Randomized, double-blinded, placebo-controlled study of effect of wheat bran fiber and calcium on fecal bile acids in patients with resected adenomatous colon polyps.

BACKGROUND: Ongoing epidemiologic and nutritional studies suggest that colorectal carcinogenesis is consistent with complex interactions between genetic susceptibility and environmental and dietary factors. Among the dietary components found to reduce colon cancer risk are high intakes of dietary fiber and calcium. PURPOSE: We designed and conducted a randomized, double-blinded, placebo-controlled trial involving supplementation of the customary dietary intake with fiber and calcium and measurements of fecal bile acids to examine the potential mechanisms by which added dietary interventions might reduce colorectal cancer risk. METHODS: In a randomized, double-blinded, phase II study, we used a factorial design to measure the effects of dietary wheat bran fiber (2.0 or 13.5 g/day) in the form of cereal and supplemental calcium carbonate (250 or 1500 mg/day elemental calcium) taken as a tablet on fecal bile acid concentrations and excretion rates. Measurements were made at base-line randomization (i.e., after a 3-month placebo run-in period using 2.0 g wheat bran fiber plus 250 mg calcium carbonate) and after 3 and 9 months on treatment in a randomly selected 52-patient subsample of the 95 fully assessable study participants who had a history of colon adenoma resection. Concentrations of fecal bile acids, total, primary (i.e., chenodeoxycholic and cholic), and secondary (i.e., deoxycholic, lithocholic, and ursodeoxycholic), were measured in 72-hour stool samples by gas-liquid chromatography. All P values resulted from two-sided tests. RESULTS: All geometric mean fecal bile acid concentrations and excretion rates were lower at 9 months than at 0 months or 3 months on treatment in the high-dose fiber, high-dose calcium, and high-dose fiber/high-dose calcium treatment groups. The high-dose fiber effect at 9 months of supplementation was statistically significant with respect to virtually all geometric mean fecal bile acid concentrations and excretion rates. For example at 9 months versus 0 months, high-dose fiber supplementation caused a reduction in fecal concentrations of total bile acids (52% reduction; P = .001) and deoxycholic acid (48% reduction; P = .003). High-dose calcium supplementation also had a significant, but lower, effect at 9 months versus 0 months on the geometric mean total bile acid (35% reduction; P = .044) and deoxycholic fecal bile acid (36% reduction; P = .052) concentrations. CONCLUSIONS: High-dose wheat bran fiber and calcium carbonate supplements given for 9 months are associated with statistically significant reductions in both total and secondary fecal bile acid concentrations and excretion rates in patients with resected colon adenomas. This study supports the hypothesis that one of the important ways in which a high intake of wheat bran fiber and calcium may reduce the risk of colorectal neoplasia and cancer is by reduction of the concentrations of fecal bile acids. IMPLICATION: Phase III studies of these agents in the prevention of adenoma recurrence are necessary to confirm this hypothesis and have now been initiated at multiple institutions.

Bile acid metabolism and fiber.

Studies in experimental animals and in humans have shown a definite interaction of dietary fiber with bile acid metabolism. In experimental animals, some types of fiber have been shown to increase bile acid excretion as well as increase pool size and turnover of bile acids. In man, increases in bile acid excretion have been observed but not consistently. Alternations in excretion and biliary bile acid levels indicate an influence of dietary fiber in bile acid metabolism. In vitro experiments have attempted to determine the nature of the fiber-bile acid interaction. Some types of fiber and some components of fiber have been shown to bind bile acids and bile salts in appreciable quantities. The capacity for various types of fiber to bind bile acids or bile salts is quite variable, and a high capacity seems to correspond with a hypocholesteremic effect. A great deal of research is still needed for elucidation of these interactions of fiber and bile acid metabolism and the resultant beneficial effects on cholesterol metabolism and the disease-related abnormalities in cholesterol metabolism.

Increasing amounts of dietary fiber provided by foods normalizes physiologic response of the large bowel without altering calcium balance or fecal steroid excretion.

