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The value of soy protein as part of the cholesterol-lowering diet has been questioned by recent studies. The apparent lack of effect may relate to the absence of dietary factors that increase colonic fermentation and potentiate the cholesterol-lowering effect of soy. Therefore, unabsorbable carbohydrates (prebiotics) were added to the diet with the aim of increasing colonic fermentation and so potentially increasing the hypocholesterolemic effect of soy. Twenty-three hyperlipidemic adults (11 male, 12 female; 58 +/- 7 years old; low-density lipoprotein cholesterol [LDL-C], 4.18 +/- 0.58 mmol/L) completed three 4-week diet intervention phases-a low-fat dairy diet and 10 g/d prebiotic (oligofructose-enriched inulin, a fermentable carbohydrate), a soy food-containing diet (30 g/d soy protein, 61 mg/d isoflavones from soy foods) and 10 g/d placebo (maltodextrin), and a soy food-containing diet with 10 g/d prebiotic--in a randomized controlled crossover study. Intake of soy plus prebiotic resulted in greater reductions in LDL-C (-0.18 +/- 0.07 mmol/L, P = .042) and in ratio of LDL-C to high-density lipoprotein cholesterol (-0.28 +/- 0.11, P = .041) compared with prebiotic. In addition, high-density lipoprotein cholesterol was significantly increased on soy plus prebiotic compared with prebiotic (0.06 +/- 0.02 mmol/L, P = .029). Differences in bifidobacteria, total anaerobes, aerobes, and breath hydrogen did not reach significance. Soy foods in conjunction with a prebiotic resulted in significant improvements in the lipid profile, not seen when either prebiotic or soy alone was taken. Coingestion of a prebiotic may potentiate the effectiveness of soy foods as part of the dietary strategy to lower serum cholesterol., (Copyright 2010 Elsevier Inc. All rights reserved.)

Effective diets reduce blood lipids and oxidative damage, both of which have been linked to the complications of diabetes and coronary heart disease. Our objective was to assess the effect of adding strawberries, as a source of antioxidants, to improve the antioxidant effect of a cholesterol-lowering diet (dietary portfolio). To this end, 28 hyperlipidemic subjects who had followed the dietary portfolio consisting of soy, viscous fiber, plant sterol, and nuts for a mean of 2.5 years were randomized to receive supplements of strawberries (454 g/d, 112 kcal) or additional oat bran bread (65 g/d, 112 kcal, approximately 2 g beta-glucan) (control) in a randomized 1-month crossover study with a 2-week washout. Strawberry supplementation resulted in a greater reduction in oxidative damage to low-density lipoprotein (LDL) measured as thiobarbituric acid-reactive substances in the LDL fraction (P = .014). At the end of the strawberry period, reductions in LDL cholesterol and in the ratio of total to high-density lipoprotein cholesterol were maintained close to 1-year values at -13.4% +/- 2.1% and -15.2% +/- 1.7%, respectively (P < .001), and were similar to the post-oat bran bread values. Strawberries also improved the palatability of the diet. We conclude that strawberry supplementation reduced oxidative damage to LDL while maintaining reductions in blood lipids and enhancing diet palatability. Added fruit may improve the overall utility of diets designed to lower coronary heart disease risk.

The National Cholesterol Education Program Adult Treatment Panel III guidelines advocate effective combinations of cholesterol-lowering dietary components. This approach (dietary portfolio) produces large reductions in serum cholesterol, but the contribution of individual components remains to be established. We therefore assessed the effect of eliminating one out of the 4 dietary portfolio components. Plant sterols were selected because at 2 g/d, they have been reported to reduce low-density lipoprotein cholesterol (LDL-C) by 9% to 14%. Forty-two hyperlipidemic subjects were prescribed diets high in soy protein (22.5 g/1000 kcal), viscous fibers (10 g/1000 kcal), and almonds (23 g/1000 kcal) for 80 weeks. Subjects were instructed to take these together with plant sterols (1.0 g/1000 kcal) except between weeks 52 and 62. While taking the full dietary portfolio, including plant sterols, mean LDL-C reduction from baseline was 15.4% +/- 1.6% (P < .001). After sterol elimination, mean LDL-C reduction was 9.0% +/- 1.5% (P < .001). Comparable LDL-C reductions were also seen for the 18 subjects with a complete data set: on plant sterols, 16.7% +/- 3.1% (P < .001) and off plant sterols, 10.3% +/- 2.6% (P < .001), resulting in a 6.3% +/- 2.0% (P = .005) difference attributable to plant sterols. Compliance in this group of 18 was 67.0% +/- 5.9% for plant sterols and 61.9% +/- 4.8% for the other components. In combination with other cholesterol-lowering foods and against the background of a low-saturated fat diet, plant sterols contributed over one third of the LDL-C reduction seen with the dietary portfolio after 1 year of following dietary advice.

