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Metabolic Effects of Dietary Fiber DAVID KRITCHEVSKY, PhD Philadelphia DIETARY FIBER has been defined as plant material that is not digested by enzymes of the human gastrointestinal tract. The plant materials that we call fiber are the structural components of plant cell walls. The amount and type of this material vary widely over the plant kingdom but can be broadly subdivided into polysaccharides (cellulose and noncellulosic polysaccharides) and lignins. These materials differ from one plant to another and may vary in the same plant, being affected by age and environment. The cellulosic materials form cellules and fibrils; the gums and mucilages form the cement substance of cell walls and seeds, and the woody material is a
complex, cross-linked phenylpropane polymer, lignin. Cellulose is a linear homoglycan composed of a chain of glucose residues in a 1-4- , linkage. The noncellulose types of polysaccharide are branched chain materials containing a number of different sugars. Hemicellulose has a main chain containing xylose, mannose, galactose and glucose with side chains of arabinose, galactose and glucuronic acid. Galacturonic acid represents the main chain of pectic substances whose side chains contain rhamnose, arabinose, fucose and xylose. The principal chains of gums and mucilages are more complex, the former containing galactose, galacturonic acid-rhamnose and glucuronic acidmannose and the latter galacturonic acid-rhamnose, arabinose-xylose, glucose-mannose and galactose-mannose. The side chains of mucilages and of algal polysaccharides contain only galactose, whereas side chains of gums contain xylose and fucose as well as galactose. The main chains Refer to: Kritchevsky D: Metabolic effects of dietary fiber (Clinical Nutrition Symposium). West J Med 130:123-127, Feb 1979 From the Wistar Institute of Anatomy and Biology, Philadelphia. Supported, in part, by grants (HL03299 and HL05209) and a Research Career Award (HL0734) from The National Institutes of Health. Reprint requests to: David Kritchevsky, PhD, Wistar Institute of Anatomy and Biology, 36th Street at Spruce, Philadelphia, PA 19104.
of algal polysaccharides contain mannose, xylose, guluronic acid and glucose. Lignin is a polymer of sinapyl, coniferyl and coumaryl alcohols. Cell walls also contain proteins, phytic acid, silica, tannins, steroid glycosides and cutins, which are polymeric esters of fatty acids. Until recently, the only measure of fiber content was a 150-year-old method involving treatment with acid and alkali. The residues left after these treatments were grouped together as crude fiber. This fraction represented only cellulose and lignin and did not account for any of the variety of other substances. At this writing most published data for fiber content of food are given as crude fiber. Van Soest' has developed a system in which aliquots of material are treated with a neutral solution of detergent or an acidic detergent solution. The former treatment yields total cell wall constituents and the latter cellulose and lignin. Treatment with strong (72 percent) sulfuric acid at room temperature yields lignin only. The system permits calculation of cellulose content by difference. Southgate2,3 has developed a complex method, involving enzymatic hydrolysis plus other hydrolysis and extraction procedures, which yields much more comprehensive information. Southgate4 has analyzed a number of foodstuffs. His analysis shows the wide gap between total dietary fiber as determined by Southgate and crude fiber as determined by the older standardized method and quoted in the United States Department of Agriculture's Handbook 8,5 which is virtually (and deservedly) the bible of nutritionists. To give a few examples: the total dietary fiber content (grams per 100 grams) of broccoli, peaches, peanuts and cocoa powder is 4.1, 2.3, 9.3 and 43.3, respectively; their crude fiber content is 1.5, 0.6, 2.4 and 4.3. With introduction of the Van Soest and Southgate methods more accurate information concerning the true composition of dietary fiber is forthcoming. Such inforTHE WESTERN JOURNAL OF MEDICINE
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mation is necessary to understand better the physiological effects of fiber. The effect of fiber on laxation was known to Hippocrates (quoted in reference 6). Cowgill and co-workers78 and Williams and Olmstead9 described the laxative effects of bran and other foods such as cabbage and cereals. Williams and Olmstead9 were not able to correlate laxative effects with composition. Burkitt'0"'1 noted rapid transit time and increased stool weight in African children on a high residue diet compared with English school boys. Not all fiber is effective in this respect; agar and psyllium seed colloid are the bases of commercial laxatives. Wheat bran is particularly good for decreasing transit time and increasing frequency of defecation and stool bulk. Addition of 16 grams of bran to the daily diet can double fecal weight.'2 On the other hand, pectin'3 and lignin'4 have little effect on transit time or stool bulk. Fiber is resistant to enzymes of the alimentary tract but can be digested by bacterial enzymes. This breakdown occurs in the colon and 30 percent to 80 percent of cellulose and 55 percent to 85 percent of hemicellulose can be lost in this way.'5-'8 About 90 percent of pectin is digested'9'20 but only 30 percent or less of wheat bran is,2' and practically no lignin is digested.'6,'8 Fiber degradation produces hydrogen, -carbon dioxide, water, methane and C2-C4 fatty acids. These products can also act to increase laxation.22
Diverticular Disease Based on their observatiolr of the large difference in incidence of diverticulosis in Western countries and African countries, Painter and Burkitt23 postulated that a low fiber diet resulted in high colonic pressure and the appearance of diverticulae. In the past, a low residue diet was recommended in diverticular disease,24'25 but today the reverse is being suggested. Bran has been found to be very effective in treatment of this condition.26-29 Painter and co-workers27 fed 3 to 45 grams of bran daily (mean 13 grams) to patients with diverticular disease and found relief of symptoms in 83 percent. There is little information on the treatment of diverticular disease by using fiber other than bran. Fiber is also being used in treatment of irritable bowel syndrome.30
Cancer of the Colon There are two currently popular hypotheses regarding diet and the cause of cancer of the
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colon. Burkitt3'-33 has pointed out that cancer of the colon is rare in populations subsisting on high residue diets. He has postulated that the lack of fiber in the Western diet permits greater exposure of the lining of the colon to carcinogens that may be present in feces and the slower transit time allows more time for bacterial transformation of dietary or secretory material to possible carcinogenic agents. Drasar and Irving34'35 have found little correlation between dietary fiber and cancer of the colon but found high correlation of cancer of the colon with ingestion of animal fat and animal protein. There is a parallel between standard of living, Westernization of the diet and incidence of cancer of the colon.36-38 It might be of interest to digress for a moment and discuss other aspects of diet and cancer of the colon. Stavraky39 has pointed out that the intranational differences in cancer of the colon found in countries such as the United States, Scotland and Canada lend no support to a theory involving specific dietary components. Although the consumption of beef in the United States doubled between 1945 and 1970, the death rate from cancer of the colon was unchanged.40 Within the United States, mortality from cancer of the bowel is highest in the Northeast and lowest in the Southeast.4' The diet in these two regions is not remarkably different. Populations such as Seventh Day Adventists who are largely vegetarian and who eschew pork have a low incidence of colon cancer,42 but so do Mormons43 who eat meat regularly. Clearly there is still much to be elucidated here. Experiments with animals have shown that some types of fiber can protect against induced colon cancer. More than 20 years ago it was found that rats fed stock diets exhibited fewer 2-acetylaminofluorene-induced tumors than did rats fed semipurified diets.44'45 Wilson and associates46 and Fleiszer and co-workers47 reported that dietary bran protected against tumors induced by dimethylhydrazine. Watanabe and coworketsM8 tested several dietary fibers for their effect on appearance of tumors of the colon caused by injection of dimethylhydrazine or intrarectal instillation of azoxymethane. Bran had little effect, pectin offered some protection and alfalfa enhanced tumor incidence. Alfalfa has been found to denude the colonic epithelium49 which may explain the findings. Barbolt and Abraham50 have found bran to protect rats from
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C mmdNwfddton M~~~~~ colonic tumors caused by feeding of dimethylhydrazine. The data suggest that the effects of fiber in experimental colon carcinogenesis vary depending on the type of fiber used and the mode of administration of the carcinogen. Insofar as the question of diet and cancer of the colon in man is concerned, it would appear as if a few pieces of the jigsaw puzzle are still missing.