Nine healthy, young men consumed constant diets to determine selected large-bowel, serum cholesterol and triacylglycerol, and calcium balance responses to 3 amounts of fiber provided by a mixture of fruit, vegetables, and grains. The diets, each consumed for 1 mo, contained 16, 30, and 42 g total fiber/d, of which 2.9, 4.8, and 7.7 g, respectively, was soluble. Mean daily wet and dry stool weights increased with each fiber addition. The first fiber addition increased defecation frequency and decreased fecal pH, bile acid concentration, and neutral steroid concentration; the second addition had no further effect. Mean weight of each defecation and stool moisture did not increase and serum cholesterol and triacylglycerol concentrations, calcium balance, and gastrointestinal transit time did not decrease as fiber intake increased. We conclude that 1) fiber provided by a mixed-food diet increases stool weight as effectively as does wheat or oat bran; 2) even high amounts of dietary fiber do not change transit time or defecation frequency if they are already approximately 1 and 2-3 d, respectively; 3) food patterns consistent with the food pyramid and incorporating legumes and whole grains are necessary to achieve recommended fiber intakes of 20-35 g/d, even if energy intake is > 12.55 MJ (3000 kcal); 4) soluble fiber provided by a mixture of whole foods has no effect on serum cholesterol concentrations or output of fecal bile acids; and 5) mixed-food fiber has little effect on calcium balance when calcium intakes are high (> or = 1.5 g/d).

Long-term effect of soluble-fiber foods on postprandial fat metabolism in dyslipidemic subjects with apo E3 and apo E4 genotypes.

To determine the long-term effect of soluble fiber on postprandial fat metabolism, we studied 33 dyslipidemic subjects, 16 with apolipoprotein (apo) E3/3 (E3) and 17 with E3/4 or E4/4 (E4) genotypes. They ate preweighed low-fat (20% of energy), high-fiber (> 5.7 g/MJ) diets for two 4-mo periods separated by a 2-mo washout period according to a randomized, crossover design. One diet contained foods rich in insoluble fiber and the other foods rich in soluble fiber. On 1 d during the last 2 wk of each diet, subjects ingested a standard, fiber-free, fatty liquid meal containing retinyl palmitate as a marker of intestinally derived lipoproteins. Plasma samples were obtained at hourly intervals for 10 h. Compared with the insoluble-fiber diet, soluble fiber reduced fasting plasma total cholesterol in both E3 (6.6 +/- 2.1%, P = 0.007)and E4 subjects (5.6 +/- 2.1%, P = 0.017). Soluble fiber increased fecal total bile acid output in both E3 (76 +/- 18%, P < 0.001) and E4 subjects (85 +/- 19%, P < 0.001). The incremental area under the chylomicron triacylglycerol response curve was significantly greater after soluble fiber than after insoluble fiber in E3 (3.56 +/- 0.56 compared with 2.87 +/- 0.38 mmol x h/L, respectively, P = 0.046) but not in E4 subjects (5.19 +/- 0.78 compared with 4.92 +/- 0.81 mmol x h/L). Kinetic analysis suggested an increase in retinyl palmitate absorption in E3 subjects after soluble fiber, but no difference in E4 subjects. These results suggest that a long-term increase in dietary soluble fiber has no effect on postprandial fat metabolism in subjects with an apo E3/4 or E4/4 genotype. However, soluble fiber enhances apparent fat absorption in E3 subjects, which could be due to an increased bile acid pool and increased micelle formation.

Dietary fiber and lymphatic absorption of cholesterol in the rat.

The indirect effects of short-term (3-day) feeding of several types of dietary fiber and nonnutritive materials on the subsequent absorption of cholesterol has been investigated in thoracic duct cannulated rats. Absorption was studied at timed intervals over 24 hr after duodenal introduction of a tracer dose of cholesterol at least 20 hr after the last feeding. In animals fed for 3 days with diets containing cholestryamine, bran, or cellulose, cholesterol absorption was significantly less than in control animals maintained on rat chow. Rats fed for 3 days with an alfalfa-containing diet showed large variations in cholesterol absorption that were not significantly different from controls. However, after 5 weeks, rats on the alfalfa diet showed a marked reduction in lymphatic absorption of the tracer sterol. These indirect effects of cholestryamine and fibers on cholesterol absorption were not attributable to a common mechanism; i.e., differences in transit times that were not significant, or dirrect binding of bile acids and cholesterol by the test materials.