Antibiotics were once proposed as hypercholesterolemic agents although the mechanism is unclear, despite broad implications, including providing an alternative approach to cholesterol reduction, with potential relevance for current trials of antibiotics to reduce cardiovascular disease, and possible confounding of routine diagnostic cholesterol measurements. The effect on serum lipids of antibiotics against aerobes and anaerobes, together with possible mechanisms, was therefore explored. Twenty-two men and women took antibiotics for 10 days (either ciprofloxacin for 13 subjects or metronidazole for 10 subjects), with 10 days control in random order separated by 2-week washout periods. Subjects maintained low-fat diets throughout the study. Blood samples and blood pressure were obtained on days 0 and 10 of each phase with 3-day fecal collections and 12-hour breath gas collections at the end of each phase. The results indicated that metronidazole markedly reduced low-density lipoprotein cholesterol (-14.0 +/- 4.0%, P = .006), oxidized low-density lipoprotein (-23.0 +/- 5.1%, P = .002), and the apolipoprotein B/A-I ratio (-18.0 +/- 2.8%, P < .001), whereas the reduction with ciprofloxacin was less pronounced (apolipoprotein B/A-I, -5.0 +/- 1.8%, P = .017). Neither antibiotic altered C-reactive protein or blood pressure. The low-density lipoprotein cholesterol reduction related to an increase in bifidobacteria (r = -0.46, P = .029), but not to markers of colonic fermentation. We conclude that antibiotics can reduce serum lipids acutely. These effects may confound diagnostic measurements but indicate possible links between colonic microflora and blood lipids and the need to study ways of altering colonic microflora by nonantibiotic means as a potential therapeutic option.

Reductions in low-density lipoprotein-cholesterol (LDL-C) result from diets containing almonds, or diets that are either low in saturated fat or high in viscous fibers, soy proteins, or plant sterols. We have therefore combined all of these interventions in a single diet (portfolio diet) to determine whether cholesterol reductions could be achieved of similar magnitude to those reported in recent statin trials which reduced cardiovascular events. Twenty-five hyperlipidemic subjects consumed either a portfolio diet (n=13), very low in saturated fat and high in plant sterols (1.2 g/1,000 kcal), soy protein (16.2 g/1,000 kcal), viscous fibers (8.3 g/1,000 kcal), and almonds (16.6 g/1,000 kcal), or a low-saturated fat diet (n=12) based on whole-wheat cereals and low-fat dairy foods. Fasting blood, blood pressure, and body weight were obtained at weeks 0, 2, and 4 of each phase. LDL-C was reduced by 12.1% +/- 2.4% (P<.001) on the low-fat diet and by 35.0% +/- 3.1% (P<.001) on the portfolio diet, which also reduced the ratio of LDL-C to high-density lipoprotein-cholesterol (HDL-C) significantly (30.0% +/- 3.5%; P<.001). The reductions in LDL-C and the LDL:HDL-C ratio were both significantly lower on the portfolio diet than on the control diet (P<.001 and P<.001, respectively). Mean weight loss was similar on test and control diets (1.0 kg and 0.9 kg, respectively). No difference was seen in blood pressure, HDL-C, serum triglycerides, lipoprotein(a) [Lp(a)], or homocysteine concentrations between diets. Combining a number of foods and food components in a single dietary portfolio may lower LDL-C similarly to statins and so increase the potential effectiveness of dietary therapy.