Gallstones Dam5- 52 has reviewed factors that affect gallstone formation. Gallstones can be induced in hamsters by feeding a diet containing 74 percent glucose, 20 percent casein, salt mix, vitamin mix and choline chloride. The diet need not contain either fat or cholesterol. Replacement of the glucose with rice starch reduces gallstone formation almost to zero. Bergman and van der Linden53 fed this type of diet to lhamsters and augmented it with 5 percent pectin, lignin or psyllium colloid. None of the hamsters fed lignin or psyllium were found to have gallstones, 29 percent of those fed pectin had gallstones, whereas 58 percent of the controls had gallstones. Gallstones formed in mice fed a lithogenic diet were dissolved when the mice were returned to laboratory ration.54 Rabbits fed a semipurified diet containing 30 percent casein and 15 percent beef tallow exhibited gallstones (3/5) but when 5 percent pectin was added to the diet no gallstones were observed.55 It has been suggested that a diminished bile acid pool plays a role in cholelithiasis in man.56-58 Nigerians ingesting a high fiber diet have increased bile acid pool size and increased bile acid synthesis rates compared with populations eating a "Western" diet.59 Pomare, Heaton and associates60 showed that when patients with gallstones were fed wheat bran (an average of 57 grams per day) their chenodeoxycholic acid pool increased significantly, the deoxycholic acid pool fell and the cholesterol saturation of their bile diminished. The mechanism of action of fiber in affecting cholelithiasis is unknown, but it may be related to the increases in bile acid pool size that have been observed in rats6' and monkeys.62
Lipid Metabolism The influence of dietary fiber on lipid metabolism and atherosclerosis has been the subject of several recent reviews.6365 A review of the literature relating to the effect
of saturated fat on atherosclerosis in rabbits showed that the fat was atherogenic only when fed as part of a semipurified diet.66 It was further shown67'68 that addition of coconut oil to the fatfree residue of commercial rabbit ration was not atherogenic. Moore69 added wheat straw to a semipurified, cholesterol-free atherogenic diet and showed that serum lipid levels and atherosclerosis were much lower than those of rabbits fed cellulose or cellophane. Cellulose is ineffective in lowering cholesterol levels of rats70-72 or rabbits.73 Pectin and lignin, on the other hand, are hypocholesteremic in these species.73-77 Pectin inhibits atherogenesis in chickens.78 In rats fed a variety of starches in diets containing cholesterol and hydrogenated peanut oil there was an inverse relationship between the fiber content of the starch and accumulation of cholesterol in serum, liver and aorta.79 Fiber plays some role in bile acid metabolism. Portman80 reported that rats fed a semipurified diet excreted a smaller quantity of steroids than did rats fed commercial ration. Leveille and Sauberlich74 reported that rats fed pectin in a diet containing cholesterol excreted more bile acid but no more neutral steroid than did controls. A number of investigators have shown that dietary fiber along with other ingredients of the diet can bind appreciable quantities of bile acids and bile salts.81-87 This action may be important in assessing the mode of action of fiber but more data are needed. Vegetarians ingest more fiber than do persons eating a mixed diet, and they have lower cholesterol levels.88-89 Bran has been used extensively as a dietary source of fiber but with one exception90 has been found to have no hypocholesteremic effect.9' Pectin13'92-96 fed at levels of 6 to 50 grams per day has a hypocholesteremic effect in man. Pectin results in a large increase in bile acid excretion and a smaller one in neutral steroid excretion.'3'96 Guar gum (6 to 36 grams per day) also has a hypocholesteremic effect.94'97 Antonis and Bersohn98 found that the level of fat in the diet affected excretion of steroids in the feces; therefore, on a low fat-high fiber diet excretion of both acidic and neutral steroids was increased, but on a high fat diet fiber only affected neutral steroid excretion. Grande99 summarized data on a number of studies in which dietary sucrose was replaced equicalorically by starch (as bread, legumes, fruit THE WESTERN JOURNAL OF MEDICINE
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and the like). A fall in serum cholesterol levels was noted in every study. The, foods containing starch contained varying amounts of fiber. Dietary fiber has been shown to improve glucose tolerance. The materials tested have been pectin, guar and bran.'00-'03 Kiehm and co-workers'03 fed diabetic patients a 2,200 calorie diet in which about 75 percent of the calories were present as carbohydrate, two thirds as complex carbohydrate. Serum glucose, triglyceride and cholesterol levels fell by 26 percent, 15 percent and 24 percent, respectively. Ingestion of fiber is not without hazard. Increase in volatile gas in the large intestine can lead to sigmoid volvulus, a twisting of the large intestine. This condition has been found to be more prevalent among populations ingesting a high fiber diet.'04 High fiber diets, especially those containing phytate, may decrease bioavailability of necessary divalent cations.'05-'08 Some types of fiber contain inhibitors of trypsin and chymotrypsin which could influence digestion and be deleterious in persons ingesting marginally adequate diets.109,110 Beneficial effects from increased dietary fiber have been claimed for a wide spectrum of diseases. The two that have received the most attention, heart disease and cancer, are diseases whose causes are still unclear. To compound the confusion, fiber is a generic term covering a variety of complex structures with different chemical and physical properties. Still, dietary fiber may be effective in treating some aspects of these diseases. What needs to be learned is the mechanism or mechanisms of action involved in the hypocholesteremic and antiatherogenic effects of certain types of fiber. The same is true for the much smaller area of work involving effects of fiber in carcinogenesis. Realistic dietary recommendations depend upon elucidation of the modes of action of fiber. REFERENCES 1. Van Soest PJ, McQueen RW: The chemistry and estimation of fiber. Proc Nutr Soc 32:123-130, 1973 2. Southgate DAT: Determination of carbohydrates in foodsII. Unavailable carbohydrates. J Sci Food Agric 20:331-336, 1969 3. Southgate DAT: The analysis of dietary fiber, In Spiller GA, Amen RJ (Eds): Fiber in Human Nutrition. New York, NY, Plenum Press, 1976, pp 73-107 4. Southgate DAT, Bailey B, Collinson E, et al: A guide to calculating intakes of dietary fiber. J Human Nutr 30:303-313,
1976
5. Watt BK, Merrill AL: Composition of Foods (Agriculture Handbook 8). US Dept of Agriculture, 1975 6. McCance RA, Widdowson EM: Old thoughts and new work on breads white and brown. Lancet 2:205-210, 1955 7. Cowgill GR, Anderson WE: Laxative effect of wheat bran and washed bran in healthy man. JAMA 98:1866-1875, 1932 8. Cowgill GR, Sullivan AJ: Further studies on the use of wheat bran as a laxative. JAMA 100:795-802, 1933