Effect of chronic intake of dietary fibers on the ultrastructural topography of rat jejunum and colon: a scanning electron microscopy study.

This report is an attempt to quantitate the observable topographical characteristics of small and large intestine after a specific dietary regimen under well-defined states of lipid absorption and metabolism. Alfalfa, white wheat bran, cellulose, and pectin were fed for 6 wk at a level of 15 g/100 g diet to four groups of rats (12 rats per dietary group). A 5th control group was maintained on Purina Rat Chow. Three animals from each group were blind-coded for morphological assessment. After anesthesia, the jejunum and mid-colon were removed and processed for scanning electron microscopy. Beginning with the mildest mucosal surface changes, the observed order in terms of increasing severity is bran less than cellulose less than pectin less than alfalfa. Our observations suggest that altered rates of cell loss in intestinal tract cytokinetics may be occurring with particular feeding patterns and should be considered as a possible mechanism in the nutritional consequences of dietary fiber intake.

Interactions of alfalfa plant and sprout saponins with cholesterol in vitro and in cholesterol-fed rats.

The in vitro interactions of saponins from alfalfa plant and alfalfa sprouts with cholesterol and the effects of alfalfa plant and sprout and saponin-free alfalfa plant on diet-induced liver cholesterol accumulation, bile acid excretion, and jejunal and colonic morphology were examined. Cholesterol-saponin interactions have been suggested as mechanisms for the observed hypocholesterolemic effects of alfalfa as well as the changes in intestinal morphology. Alfalfa plant saponins bound significant quantities of cholesterol both from ethanol solution and from micellar suspension. Alfalfa sprout saponins interacted with cholesterol to a lesser but significant extent. Sprout saponins also inhibited growth of Trichoderma viride significantly, another measure of saponin-cholesterol interaction. Bile acid adsorption was greatest for alfalfa plant and was not reduced by removal of saponins from the plant material. The ability of alfalfa to reduce liver cholesterol accumulation in cholesterol-fed rats was enhanced by removal of saponins and alfalfa sprouts did not prevent accumulation. Removal of saponins from alfalfa reduced the changes in intestinal morphology previously reported, but interaction with membrane cholesterol did not appear to be the cause of this effect of saponins. Saponin-cholesterol interaction is an important part of the hypocholesterolemic action of alfalfa but interaction of bile acids with other components of alfalfa may be of equal importance.

Fatty acid composition of mature human milk of Egyptian and American women.

Fatty acid composition of mature human milk of rural Egyptian and American women was determined by gas-liquid chromatography. Milk of Egyptian women contained significantly higher percentages of capric, lauric, myristic, linoleic and arachidonic acids, saturated fatty acids (SFA), and polyunsaturated fatty acids (PUFA). Conversely, milk of American women contained higher percentages of stearic and oleic acids, total unsaturated fatty acids, and monounsaturated fatty acids. The PUFA:SFA ratio in Egyptian samples was 0.54 +/- 0.18 compared to 0.47 +/- 0.22 in American samples. Increased percentages of medium-chain SFA in Egyptian milk suggested increased mammary gland lipid synthesis. Analysis of Egyptian diets indicated high-carbohydrate and low-fat intakes may have resulted in limited availability and incorporation of dietary fatty acids into milk triglycerides. Thus, increased percentages of medium-chain SFA observed in Egyptian milk may reflect mammary gland synthesis in an attempt to maintain lipid concentrations in milk.

Cholesterol vehicle in experimental atherosclerosis. Part 16. Effect of peanut oil on pre-established lesions.

Rabbits were fed an atherogenic diet (2% cholesterol and 6% corn oil) for 8 weeks and then divided into groups of equal average serum cholesterol levels. One group was autopsied, and the others were returned to cholesterol-free diets consisting of commercial laboratory ration or ration augmented with 6% corn oil, peanut oil or PGF, a fat designed to resemble peanut oil minus arachidic and behenic acids. The animals were maintained on the diets for 8 more weeks. On all regimens, severity of atherosclerosis was exacerbated. The extent of exacerbation was significantly less in rabbits fed corn oil than in the others. The extent of exacerbation of lesions appears to be a function of the level of unsaturation of the dietary fats.