Plant sterols, soy proteins, and viscous fibers are advised for cholesterol reduction but their combined effect has never been tested. We therefore assessed their combined effect on blood lipids in hyperlipidemic subjects who were already consuming a low-saturated fat, low-cholesterol diet before starting the study. The test (combination) diet was 1 month in duration and was very low in saturated fat and high in plant sterols (1 g/1,000 kcal), soy protein (23 g/1,000 kcal), and viscous fibers (9 g/1,000 kcal) obtained from foods available in supermarkets and health food stores. One subject also completed 2 further diet periods: a low-fat control diet and a control diet plus 20 mg/d lovastatin. Fasting blood lipids, blood pressure, and body weight were measured prior to and at weekly intervals during the study. The combination diet was rated as acceptable and very filling. The diet reduced low-density lipoprotein (LDL)-cholesterol by 29.0% +/- 2.7% (P <.001) and the ratio of LDL-cholesterol to high-density lipoprotein (HDL)-cholesterol by 26.5% +/- 3.4% (P <.001). Near maximal reductions were seen by week 2. In the subject who took Mevacor and control diets each for 4 weeks, the reduction in LDL:HDL-cholesterol on Mevacor was similar to the combination diet. We conclude that acceptable diets of foods from supermarkets and health food stores that contain recognized cholesterol-lowering dietary components in combination (a dietary portfolio) may be as effective as the starting dose of older first-line drugs in managing hypercholesterolemia., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

This study sought to determine effects of high- and low-isoflavone soy protein foods on acute-phase proteins and proinflammatory cytokines and whether isoflavone phytoestrogens might act as estrogens, which enhance the immune response. Forty-one hypercholesterolemic men and postmenopausal women underwent three 1-month diets consisting of a low-fat dairy food control phase and high- and low-isoflavone soy food test phases (50 g/d and 52g/d soy protein, respectively, and 73 mg/d and 10 mg/d isoflavone, respectively). Diets were low in saturated fat (<5% of energy) and cholesterol (<50 mg/d). Fasting blood analytes and blood pressure were measured at the start and end of each phase. For the entire group of subjects, no treatment differences were observed for acute-phase proteins or proinflammatory cytokines. However, a significant interaction was noted between diet and sex. Assessing the results of men and women separately, women showed significantly higher interleukin-6 (IL-6) values after the high-isoflavone soy diet (P =.013) compared to control values. For women, the difference between the high- and low-isoflavone IL-6 values was significant using the unadjusted data (P =.048) but not after adjustment. No significant effects were seen for men or women in C-reactive protein (CRP), serum amyloid A (SAA), or tumor necrosis factor-alpha (TNF-alpha). Thus, high levels of isoflavone intake appear to increase serum concentrations of IL-6 in women. This finding may indicate an estrogenic effect of soy isoflavones in enhancing the immune response and provide a possible explanation through enhanced immune surveillance for lower incidence of certain cancers in soy-eating parts of the world., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

We tested the effects of feeding a diet very high in fiber from fruit and vegetables. The levels fed were those, which had originally inspired the dietary fiber hypothesis related to colon cancer and heart disease prevention and also may have been eaten early in human evolution. Ten healthy volunteers each took 3 metabolic diets of 2 weeks duration. The diets were: high-vegetable, fruit, and nut (very-high-fiber, 55 g/1,000 kcal); starch-based containing cereals and legumes (early agricultural diet); or low-fat (contemporary therapeutic diet). All diets were intended to be weight-maintaining (mean intake, 2,577 kcal/d). Compared with the starch-based and low-fat diets, the high-fiber vegetable diet resulted in the largest reduction in low-density lipoprotein (LDL) cholesterol (33% +/- 4%, P <.001) and the greatest fecal bile acid output (1.13 +/- 0.30 g/d, P =.002), fecal bulk (906 +/- 130 g/d, P <.001), and fecal short-chain fatty acid outputs (78 +/- 13 mmol/d, P <.001). Nevertheless, due to the increase in fecal bulk, the actual concentrations of fecal bile acids were lowest on the vegetable diet (1.2 mg/g wet weight, P =.002). Maximum lipid reductions occurred within 1 week. Urinary mevalonic acid excretion increased (P =.036) on the high-vegetable diet reflecting large fecal steroid losses. We conclude that very high-vegetable fiber intakes reduce risk factors for cardiovascular disease and possibly colon cancer. Vegetable and fruit fibers therefore warrant further detailed investigation., (Copyright 2001 by W.B. Saunders Company)