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9. Williams RD, Olmstead WH: The manner in which food controls the bulk of the feces. Ann Intern Med 10:717-727, 1936 10. Burkitt DP: Epidemiology of cancer of the colon and rectum. Cancer 28:3-13, 1971 11. Burkitt DP: Epidemiology of large bowel disease: The role of fibre. Proc Nutr Soc 32:145-149, 1973 12. Eastwood MA, Kirkpatrick JR, Mitchell WD, et al: Effects of dietary supplements of wheat bran on faeces and bowel function. Br Med J 4:392-394, 1973 13. Kay RM, Truswell AS: Effect of citrus pectin on blood lipids and fecal steroid excretion in man. Am J Clin Nutr 30: 171-175, 1977 14. Eastwood MA, Girdwood RH: Lignin: A bile salt sequestering agent. Lancet 2:1170-1172, 1968 15. Williams RD, Olmstead WH: The effect of cellulose, hemicellulose and lignin on the weight of the stool: A contribution to the study of laxation in man. J Nutr 11:433-449, 1936 16. Southgate DAT, Branch WJ, Hill MJ, et al: Metabolic responses to dietary supplements of bran. Metabolism 25:1129-1135, 1976 17. Milton-Thompson GJ, Lewis B: The breakdown of dietary cellulose in man. Gut 12:853-854, 1971 18. Southgate DAT, Durnin JVGA: Calorie conversion factorsAn experimental reassessment of the factors used in the calculation of energy value of human diets. Br J Nutr 24:517-535, 1970 19. Pilnik W, Voragen AGJ: Pectic substances and other uronides, In Hulme AC (Ed): The Biochemistry of Fruits and Their Products. London, Academic Press, 1973 pp 53-87 20. Werch SC, Ivy AC: A study of the metabolism of ingested pectin. Am J Dis Child 62:499-511, 1941 21. Van Soest PJ, Robertson JB: What is fibre and fibre in food? Nutr Rev 35:12-22, Mar 1977 22. Cummings JH: Progress report: Dietary fibre. Gut 14:6981, 1973 23. Painter NS, Burkitt DP: Diverticular disease of the colon: A deficiency disease of Western civilization. Brit Med J 2:450-454, 1971 24. Spriggs EI, Marxer DA: Multiple diverticula of the colon. Lancet 1:1067-1074, 1927 25. Willard JH, Borkus H: Clinical and therapeutic status of cases of colonic diverticuloses seen in office practice. Am J Dig Dis 3:137-140, 1972 26. Findlay JM, Smith AN, Mitchell WD, et al: Effects of unprocessed bran on colon function in normal subjects and in diverticular disease. Lancet 1:146-149, 1974 27. Painter NS, Almeida AZ, Colebourne KW: Unprocessed bran in treatment of diverticular disease of the colon. Br Med J 1:137-140, 1972 28. Findlay JM, Mitchell WD, Eastwood MA, et al: Intestinal streaming patterns in cholerrhioeic enteropathy and diverticular disease. Gut 15:207-212, 1974 29. Brodribb AJM: Treatment of symptomatic diverticular disease with a high fibre diet. Lancet 1:665-666, 1977 30. Manning AP, Heaton KW, Harvey RF, et al: Wheat fibre and the irritable bowel syndrome. Lancet 2:417-418, 1977 31. Burkitt DP: Related disease-related cause. Lancet 2:12291231, 1969 32. Burkitt DP, Walker ARP, Painter NS: Effect of dietary fiber on stools and transit times and its relation to disease. Lancet 2:1408-1411, 1972 33. Burkitt DP, Walker ARP, Painter NS: Dietary fiber and disease. JAMA 229:1068-1074, 1974 34. Drasar BS, Irving D: Environmental factors and cancer of the colon and breast. Br J Cancer 27:167-172, 1973 - 35. Drasar BS, Irving D: Fibre and cancer of the colon. Br J Cancer 28:462-463, 1973 36. Haenszel W, Berg JW, Segi M, et al: Large-bowel cancer in Hawaiian Japanese. J Natl Cancer Inst 51:1765-1779, 1973 37. Steward HL: Geographic pathology of cancer of the colon and rectum. Cancer 28:25-28, 1971 38. Wynder EL, Shigematsu T: Environmental factors of cancer of the colon and rectum. Cancer 20:1520-1561, 1967 39. Stavraky KM: The role of ecological analysis in the etiology of disease: A discussion with reference to large bowel cancer. J Chron Dis 29:435-444, 1976 40. Enstrom JE: Colorectal cancer and consumption of beef and fat. Br J Cancer 32:432-439, 1975 41. Blot WJ, Fraumeni FJ Jr, Stone BJ, et al: Geographic patterns of large bowel cancer in the United States. J Natl Cancer Inst 57:1225-1231, 1976 42. Phillips RL: Role of life style and dietary habits in risk of cancer among Seveenth-Day Adventists. Cancer Res 35:3513-3522, 1975 43. Lyon JL, Klauber MR, Gardner JW, et al: Cancer incidence in Mormons and non-Mormons in Utah. N Engl J Med 294:129-133, 1976 44. Wilson RH, DeEds F: Importance of diet in studies of chronic toxicity. Arch Ind Hyg Occup Med 1:73-80, 1950 45. Engel RN, Copeland DH: Protective action of stock diets against the cancer-inducing action of 2-acetylaminofluorene in rats. Cancer Res 12:211-215, 1952 46. Wilson RB, Hutcheson DP, Wideman L: Dimethylhydrazine-
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induced colon tumors in rats fed diets containing beef fat or corn oil with and without wheat bran. Am J Clin Nutr 30:176-181, 1977 47. Fleiszer D, Murray D, MacFarlane J, et al: Protective effect of dietary fibre against chemically induced bowel tumors in rats. Lancet 2:552-553, 1978 48. Watanabe K, Reddy BS, Kritchevsky D: Effect of various dietary fibers and food additives on azoxymethane or methylnitrosourea-induced colon carcinogenesis in rats. Fed Proc 37:262, 1978 49. Cassidy MM, Grund B, Lightfoot F, et al: Alterations in topographical ultrastructure of rat jejunum and colon induced by feeding with alfalfa and cholestyramine. Fed Proc 37:543, 1978 50. Barbolt TA, Abraham R: The effect of bran on dimethylhydrazine-induced colon carcinogenesis in the rat. Proc Soc Exp Biol Med 157:656-659, 1978 51. Dam H: Nutritional aspects of gallstone formation with particular reference to alimentary production of gallstones in laboratory animals. World Rev Nutrition Dietetics 11: 199-239, 1969 52. Dam H: Determinants of cholesterol lithiasis in man and animals. Am J Med 51:598-613, 1971 53. Bergman F, Van der Linden W: Effect of dietary fibre on gallstone formation in hamsters. Z Ernahrungswiss 14:217-223, 1975 54. Caldwell FT Jr, Levitsky K, Rosenberg B: Dietary production and dissolution of cholesterol gallstones in the mouse. Am J Physiol 209:473478, 1965 55. Borgman RF, Wardlaw FB: Serum cholesterol and cholelithiasis in rabbits treated with pectin and cholestyramine. Am J Vet Res 35:1445-1447, 1974 56. Admirand WH, Small DM: The physico-chemical basis of cholesterol gallstone formation in man. J Clin Invest 47:10431052, 1968 57. Bell CC, Viacevic ZR, Prazick J, et al: Evidence that a diminished bile acid pool precedes the formation of cholesterol gallstones in man. Surg Gynecol Obstet 136:961-965, 1973 58. Strasberg SM, Fisher MM: Pathogenesis of human cholesterol cholelithiasis. Can Med Assoc J 112:484-488, 1975 59. Falaiye JM: Bile salt patterns in Nigerians on a high fibre diet. Lancet 1:1002, 1975 60. Pomare EW, Heaton KW, Low-Beer TS, et al: The effect of wheat bran upon bile salt metabolism and upon the lipid composition of bile in gallstone patients. Am J Dig Dis 21:521-526, 1976 61. Boyd GS, Eastwood MA: Studies on the quantitative distribution of bile salts along the rat small intestine under varying dietary regimes. Biochem Biophys Acta 152:159-164, 1968 62. Osuga T, Portman OW, Tanaka N, et al: The effect of diet on hepatic bile acid metabolism in squirrel monkeys with and without cholesterol gallstones. J Lab Clin Med 88:649-661, 1976 63. Story JA, Kritchevsky D: Dietary fiber and lipid metabolism, In Spiller GA, Amen RJ (Eds): Fiber in Human Nutrition. New York, Plenum Press 1976, pp 171-184 64. Kay RM, Strasberg SM: Origin, chemistry, physiological effects and clinical importance of dietary fibre. Clin Invest Med 1:9-24 1978 65. Kritchevsky D: Fiber, lipids and atherosclerosis. Am J Clin Nutr 31(Oct supplement):65-74, 1978 66. Kritchevsky D: Experimental atherosclerosis in rabbits fed cholesterol-free diets. J Atheroscler Res 4:103-105, 1964 67. Kritchevsky D, Tepper SA: Factors affecting atherosclerosis in rabbits fed cholesterol-free diets. Life Sci 4:1467-1471, 1965 68. Kritchevsky D, Tepper SA: Experimental atherosclerosis in rabbits fed cholesterol-ffee diets: Influence of chow components. J Atheroscler Res 8:357-369, 1968 69. Moore JH: The effect of the type of roughage in the diet on plasma cholesterol levels and aortic atherosis in rabbits. Br J Nutr 21:207-215, 1967 70. Wells AF, Ershoff BH: Beneficial effects of pectin in prevention of hypercholesterolemia and increase in liver cholesterol in cholesterol-fed rats. J Nutr 74:87-92, 1961 71. Kiriyama S, Okazaki Y, Yoshida A: Hypocholesterolemic effect of polysaccharides and polysaccharide-rich foodstuffs in cholesterol-fed rats. J Nutr 97:382-388, 1969 72. Tsai AC, Elias J, Kelly JJ, et al: Influence of certain dietary fibers on serum and tissue cholesterol levels in rats. J Nutr 106: 118-223, 1976 73. Hamilton RMG, Carroll KK: Plasma cholesterol levels in rabbits fed low fat, low cholesterol diets: Effect of dietary proteins, carbohydrates and fibre from different sources. Atherosclerosis 24:47-62, 19,76 74. Leveille GA, Sauberlich HE: Mechanism of the cholesteroldepressing effect of pectin in the cholesterol-fed rat. J Nutr 88: 209-214, 1966 75. Berenson LM, Bhandaru RR, Radhakrishnamurthy B, et al: The effect of dietary pectin on serum lipoprotein cholesterol in rabbits. Life Sci 16:1533-1544, 1975 76. Judd PA, Kay RM, Truswell AS: Cholesterol lowering effect of lignin in rats. Proc Nutr Soc 35:71A, 1976 77. Story JA, Czarnecki SK, Baldino A, et al: Effect of components of fiber on dietary cholesterol in the rat. Fed Proc 36: 1134, 1977