Experimental atherosclerosis in rabbits fed cholesterol-free diets. Part 7. Interaction of animal or vegetable protein with fiber.

Rabbits were maintained for 10 months on a semipurified, cholesterol-free atherogenic regimen. All diets contained sucrose (40%) and hydrogenated coconut oil (14%). The protein (25%) was either casein or soya protein and the fiber (15%) was either wheat straw, alfalfa, or cellulose. Within either protein group the order for induction of cholesteremia was cellulose=wheat straw greater than alfalfa. For atherogenesis, the effect was cellulose greater than wheat straw greater than alfalfa Soya-wheat straw or soya-cellulose diets were less cholesteremic and atherogenic than their casein counterparts. When alfalfa was the fiber, the two types of protein were almost equivalent. Our results show that casein may be more cholesteremic and atherogenic than soya protein under certain conditions (cellulose or wheat straw as fiber) but the addition of alfalfa to the diet renders the two proteins equivalent.

Experimental atherosclerosis in rabbits fed cholesterol-free diets. Part 9. Beef protein and textured vegetable protein.

Rabbits were fed a semipurified diet containing 40% sucrose, 25% protein, 15% fiber and 14% tallow. The proteins fed were beef (B), textured vegetable protein (TVP) and casein (C). One diet contained beef-TVP (1 : 1) and in another a soy carbohydrate fraction, spent flakes, was added to the diet; it provided 2.2% protein and 10.5% fiber. TVP provided 6.4% soluble carbohydrate and 10.5% fiber. The diets were fed from 8 months. Diets containing beef protein or casein gave significantly higher serum cholesterol levels and atherosclerosis and significantly lower serum HDL-cholesterol than did the other 3 diets. The beef-TVP (1 : 1) diet gave low serum cholesterol (67% below beef) levels and atherosclerosis (47% below beef). This effect is probably due to the protein. The diet containing spent flakes gave low serum cholesterol levels (44% below beef) and atherosclerosis (45% below beef). This effect is attributed to the different fiber. The lowest serum cholesterol levels and least severe atherosclerosis were observed in the rabbits fed TVP.

Stress- and morphine-induced elevations of plasma and tissue cholesterol in mice: reversal by naltrexone.

Our earlier studies indicated that stress-induced facilitation of gallstone formation could be prevented by the opiate antagonist naltrexone. In view of the possible link between gallstone formation and atherosclerosis, the present study examined the possibility that endogenous opioids might also mediate stress-induced hypercholesterolemia. A 28-day immobilization stress schedule was used to induce increases in plasma, aortic and liver cholesterol of mice maintained on a high cholesterol diet. These stress-induced increases in plasma, hepatic and aortic cholesterol were reversed by pretreatment with the opiate antagonist, naltrexone (1 mg/kg). Exposure of mice to morphine (0.1% in the drinking water for 28 days) resulted in elevations of plasma, liver, and aortic cholesterol levels, similar to those observed following immobilization. In contrast, chronic exposure to the peripherally restricted opiate agonist, loperamide (0.1% in the drinking water for 28 days), was ineffective. The antagonism by naltrexone and duplication by morphine but not loperamide suggest that stress-induced hypercholesterolemia may require the activation of central endogenous opioid systems.

Dietary fiber and colorectal cancer: what is appropriate advice?

Two recent studies question the role of dietary fiber in the prevention of colorectal cancer. However, the duration of dietary intervention, dose of fiber, and the complexity of polyp formation and transformation to carcinomas make interpretation of such studies difficult. Multiple rationales exist for promoting the consumption of high-fiber, low-fat, fruit- and vegetable-rich diets.

Cardiovascular disease and fiber: is insulin resistance the missing link?

