigation did not find a beneficial effect of consumption of Lactobacillus acidophilus DDS-1 and Bifidobacterium longum on plasma lipids. The lack of effect may be due to subject characteristics, dose of bacteria, mode of administration, or the species/strain employed. The ability of probiotic bacteria to lower cholesterol appears to depend in part on the initial cholesterol concentration. With the exception of one study (31), baseline TC in studies that demonstrated a hypocholesterolemic effect were >5.68 mmol/L (29,30,32). In contrast, baseline TC in all but one (36) of the studies that did not show a hypocholesterolemic effect (34,35,37) was between 5.35 and 5.68 mmol/L, similar to the baseline TC in this study.
Probiotic bacteria were provided at 109 cfu/d in this study, a dose comparable to the amount provided in studies demonstrating a hypocholesterolemic effect with fermented milk products (29–32). Although it is difficult to ascertain whether the quantity of bacteria present in the gut was sufficient for a hypocholesterolemic effect, analyses of fecal microflora in this study demonstrated an increase in Bifidobacteria after probiotic consumption (personal communication, Dr. Joellen Feirtag, Department of Food Science and Nutrition, University of Minnesota).
This study provided probiotic bacteria via capsules to improve ease of distribution and avoid requiring women to consume study-related foods in addition to the protein powder. However, a dairy medium appears to be the most efficacious route of administering probiotic bacteria. The majority of studies employing fermented milk/yogurt products demonstrated a hypocholesterolemic effect (29–32), compared with the lack of success in placebo-controlled studies using nondairy foods (35) or capsules (37) as a vehicle.
Finally, the ability of bacteria to exert a cholesterol-lowering effect appears to be a species- and strain-specific trait. In placebo-controlled trials using fermented milk products or capsules, some strains (31) of Lactobacillus acidophilus exerted a cholesterol-lowering effect, whereas other strains (34,36,37) were not effective. Similarly, a fermented milk product containing Bifidobacterium longum BL1 lowered total cholesterol (32), whereas a milk product fermented with Bifidobacterium longum 913 and Lactobacillus acidophilus 145 did not alter TC but increased HDL-C (36). Therefore, it is possible that the strains of Bifidobacterium longum and Lactobacillus acidophilus used in this study may not have hypocholesterolemic properties.
The results of this study confirm a favorable effect of soy on plasma lipids regardless of equol producer status, but do not support independent effects of the probiotic bacteria Lactobacillus acidophilus DDS+1 and Bifidobacterium longum. In addition, consumption of these bacteria did not appear to augment the effects of soy consumption. Continued research is warranted to elucidate the quantitative contributions of the active components in soy, to determine the effect of equol producer status, and to establish an optimal dose of soy for maximal effectiveness and adherence.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported by U.S. Army Department of Defense Grant DAMD17–99-1–9297, General Clinical Research Center grant M01-RR00400 from the National Center for Research Resources, and the Minnesota Agricultural Experiment Station R.
4 Abbreviations used: CHD, coronary heart disease; HDL-C, HDL-cholesterol; LDL-C, LDL-cholesterol; TC, total cholesterol; TG, triglyceride.
Manuscript received 15 July 2004. Initial review completed 4 August 2004. Revision accepted 3 September 2004.
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LITERATURE CITED |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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