C dNdMa,,~~~~~~~ 78. Fisher H, Soller WG, Griminger P: The retardation by pectin of cholesterol-induced atherosclerosis in the fowl. J Atheroscier Res 6:292-298, 1966 79. Vijayagopal P, Kurup PA: Effect of dietary starches on the serum, aorta and hepatic lipid levels in cholesterol-fed rats. Atherosclerosis 11:257-264, 1970 80. Portman OW: Nutritional influences on the metabolism of bile acids. Am J Clin Nutr 8:462-470, 1960 81. Eastwood MA, Hamilton D: Studies on the adsorption of bile salts to non-absorbed components of diet. Biochim Biophys Acta 152:165-173, 1968 82. Kritchevsky D, Story JA: Binding of bile salts in vitro by non-nutritive fiber. J Nutr 104:458-462, 1974 83. Birkner HJ, Kern F Jr: In vitro adsorption of bile salts to food residues, salicylozosulfapyridine and hemicellulose. Gastroenterology 67:237-244, 1974 84. Balmer J, Zilversmit DB: Effects of dietary roughage on cholesterol absorption, cholesterol turnover and steroid excretion in the rat. J Nutr 104:1319-1328, 1974 85. Story JA, Kritchevsky D: Comparison of the binding of various bile acids and bile salts in vitro by several types of fiber. J Nutr 106:1292-1294, 1976 86. Story JA, Kritchevsky D: Binding of sodium taurocholate by various foodstuffs. Nutr Rep Int 11:161-163, 1975 87. Kritchevsky D, Story JA, Walker ARP: Binding of sodium taurocholate by cereal products. So Afr Med J 50:1831, 1976 88. Hardinge MG, Stare FJ: Nutritional studies of vegetarians -II. Dietary and serum levels of cholesterol. Am J Clin Nutr 2: 83-88, 1954 89. Hardinge MG, Chambers AC, Crooks H, et al: Nutritional studies of vegetarians-IlI. Dietary levels of fiber. Am J Clin Nutr 6:523-525, 1958 90. Munoz JM, Sandstead HH, Jacob RA, et al: Effects of some cereal brans on glucose tolerance and plasma lipids of normal men. Fed Proc 37:755, 1978 91. Truswell AS, Kay RM: Bran and blood lipids. Lancet 1: 367, 1976 92. Keys A, Grande F, Anderson JT: Fiber and pectin in the diet and serum cholesterol concentration in man. Proc Soc Exp Biol Med 106:555-558, 1961 93. Palmer GH, Dixon DG: Effect of pectin dose on serum cholesterol levels. Am J Clin Nutr 18:437-442, 1966 94. Jenkins DJA, Leeds AR, Newton C, et al: Effect of pectin, guar gum and wheat fibre on serum cholesterol. Lancet 1:11161117, 1975 95. Durrington PN, Manning AP, Bolton CH, et al: Effect of pectin on serum lipids and lipoproteins, whole gut transit time and stool weight. Lancet 2:394-396, 1976 96. Miettinen TA, Tarpila S: Effect of pectin on serum cholesterol, fecal bile acids and biliary lipids in normolipidemic and hyperlipidemic individuals. Clin Chim Acta 79:471-477, 1977 97. Fahrenbach MJ, Riccardi BA, Saunders JC, et al: Comparative effects of guar gum and pectin on human serum cholesterol levels. Circulation 32 (Suppl II):11, 1965 98. Antonis A, Bersohn I: The influence of diet on fecal lipids in South African white and Bantu prisoners. Am J Clin Nutr 11: 142-155, 1962 99. Grande F: Sugars in cardiovascular disease, In Sipple HL, McNutt KW (Eds): Sugars in Nutrition. New York, Academic Press, 1974, pp 401-437 100. Jenkins DJA, Leeds AR, Gassull MA, et al: Decrease in postprandial insulin and glucose concentrations by guar and pectin. Ann Intern Med 86:20-23, 1977 101. Jenkins DJA, Goff DV, Leeds AR, et al: Unabsorbable carbohydrates and diabetes: Decreased postprandial hyperglycemia. Lancet 2:172-174, 1976 102. Jenkins DJA, Wolever TMS, Haworth R, et al: Guar gum in diabetes. Lancet 2:1086-1087, 1976 103. Kiehm TG, Anderson JW, Ward DM: Beneficial effects of a high carbohydrate, high fiber diet on hyperglycemic diabetic men. Am J Clin Nutr 29:895-899, 1976 104. Saidi F: The high incidence of intestinal volvulus in Iran. Gut 10:838-841, 1969 105. Reinhold JG, Parsa A, Kariman N, et al: Availability of zinc in leavened and unleavened wholemeal wheaten breads as measured by solubility and uptake by rat intestine in vitro. J Nutr 104:976-982, 1974 106. Reinhold JC, Nasr K, Lahimgarzadeh A, et al: Effects of purified phytate and phytate-rich bread upon metabolism of zinc, calcium, phosphorus and nitrogen in man. Lancet 1:283-288, 19173 107. Reinhold JG, Faradji B, Abadi P, et al: Decreased absorption of calcium, magnesium, zinc and phosphorus by humans due to increased fiber and phosphorus consumption as wheat bread. J Nutr 106:493-503, 1976 108. Dobbs RJ, Baird IM: Effect of whole-meal and white bread on iron absorption in normal people. Br Med J 1:16411642, 1977 109. Mistuanaga T: Some properties of protease inhibitors in wheat grain. J Nutr Sci Vitaminol 20:153-159, 1974 110. Schneeman BO: The effect of plant fiber on trypsin and chymotrypsin activity in vitro. Fed Proc 36:1118, 1977
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Clinical Nutrition
Metabolic Effects of Dietary Fiber DAVID KRITCHEVSKY, PhD Philadelphia DIETARY FIBER has been defined as plant material that is not digested by enzymes of the human gastrointestinal tract. The plant materials that we call fiber are the structural components of plant cell walls. The amount and type of this material vary widely over the plant kingdom but can be broadly subdivided into polysaccharides (cellulose and noncellulosic polysaccharides) and lignins. These materials differ from one plant to another and may vary in the same plant, being affected by age and environment. The cellulosic materials form cellules and fibrils; the gums and mucilages form the cement substance of cell walls and seeds, and the woody material is a
complex, cross-linked phenylpropane polymer, lignin. Cellulose is a linear homoglycan composed of a chain of glucose residues in a 1-4- , linkage. The noncellulose types of polysaccharide are branched chain materials containing a number of different sugars. Hemicellulose has a main chain containing xylose, mannose, galactose and glucose with side chains of arabinose, galactose and glucuronic acid. Galacturonic acid represents the main chain of pectic substances whose side chains contain rhamnose, arabinose, fucose and xylose. The principal chains of gums and mucilages are more complex, the former containing galactose, galacturonic acid-rhamnose and glucuronic acidmannose and the latter galacturonic acid-rhamnose, arabinose-xylose, glucose-mannose and galactose-mannose. The side chains of mucilages and of algal polysaccharides contain only galactose, whereas side chains of gums contain xylose and fucose as well as galactose. The main chains Refer to: Kritchevsky D: Metabolic effects of dietary fiber (Clinical Nutrition Symposium). West J Med 130:123-127, Feb 1979 From the Wistar Institute of Anatomy and Biology, Philadelphia. Supported, in part, by grants (HL03299 and HL05209) and a Research Career Award (HL0734) from The National Institutes of Health. Reprint requests to: David Kritchevsky, PhD, Wistar Institute of Anatomy and Biology, 36th Street at Spruce, Philadelphia, PA 19104.