Consumption of soy protein may reduce the risk of cardiovascular disease both through reduction in serum lipids and by the antioxidant properties of protein-associated soy isoflavones. However, the effect that processing required for the manufacture of breakfast cereals may have on the lipid lowering and antioxidant activities of soy has not been studied. We have therefore assessed the health benefits of soy incorporation into breakfast cereals. Twenty-five hyperlipidemic men and women took soy (providing 36 g/d soy protein and 168 mg/d isoflavones) and control breakfast cereals, each for 3 weeks in a randomized crossover study with a 2-week washout period between treatments. Fasting blood samples were obtained pretreatment and at weeks 2 and 3 of each treatment. No significant difference was seen in serum lipids between treatments at week 3 apart from a 3.8% +/- 1.5% higher apolipoprotein A-1 level on control versus soy (P = .021). However, oxidized low-density lipoprotein (LDL) was reduced on the test compared with the control both as total dienes in LDL and as the ratio of conjugated dienes to cholesterol in the LDL fraction by 9.2% +/- 4.3% (P = .042) and 8.7% +/- 4.2% (P = .050), respectively. High isoflavone intakes in soy breakfast cereals may decrease the risk of cardiovascular disease by reducing oxidized LDL, while having no significant effect on the absolute concentration of LDL cholesterol.

Plant-derived estrogen analogs (phytoestrogens) may confer significant health advantages including cholesterol reduction, antioxidant activity, and possibly a reduced cancer risk. However, the concern has also been raised that phytoestrogens may be endocrine disrupters and major health hazards. We therefore assessed the effects of soy foods as a rich source of isoflavonoid phytoestrogens on LDL oxidation and sex hormone receptor activity. Thirty-one hyperlipidemic subjects underwent two 1-month low-fat metabolic diets in a randomized crossover study. The major differences between the test and control diets were an increase in soy protein foods (33 g/d soy protein) providing 86 mg isoflavones/2,000 kcal/d and a doubling of the soluble fiber intake. Fasting blood samples were obtained at the start and at weeks 2 and 4, with 24-hour urine collections at the end of each phase. Soy foods increased urinary isoflavone excretion on the test diet versus the control (3.8+/-0.7 v 0.0+/-0.0 mg/d, P < .001). The test diet decreased both oxidized LDL measured as conjugated dienes in the LDL fraction (56+/-3 v 63+/-3 micromol/L, P < .001) and the ratio of conjugated dienes to LDL cholesterol (15.0+/-1.0 v 15.7+/-0.9, P = .032), even in subjects already using vitamin E supplements (400 to 800 mg/d). No significant difference was detected in ex vivo sex hormone activity between urine samples from the test and control periods. In conclusion, consumption of high-isoflavone foods was associated with reduced levels of circulating oxidized LDL even in subjects taking vitamin E, with no evidence of increased urinary estrogenic activity. Soy consumption may reduce cardiovascular disease risk without increasing the risk for hormone-dependent cancers.

An increased intake of soluble fiber and soy protein may improve the blood lipid profile. To assess any additional benefit on serum lipids of providing soy protein and soluble-fiber foods to hyperlipidemic subjects already consuming low-fat, low-cholesterol therapeutic diets, 20 hyperlipidemic men and postmenopausal women completed 8-week test and control dietary treatments in a randomized crossover design as part of an ad libitum National Cholesterol Education Program (NCEP) step 2 therapeutic diet (<7% saturated fat and <200 mg/d cholesterol). During the test phase, foods high in soy, other vegetable proteins, and soluble fiber were provided. During the control phase, low-fat dairy and low-soluble-fiber foods were provided. Fasting blood lipid and apolipoprotein levels were measured at 4 and 8 weeks of each phase. On the test diet, 12 +/- 2 g/d soy protein was selected from the foods chosen. Direct comparison of test and control treatments indicated an elevated high-density lipoprotein (HDL) cholesterol concentration on the test diet (6.4% +/- 2.4%, P = .013) and a significantly reduced total to HDL cholesterol ratio (-5.9% +/- 2.3%, P = .020). The proportion of conjugated dienes in the low-density lipoprotein (LDL) cholesterol fraction was significantly reduced (8.5% +/- 3.3%, P = .020) as a marker of oxidized LDL. A combination of acceptable amounts of soy, vegetable protein, and soluble-fiber foods as part of a conventional low-fat, low-cholesterol therapeutic diet is effective in further reducing serum lipid risk factors for cardiovascular disease.