Multiple mechanisms are likely for any effect of fiber on cardiovascular disease risk. One component that is described is the hypocholesterolemic activity of soluble fibers as they bind bile acids. New epidemiologic evidence indicates that fiber's modulation of insulin secretion and resistance deserves additional attention.

Combined effect of vegetable protein (soy) and soluble fiber added to a standard cholesterol-lowering diet.

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.

Effect of a very-high-fiber vegetable, fruit, and nut diet on serum lipids and colonic function.

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.

Bile acid analysis: methods and problems.

What is the ideal method for analysis of faecal bile acids? Selection of an ideal system for a specific situation requires consideration of several factors, eg the information sought, availability of equipment and time constraints. Each laboratory will select procedures based on these constraints. A situation in which a large number of subjects are to be screened for total bile acid concentration might suggest use of single-day collections, lyophilization prior to homogenization, extraction using the Evrard and Janssen method and quantification by 3 alpha-hydroxysteroid dehydrogenase. However if the ratio of glycine to taurine conjugates and the daily excretion were of interest, separation of subclasses with Lipidex 1000 followed by both gas chromatography (of free bile acids) and HPLC (of conjugated bile acids) would be selected. There is not a best method for all situations. What does the future hold for improving this methodology in order to improve our ability to use faecal bile acid analysis clinically? The biggest problem facing the application of faecal bile acid analysis to clinical situations in the lack of ability to devise a rapid method (24-48 h) which retains the accuracy of current methods. One promising development is the potential application of immunological methods to faecal bile acids. These detection methods have been applied primarily to serum to date but if extraction and/or purification methods could be coupled with this method of quantification, a clinically acceptable method may result.(ABSTRACT TRUNCATED AT 250 WORDS)

Morphine-induced alterations in plasma and tissue cholesterol levels.

In rats fed a cholesterol-cholic acid supplemented diet, implantation of a 75 mg morphine pellet elevated total plasma cholesterol, raised low density lipoprotein (LDL) plus very low density lipoprotein (VLDL) cholesterol, and lowered high density lipoprotein (HDL) cholesterol levels. The resultant increase of the atherogenic index was accompanied by enhanced aortic cholesterol deposition. These alterations were prevented by daily administration of naltrexone (1.0 mg/kg, sc), and were not associated with hyperphagic or hepatotoxic actions of morphine. An increase in total plasma cholesterol and in LDL plus VLDL cholesterol was also observed in morphine pelleted rats maintained on a normal diet. The possible implications of opiate-induced hypercholesterolemia are discussed.

Fiber, hypercholesteremia, and atherosclerosis.

Epidemiological data suggest that populations subsisting on high fiber diets are free of a number of the diseases of Western civilization, among them coronary heart disease. Studies in animals and man show that each type of fiber exerts its own specific influence. Thus, in man bran has no effect on serum lipids, but pectin lowers cholesterol levels. In animals fed atherogenic diets, alfalfa and pectin exert some measure of protection, but cellulose does not. To fully understand the mode of action of dietary fiber, it is necessary to ascertain the mechanism(s) of action of each chemical component of that fiber.

Effect of type of diet and feeding status on modulation of hepatic HMG-CoA reductase in rats.

The effect of diet type and feeding status on hepatic HMG-CoA reductase (HMGR) [mevalonate: NADP+ oxidoreductase (acylating CoA); EC 1.1.1.34] was studied in rats. Animals fed a ground, commercial, stock diet exhibited higher expressed and total activities of HMGR in the fed state than animals fed a semi-purified diet. The differences did not appear in meal-trained animals when measured before the onset of the meal after a 22-hr fast. When expressed activity was taken as a per cent of total activity, fed animals from both diet groups used about 10% of their available activity. When animals on commercial diets were fasted, 20% of the activity was expressed. Fasted animals on the semi-purified diet also increased the per cent of expressed reductase activity, but this increase was not as great (13.3%). These data suggest that, in the rat, regulation of cholesterol synthesis in response to decreased total HMGR during fasting and increased levels after a meal results from alterations in the percentage of enzyme which is expressed. The semi-purified diet used here resulted in consistently lower levels of HMG-CoA reductase activity than the commercial diet regardless of feeding pattern.