of algal polysaccharides contain mannose, xylose, guluronic acid and glucose. Lignin is a polymer of sinapyl, coniferyl and coumaryl alcohols. Cell walls also contain proteins, phytic acid, silica, tannins, steroid glycosides and cutins, which are polymeric esters of fatty acids. Until recently, the only measure of fiber content was a 150-year-old method involving treatment with acid and alkali. The residues left after these treatments were grouped together as crude fiber. This fraction represented only cellulose and lignin and did not account for any of the variety of other substances. At this writing most published data for fiber content of food are given as crude fiber. Van Soest' has developed a system in which aliquots of material are treated with a neutral solution of detergent or an acidic detergent solution. The former treatment yields total cell wall constituents and the latter cellulose and lignin. Treatment with strong (72 percent) sulfuric acid at room temperature yields lignin only. The system permits calculation of cellulose content by difference. Southgate2,3 has developed a complex method, involving enzymatic hydrolysis plus other hydrolysis and extraction procedures, which yields much more comprehensive information. Southgate4 has analyzed a number of foodstuffs. His analysis shows the wide gap between total dietary fiber as determined by Southgate and crude fiber as determined by the older standardized method and quoted in the United States Department of Agriculture's Handbook 8,5 which is virtually (and deservedly) the bible of nutritionists. To give a few examples: the total dietary fiber content (grams per 100 grams) of broccoli, peaches, peanuts and cocoa powder is 4.1, 2.3, 9.3 and 43.3, respectively; their crude fiber content is 1.5, 0.6, 2.4 and 4.3. With introduction of the Van Soest and Southgate methods more accurate information concerning the true composition of dietary fiber is forthcoming. Such inforTHE WESTERN JOURNAL OF MEDICINE
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mation is necessary to understand better the physiological effects of fiber. The effect of fiber on laxation was known to Hippocrates (quoted in reference 6). Cowgill and co-workers78 and Williams and Olmstead9 described the laxative effects of bran and other foods such as cabbage and cereals. Williams and Olmstead9 were not able to correlate laxative effects with composition. Burkitt'0"'1 noted rapid transit time and increased stool weight in African children on a high residue diet compared with English school boys. Not all fiber is effective in this respect; agar and psyllium seed colloid are the bases of commercial laxatives. Wheat bran is particularly good for decreasing transit time and increasing frequency of defecation and stool bulk. Addition of 16 grams of bran to the daily diet can double fecal weight.'2 On the other hand, pectin'3 and lignin'4 have little effect on transit time or stool bulk. Fiber is resistant to enzymes of the alimentary tract but can be digested by bacterial enzymes. This breakdown occurs in the colon and 30 percent to 80 percent of cellulose and 55 percent to 85 percent of hemicellulose can be lost in this way.'5-'8 About 90 percent of pectin is digested'9'20 but only 30 percent or less of wheat bran is,2' and practically no lignin is digested.'6,'8 Fiber degradation produces hydrogen, -carbon dioxide, water, methane and C2-C4 fatty acids. These products can also act to increase laxation.22
Diverticular Disease Based on their observatiolr of the large difference in incidence of diverticulosis in Western countries and African countries, Painter and Burkitt23 postulated that a low fiber diet resulted in high colonic pressure and the appearance of diverticulae. In the past, a low residue diet was recommended in diverticular disease,24'25 but today the reverse is being suggested. Bran has been found to be very effective in treatment of this condition.26-29 Painter and co-workers27 fed 3 to 45 grams of bran daily (mean 13 grams) to patients with diverticular disease and found relief of symptoms in 83 percent. There is little information on the treatment of diverticular disease by using fiber other than bran. Fiber is also being used in treatment of irritable bowel syndrome.30
Cancer of the Colon There are two currently popular hypotheses regarding diet and the cause of cancer of the
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colon. Burkitt3'-33 has pointed out that cancer of the colon is rare in populations subsisting on high residue diets. He has postulated that the lack of fiber in the Western diet permits greater exposure of the lining of the colon to carcinogens that may be present in feces and the slower transit time allows more time for bacterial transformation of dietary or secretory material to possible carcinogenic agents. Drasar and Irving34'35 have found little correlation between dietary fiber and cancer of the colon but found high correlation of cancer of the colon with ingestion of animal fat and animal protein. There is a parallel between standard of living, Westernization of the diet and incidence of cancer of the colon.36-38 It might be of interest to digress for a moment and discuss other aspects of diet and cancer of the colon. Stavraky39 has pointed out that the intranational differences in cancer of the colon found in countries such as the United States, Scotland and Canada lend no support to a theory involving specific dietary components. Although the consumption of beef in the United States doubled between 1945 and 1970, the death rate from cancer of the colon was unchanged.40 Within the United States, mortality from cancer of the bowel is highest in the Northeast and lowest in the Southeast.4' The diet in these two regions is not remarkably different. Populations such as Seventh Day Adventists who are largely vegetarian and who eschew pork have a low incidence of colon cancer,42 but so do Mormons43 who eat meat regularly. Clearly there is still much to be elucidated here. Experiments with animals have shown that some types of fiber can protect against induced colon cancer. More than 20 years ago it was found that rats fed stock diets exhibited fewer 2-acetylaminofluorene-induced tumors than did rats fed semipurified diets.44'45 Wilson and associates46 and Fleiszer and co-workers47 reported that dietary bran protected against tumors induced by dimethylhydrazine. Watanabe and coworketsM8 tested several dietary fibers for their effect on appearance of tumors of the colon caused by injection of dimethylhydrazine or intrarectal instillation of azoxymethane. Bran had little effect, pectin offered some protection and alfalfa enhanced tumor incidence. Alfalfa has been found to denude the colonic epithelium49 which may explain the findings. Barbolt and Abraham50 have found bran to protect rats from
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C mmdNwfddton M~~~~~ colonic tumors caused by feeding of dimethylhydrazine. The data suggest that the effects of fiber in experimental colon carcinogenesis vary depending on the type of fiber used and the mode of administration of the carcinogen. Insofar as the question of diet and cancer of the colon in man is concerned, it would appear as if a few pieces of the jigsaw puzzle are still missing.