Dietary treatment of hyperlipidemia focuses on reducing saturated fat and dietary cholesterol. Other aspects of diet are not emphasized at present, despite growing evidence that a number of plant components decrease serum cholesterol. We therefore determined whether a combination of two plant components, vegetable protein and soluble fiber, further reduce serum lipids when incorporated into the currently advocated low-saturated-fat diet. Thirty-one hyperlipidemic men and women ate two 1-month low-fat (<7% of total energy from saturated fat), low-cholesterol (<80 mg cholesterol/d) metabolic diets in a randomized crossover study. The major differences between test and control diets were an increased amount of vegetable protein (93% v 23% of total protein), of which 33 g/d was soy, and a doubling of soluble fiber. Fasting blood samples were obtained at the start and end of each phase. On the last 3 days of each phase, fecal collections were obtained. Compared with the low-fat control diet, the test diet decreased total cholesterol (6.2% +/- 1.2%, P < .001), low-density lipoprotein (LDL) cholesterol (6.7% +/- 1.7%, P < .001), apolipoprotein B (8.2% +/- 1.2%, P < .001), and the ratios of LDL to high-density lipoprotein (HDL) cholesterol (6.3% +/- 2.0%, P = .004) and apolipoprotein B to A-I (5.4% +/- 1.5%, P = .001). A combination of vegetable protein and soluble fiber significantly improved the lipid-lowering effect of a low-saturated-fat diet. The results support expanding the current dietary advice to include increased vegetable protein and soluble fiber intake so that the gap in effectiveness between a good diet and drug therapy is reduced.

Antibiotics are being proposed for the treatment of cardiovascular disease. In the past, antibiotics were advocated for the control of hypercholesterolemia. We have therefore investigated the relation between colonic bacterial activity and serum lipids. In a four-phase randomized crossover study, we fed a different starch supplement during each 2-week phase to 24 healthy subjects. In two phases, supplements containing resistant starches were fed that reach the colon and are largely fermented by colonic bacteria. Fecal starch recovery therefore reflects the metabolic activity of colonic microflora. The control treatments were conventional starches. Blood lipid levels were obtained at the start and 4-day fecal collections at the end of each phase. Resistant starch supplements increased fecal starch excretion by 3.8 +/- 1.2 g/d more than conventional starches (P = .006). Mean starch excretion was related positively to pretreatment serum high-density lipoprotein (HDL) cholesterol (r = -.57, P = .003) and negatively to low-density lipoprotein (LDL) cholesterol (r = -.57, P = .004), apolipoprotein B:AI (r = -.56, P = .005), and fecal output of fusobacteria (r = -.73, P = .003) and bacteroides (r = -.72, P = .003). The ratio of fusobacteria to total anaerobes was also related to pretreatment LDL cholesterol (r = .56, P = .037). Differences in starch excretion between healthy subjects, as a measure of bacterial activity, accounted for 32% of the variation in pretreatment LDL cholesterol. The activity of colonic microflora therefore appears to influence serum lipid levels. Alterations of bacterial number and activity may provide an additional strategy to control serum lipid risk factors for cardiovascular disease.

We assessed the effect of a diet high in leafy and green vegetables, fruit, and nuts on serum lipid risk factors for cardiovascular disease. Ten healthy volunteers (seven men and three women aged 33 +/- 4 years [mean +/- SEM]; body mass index, 23 +/- 1 kg/m2) consumed their habitual diet (control diet, 29% +/- 2% fat calories) and a diet consisting largely of leafy and other low-calorie vegetables, fruit, and nuts (vegetable diet, 25% +/- 3% fat calories) for two 2-week periods in a randomized crossover design. After 2 weeks on the vegetable diet, lipid risk factors for cardiovascular disease were significantly reduced by comparison with the control diet (low-density lipoprotein [LDL] cholesterol, 33% +/- 4%, P < .001; ratio of total to high-density lipoprotein [HDL] cholesterol, 21% +/- 4%, P < .001; apolipoprotein [apo] B:A-I, 23% +/- 2%, P < .001; and lipoprotein (a) [Lp(a)], 24% +/- 9%, P = .031). The reduction in apo B was related to increased intakes of soluble fiber (r = .84, P = .003) and vegetable protein (r = -.65, P = .041). On the vegetable compared with the control diet, the reduction in total serum cholesterol was 34% to 49% greater than would be predicted by differences in dietary fat and cholesterol. A diet consisting largely of low-calorie vegetables and fruit and nuts markedly reduced lipid risk factors for cardiovascular disease. Several aspects of such diets, which may have been consumed early in human evolution, have implications for cardiovascular disease prevention.