Gallstones Dam5- 52 has reviewed factors that affect gallstone formation. Gallstones can be induced in hamsters by feeding a diet containing 74 percent glucose, 20 percent casein, salt mix, vitamin mix and choline chloride. The diet need not contain either fat or cholesterol. Replacement of the glucose with rice starch reduces gallstone formation almost to zero. Bergman and van der Linden53 fed this type of diet to lhamsters and augmented it with 5 percent pectin, lignin or psyllium colloid. None of the hamsters fed lignin or psyllium were found to have gallstones, 29 percent of those fed pectin had gallstones, whereas 58 percent of the controls had gallstones. Gallstones formed in mice fed a lithogenic diet were dissolved when the mice were returned to laboratory ration.54 Rabbits fed a semipurified diet containing 30 percent casein and 15 percent beef tallow exhibited gallstones (3/5) but when 5 percent pectin was added to the diet no gallstones were observed.55 It has been suggested that a diminished bile acid pool plays a role in cholelithiasis in man.56-58 Nigerians ingesting a high fiber diet have increased bile acid pool size and increased bile acid synthesis rates compared with populations eating a "Western" diet.59 Pomare, Heaton and associates60 showed that when patients with gallstones were fed wheat bran (an average of 57 grams per day) their chenodeoxycholic acid pool increased significantly, the deoxycholic acid pool fell and the cholesterol saturation of their bile diminished. The mechanism of action of fiber in affecting cholelithiasis is unknown, but it may be related to the increases in bile acid pool size that have been observed in rats6' and monkeys.62
Lipid Metabolism The influence of dietary fiber on lipid metabolism and atherosclerosis has been the subject of several recent reviews.6365 A review of the literature relating to the effect
of saturated fat on atherosclerosis in rabbits showed that the fat was atherogenic only when fed as part of a semipurified diet.66 It was further shown67'68 that addition of coconut oil to the fatfree residue of commercial rabbit ration was not atherogenic. Moore69 added wheat straw to a semipurified, cholesterol-free atherogenic diet and showed that serum lipid levels and atherosclerosis were much lower than those of rabbits fed cellulose or cellophane. Cellulose is ineffective in lowering cholesterol levels of rats70-72 or rabbits.73 Pectin and lignin, on the other hand, are hypocholesteremic in these species.73-77 Pectin inhibits atherogenesis in chickens.78 In rats fed a variety of starches in diets containing cholesterol and hydrogenated peanut oil there was an inverse relationship between the fiber content of the starch and accumulation of cholesterol in serum, liver and aorta.79 Fiber plays some role in bile acid metabolism. Portman80 reported that rats fed a semipurified diet excreted a smaller quantity of steroids than did rats fed commercial ration. Leveille and Sauberlich74 reported that rats fed pectin in a diet containing cholesterol excreted more bile acid but no more neutral steroid than did controls. A number of investigators have shown that dietary fiber along with other ingredients of the diet can bind appreciable quantities of bile acids and bile salts.81-87 This action may be important in assessing the mode of action of fiber but more data are needed. Vegetarians ingest more fiber than do persons eating a mixed diet, and they have lower cholesterol levels.88-89 Bran has been used extensively as a dietary source of fiber but with one exception90 has been found to have no hypocholesteremic effect.9' Pectin13'92-96 fed at levels of 6 to 50 grams per day has a hypocholesteremic effect in man. Pectin results in a large increase in bile acid excretion and a smaller one in neutral steroid excretion.'3'96 Guar gum (6 to 36 grams per day) also has a hypocholesteremic effect.94'97 Antonis and Bersohn98 found that the level of fat in the diet affected excretion of steroids in the feces; therefore, on a low fat-high fiber diet excretion of both acidic and neutral steroids was increased, but on a high fat diet fiber only affected neutral steroid excretion. Grande99 summarized data on a number of studies in which dietary sucrose was replaced equicalorically by starch (as bread, legumes, fruit THE WESTERN JOURNAL OF MEDICINE
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and the like). A fall in serum cholesterol levels was noted in every study. The, foods containing starch contained varying amounts of fiber. Dietary fiber has been shown to improve glucose tolerance. The materials tested have been pectin, guar and bran.'00-'03 Kiehm and co-workers'03 fed diabetic patients a 2,200 calorie diet in which about 75 percent of the calories were present as carbohydrate, two thirds as complex carbohydrate. Serum glucose, triglyceride and cholesterol levels fell by 26 percent, 15 percent and 24 percent, respectively. Ingestion of fiber is not without hazard. Increase in volatile gas in the large intestine can lead to sigmoid volvulus, a twisting of the large intestine. This condition has been found to be more prevalent among populations ingesting a high fiber diet.'04 High fiber diets, especially those containing phytate, may decrease bioavailability of necessary divalent cations.'05-'08 Some types of fiber contain inhibitors of trypsin and chymotrypsin which could influence digestion and be deleterious in persons ingesting marginally adequate diets.109,110 Beneficial effects from increased dietary fiber have been claimed for a wide spectrum of diseases. The two that have received the most attention, heart disease and cancer, are diseases whose causes are still unclear. To compound the confusion, fiber is a generic term covering a variety of complex structures with different chemical and physical properties. Still, dietary fiber may be effective in treating some aspects of these diseases. What needs to be learned is the mechanism or mechanisms of action involved in the hypocholesteremic and antiatherogenic effects of certain types of fiber. The same is true for the much smaller area of work involving effects of fiber in carcinogenesis. Realistic dietary recommendations depend upon elucidation of the modes of action of fiber. REFERENCES 1. Van Soest PJ, McQueen RW: The chemistry and estimation of fiber. Proc Nutr Soc 32:123-130, 1973 2. Southgate DAT: Determination of carbohydrates in foodsII. Unavailable carbohydrates. J Sci Food Agric 20:331-336, 1969 3. Southgate DAT: The analysis of dietary fiber, In Spiller GA, Amen RJ (Eds): Fiber in Human Nutrition. New York, NY, Plenum Press, 1976, pp 73-107 4. Southgate DAT, Bailey B, Collinson E, et al: A guide to calculating intakes of dietary fiber. J Human Nutr 30:303-313,
1976
5. Watt BK, Merrill AL: Composition of Foods (Agriculture Handbook 8). US Dept of Agriculture, 1975 6. McCance RA, Widdowson EM: Old thoughts and new work on breads white and brown. Lancet 2:205-210, 1955 7. Cowgill GR, Anderson WE: Laxative effect of wheat bran and washed bran in healthy man. JAMA 98:1866-1875, 1932 8. Cowgill GR, Sullivan AJ: Further studies on the use of wheat bran as a laxative. JAMA 100:795-802, 1933
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9. Williams RD, Olmstead WH: The manner in which food controls the bulk of the feces. Ann Intern Med 10:717-727, 1936 10. Burkitt DP: Epidemiology of cancer of the colon and rectum. Cancer 28:3-13, 1971 11. Burkitt DP: Epidemiology of large bowel disease: The role of fibre. Proc Nutr Soc 32:145-149, 1973 12. Eastwood MA, Kirkpatrick JR, Mitchell WD, et al: Effects of dietary supplements of wheat bran on faeces and bowel function. Br Med J 4:392-394, 1973 13. Kay RM, Truswell AS: Effect of citrus pectin on blood lipids and fecal steroid excretion in man. Am J Clin Nutr 30: 171-175, 1977 14. Eastwood MA, Girdwood RH: Lignin: A bile salt sequestering agent. Lancet 2:1170-1172, 1968 15. Williams RD, Olmstead WH: The effect of cellulose, hemicellulose and lignin on the weight of the stool: A contribution to the study of laxation in man. J Nutr 11:433-449, 1936 16. Southgate DAT, Branch WJ, Hill MJ, et al: Metabolic responses to dietary supplements of bran. Metabolism 25:1129-1135, 1976 17. Milton-Thompson GJ, Lewis B: The breakdown of dietary cellulose in man. Gut 12:853-854, 1971 18. Southgate DAT, Durnin JVGA: Calorie conversion factorsAn experimental reassessment of the factors used in the calculation of energy value of human diets. Br J Nutr 24:517-535, 1970 19. Pilnik W, Voragen AGJ: Pectic substances and other uronides, In Hulme AC (Ed): The Biochemistry of Fruits and Their Products. London, Academic Press, 1973 pp 53-87 20. Werch SC, Ivy AC: A study of the metabolism of ingested pectin. Am J Dis Child 62:499-511, 1941 21. Van Soest PJ, Robertson JB: What is fibre and fibre in food? Nutr Rev 35:12-22, Mar 1977 22. Cummings JH: Progress report: Dietary fibre. Gut 14:6981, 1973 23. Painter NS, Burkitt DP: Diverticular disease of the colon: A deficiency disease of Western civilization. Brit Med J 2:450-454, 1971 24. Spriggs EI, Marxer DA: Multiple diverticula of the colon. Lancet 1:1067-1074, 1927 25. Willard JH, Borkus H: Clinical and therapeutic status of cases of colonic diverticuloses seen in office practice. Am J Dig Dis 3:137-140, 1972 26. Findlay JM, Smith AN, Mitchell WD, et al: Effects of unprocessed bran on colon function in normal subjects and in diverticular disease. Lancet 1:146-149, 1974 27. Painter NS, Almeida AZ, Colebourne KW: Unprocessed bran in treatment of diverticular disease of the colon. Br Med J 1:137-140, 1972 28. Findlay JM, Mitchell WD, Eastwood MA, et al: Intestinal streaming patterns in cholerrhioeic enteropathy and diverticular disease. Gut 15:207-212, 1974 29. Brodribb AJM: Treatment of symptomatic diverticular disease with a high fibre diet. Lancet 1:665-666, 1977 30. Manning AP, Heaton KW, Harvey RF, et al: Wheat fibre and the irritable bowel syndrome. Lancet 2:417-418, 1977 31. Burkitt DP: Related disease-related cause. Lancet 2:12291231, 1969 32. Burkitt DP, Walker ARP, Painter NS: Effect of dietary fiber on stools and transit times and its relation to disease. Lancet 2:1408-1411, 1972 33. Burkitt DP, Walker ARP, Painter NS: Dietary fiber and disease. JAMA 229:1068-1074, 1974 34. Drasar BS, Irving D: Environmental factors and cancer of the colon and breast. Br J Cancer 27:167-172, 1973 - 35. Drasar BS, Irving D: Fibre and cancer of the colon. Br J Cancer 28:462-463, 1973 36. Haenszel W, Berg JW, Segi M, et al: Large-bowel cancer in Hawaiian Japanese. J Natl Cancer Inst 51:1765-1779, 1973 37. Steward HL: Geographic pathology of cancer of the colon and rectum. Cancer 28:25-28, 1971 38. Wynder EL, Shigematsu T: Environmental factors of cancer of the colon and rectum. Cancer 20:1520-1561, 1967 39. Stavraky KM: The role of ecological analysis in the etiology of disease: A discussion with reference to large bowel cancer. J Chron Dis 29:435-444, 1976 40. Enstrom JE: Colorectal cancer and consumption of beef and fat. Br J Cancer 32:432-439, 1975 41. Blot WJ, Fraumeni FJ Jr, Stone BJ, et al: Geographic patterns of large bowel cancer in the United States. J Natl Cancer Inst 57:1225-1231, 1976 42. Phillips RL: Role of life style and dietary habits in risk of cancer among Seveenth-Day Adventists. Cancer Res 35:3513-3522, 1975 43. Lyon JL, Klauber MR, Gardner JW, et al: Cancer incidence in Mormons and non-Mormons in Utah. N Engl J Med 294:129-133, 1976 44. Wilson RH, DeEds F: Importance of diet in studies of chronic toxicity. Arch Ind Hyg Occup Med 1:73-80, 1950 45. Engel RN, Copeland DH: Protective action of stock diets against the cancer-inducing action of 2-acetylaminofluorene in rats. Cancer Res 12:211-215, 1952 46. Wilson RB, Hutcheson DP, Wideman L: Dimethylhydrazine-
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induced colon tumors in rats fed diets containing beef fat or corn oil with and without wheat bran. Am J Clin Nutr 30:176-181, 1977 47. Fleiszer D, Murray D, MacFarlane J, et al: Protective effect of dietary fibre against chemically induced bowel tumors in rats. Lancet 2:552-553, 1978 48. Watanabe K, Reddy BS, Kritchevsky D: Effect of various dietary fibers and food additives on azoxymethane or methylnitrosourea-induced colon carcinogenesis in rats. Fed Proc 37:262, 1978 49. Cassidy MM, Grund B, Lightfoot F, et al: Alterations in topographical ultrastructure of rat jejunum and colon induced by feeding with alfalfa and cholestyramine. Fed Proc 37:543, 1978 50. Barbolt TA, Abraham R: The effect of bran on dimethylhydrazine-induced colon carcinogenesis in the rat. Proc Soc Exp Biol Med 157:656-659, 1978 51. Dam H: Nutritional aspects of gallstone formation with particular reference to alimentary production of gallstones in laboratory animals. World Rev Nutrition Dietetics 11: 199-239, 1969 52. Dam H: Determinants of cholesterol lithiasis in man and animals. Am J Med 51:598-613, 1971 53. Bergman F, Van der Linden W: Effect of dietary fibre on gallstone formation in hamsters. Z Ernahrungswiss 14:217-223, 1975 54. Caldwell FT Jr, Levitsky K, Rosenberg B: Dietary production and dissolution of cholesterol gallstones in the mouse. Am J Physiol 209:473478, 1965 55. Borgman RF, Wardlaw FB: Serum cholesterol and cholelithiasis in rabbits treated with pectin and cholestyramine. Am J Vet Res 35:1445-1447, 1974 56. Admirand WH, Small DM: The physico-chemical basis of cholesterol gallstone formation in man. J Clin Invest 47:10431052, 1968 57. Bell CC, Viacevic ZR, Prazick J, et al: Evidence that a diminished bile acid pool precedes the formation of cholesterol gallstones in man. Surg Gynecol Obstet 136:961-965, 1973 58. Strasberg SM, Fisher MM: Pathogenesis of human cholesterol cholelithiasis. Can Med Assoc J 112:484-488, 1975 59. Falaiye JM: Bile salt patterns in Nigerians on a high fibre diet. Lancet 1:1002, 1975 60. Pomare EW, Heaton KW, Low-Beer TS, et al: The effect of wheat bran upon bile salt metabolism and upon the lipid composition of bile in gallstone patients. Am J Dig Dis 21:521-526, 1976 61. Boyd GS, Eastwood MA: Studies on the quantitative distribution of bile salts along the rat small intestine under varying dietary regimes. Biochem Biophys Acta 152:159-164, 1968 62. Osuga T, Portman OW, Tanaka N, et al: The effect of diet on hepatic bile acid metabolism in squirrel monkeys with and without cholesterol gallstones. J Lab Clin Med 88:649-661, 1976 63. Story JA, Kritchevsky D: Dietary fiber and lipid metabolism, In Spiller GA, Amen RJ (Eds): Fiber in Human Nutrition. New York, Plenum Press 1976, pp 171-184 64. Kay RM, Strasberg SM: Origin, chemistry, physiological effects and clinical importance of dietary fibre. Clin Invest Med 1:9-24 1978 65. Kritchevsky D: Fiber, lipids and atherosclerosis. Am J Clin Nutr 31(Oct supplement):65-74, 1978 66. Kritchevsky D: Experimental atherosclerosis in rabbits fed cholesterol-free diets. J Atheroscler Res 4:103-105, 1964 67. Kritchevsky D, Tepper SA: Factors affecting atherosclerosis in rabbits fed cholesterol-free diets. Life Sci 4:1467-1471, 1965 68. Kritchevsky D, Tepper SA: Experimental atherosclerosis in rabbits fed cholesterol-ffee diets: Influence of chow components. J Atheroscler Res 8:357-369, 1968 69. Moore JH: The effect of the type of roughage in the diet on plasma cholesterol levels and aortic atherosis in rabbits. Br J Nutr 21:207-215, 1967 70. Wells AF, Ershoff BH: Beneficial effects of pectin in prevention of hypercholesterolemia and increase in liver cholesterol in cholesterol-fed rats. J Nutr 74:87-92, 1961 71. Kiriyama S, Okazaki Y, Yoshida A: Hypocholesterolemic effect of polysaccharides and polysaccharide-rich foodstuffs in cholesterol-fed rats. J Nutr 97:382-388, 1969 72. Tsai AC, Elias J, Kelly JJ, et al: Influence of certain dietary fibers on serum and tissue cholesterol levels in rats. J Nutr 106: 118-223, 1976 73. Hamilton RMG, Carroll KK: Plasma cholesterol levels in rabbits fed low fat, low cholesterol diets: Effect of dietary proteins, carbohydrates and fibre from different sources. Atherosclerosis 24:47-62, 19,76 74. Leveille GA, Sauberlich HE: Mechanism of the cholesteroldepressing effect of pectin in the cholesterol-fed rat. J Nutr 88: 209-214, 1966 75. Berenson LM, Bhandaru RR, Radhakrishnamurthy B, et al: The effect of dietary pectin on serum lipoprotein cholesterol in rabbits. Life Sci 16:1533-1544, 1975 76. Judd PA, Kay RM, Truswell AS: Cholesterol lowering effect of lignin in rats. Proc Nutr Soc 35:71A, 1976 77. Story JA, Czarnecki SK, Baldino A, et al: Effect of components of fiber on dietary cholesterol in the rat. Fed Proc 36: 1134, 1977
C dNdMa,,~~~~~~~ 78. Fisher H, Soller WG, Griminger P: The retardation by pectin of cholesterol-induced atherosclerosis in the fowl. J Atheroscier Res 6:292-298, 1966 79. Vijayagopal P, Kurup PA: Effect of dietary starches on the serum, aorta and hepatic lipid levels in cholesterol-fed rats. Atherosclerosis 11:257-264, 1970 80. Portman OW: Nutritional influences on the metabolism of bile acids. Am J Clin Nutr 8:462-470, 1960 81. Eastwood MA, Hamilton D: Studies on the adsorption of bile salts to non-absorbed components of diet. Biochim Biophys Acta 152:165-173, 1968 82. Kritchevsky D, Story JA: Binding of bile salts in vitro by non-nutritive fiber. J Nutr 104:458-462, 1974 83. Birkner HJ, Kern F Jr: In vitro adsorption of bile salts to food residues, salicylozosulfapyridine and hemicellulose. Gastroenterology 67:237-244, 1974 84. Balmer J, Zilversmit DB: Effects of dietary roughage on cholesterol absorption, cholesterol turnover and steroid excretion in the rat. J Nutr 104:1319-1328, 1974 85. Story JA, Kritchevsky D: Comparison of the binding of various bile acids and bile salts in vitro by several types of fiber. J Nutr 106:1292-1294, 1976 86. Story JA, Kritchevsky D: Binding of sodium taurocholate by various foodstuffs. Nutr Rep Int 11:161-163, 1975 87. Kritchevsky D, Story JA, Walker ARP: Binding of sodium taurocholate by cereal products. So Afr Med J 50:1831, 1976 88. Hardinge MG, Stare FJ: Nutritional studies of vegetarians -II. Dietary and serum levels of cholesterol. Am J Clin Nutr 2: 83-88, 1954 89. Hardinge MG, Chambers AC, Crooks H, et al: Nutritional studies of vegetarians-IlI. Dietary levels of fiber. Am J Clin Nutr 6:523-525, 1958 90. Munoz JM, Sandstead HH, Jacob RA, et al: Effects of some cereal brans on glucose tolerance and plasma lipids of normal men. Fed Proc 37:755, 1978 91. Truswell AS, Kay RM: Bran and blood lipids. Lancet 1: 367, 1976 92. Keys A, Grande F, Anderson JT: Fiber and pectin in the diet and serum cholesterol concentration in man. Proc Soc Exp Biol Med 106:555-558, 1961 93. Palmer GH, Dixon DG: Effect of pectin dose on serum cholesterol levels. Am J Clin Nutr 18:437-442, 1966 94. Jenkins DJA, Leeds AR, Newton C, et al: Effect of pectin, guar gum and wheat fibre on serum cholesterol. Lancet 1:11161117, 1975 95. Durrington PN, Manning AP, Bolton CH, et al: Effect of pectin on serum lipids and lipoproteins, whole gut transit time and stool weight. Lancet 2:394-396, 1976 96. Miettinen TA, Tarpila S: Effect of pectin on serum cholesterol, fecal bile acids and biliary lipids in normolipidemic and hyperlipidemic individuals. Clin Chim Acta 79:471-477, 1977 97. Fahrenbach MJ, Riccardi BA, Saunders JC, et al: Comparative effects of guar gum and pectin on human serum cholesterol levels. Circulation 32 (Suppl II):11, 1965 98. Antonis A, Bersohn I: The influence of diet on fecal lipids in South African white and Bantu prisoners. Am J Clin Nutr 11: 142-155, 1962 99. Grande F: Sugars in cardiovascular disease, In Sipple HL, McNutt KW (Eds): Sugars in Nutrition. New York, Academic Press, 1974, pp 401-437 100. Jenkins DJA, Leeds AR, Gassull MA, et al: Decrease in postprandial insulin and glucose concentrations by guar and pectin. Ann Intern Med 86:20-23, 1977 101. Jenkins DJA, Goff DV, Leeds AR, et al: Unabsorbable carbohydrates and diabetes: Decreased postprandial hyperglycemia. Lancet 2:172-174, 1976 102. Jenkins DJA, Wolever TMS, Haworth R, et al: Guar gum in diabetes. Lancet 2:1086-1087, 1976 103. Kiehm TG, Anderson JW, Ward DM: Beneficial effects of a high carbohydrate, high fiber diet on hyperglycemic diabetic men. Am J Clin Nutr 29:895-899, 1976 104. Saidi F: The high incidence of intestinal volvulus in Iran. Gut 10:838-841, 1969 105. Reinhold JG, Parsa A, Kariman N, et al: Availability of zinc in leavened and unleavened wholemeal wheaten breads as measured by solubility and uptake by rat intestine in vitro. J Nutr 104:976-982, 1974 106. Reinhold JC, Nasr K, Lahimgarzadeh A, et al: Effects of purified phytate and phytate-rich bread upon metabolism of zinc, calcium, phosphorus and nitrogen in man. Lancet 1:283-288, 19173 107. Reinhold JG, Faradji B, Abadi P, et al: Decreased absorption of calcium, magnesium, zinc and phosphorus by humans due to increased fiber and phosphorus consumption as wheat bread. J Nutr 106:493-503, 1976 108. Dobbs RJ, Baird IM: Effect of whole-meal and white bread on iron absorption in normal people. Br Med J 1:16411642, 1977 109. Mistuanaga T: Some properties of protease inhibitors in wheat grain. J Nutr Sci Vitaminol 20:153-159, 1974 110. Schneeman BO: The effect of plant fiber on trypsin and chymotrypsin activity in vitro. Fed Proc 36:1118, 1977
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