GASTROENTEROLOGY 1992;103:1994-1977
EDITORIALS
Fiber and Colon Cancer: The Weight of the Evidence Cancers of the colon and rectum are major public health concerns throughout the world, particularly in North America and Western Europe. Approximately 156,000new cases of large bowel malignancy and more than 58,000 deaths from this disease are expected in the United States in 1992.’ Over the past 8 years, spectacular progress has been made in understanding the molecular events that occur during the transformation of normal colonic epithelium to a focus of adenocarcinoma. Studies by Vogelstein and others have shown that colon cancer develops as a result of an accumulation of genetic lesions that regulate cell growth and proliferation.’ Further research into these basic mechanisms may ultimately provide us with biomarkers that will allow us to focus our surveillance strategies on those individuals at greater risk of colonic malignancies. Understanding these fundamental mechanisms may also allow us to identify the environmental risk factors associated with colorectal cancer in hopes that changes in behavior will reduce the incidence of this disease. In the meantime, it is widely accepted that a diet generous in crude dietary fiber will result in gastrointestinal bliss and perhaps even help prevent colorectal cancer. The study in this issue by Cummings et al., which addresses the relationship between dietary fiber intake and colon cancer throughout the world, contributes to the growing body of literature that supports this belief. What is the evidence that dietary components alter the risk for colorectal cancer? Perhaps the strongest data supporting this concept came from epidemiologic studies in Japan, a country with a relatively low incidence of colorectal cancer. When Japanese individuals immigrated to countries with higher incidences of colorectal cancer, they assumed the increased risk endogenous to that country, presumably due to changes in diet. Other studies of immigrating populations showed the same shifts in cancer incidence.3 The specific dietary components associated with the changes in disease patterns have been difficult to elucidate. Population studies have implied that diets high in animal fat and calories and low in crude dietary fiber are risk factors for the development of colon cancer. Unfortunately, few studies have been
able to isolate the independent effects of these variables. It is important to consider the fact that diets low in fiber are often high in animal fat and calories. Nonetheless, dietary fiber content has enjoyed the greatest popularity as an important modifier of one’s risk for colorectal cancer. The role of a low-fiber diet in the genesis of gastrointestinal disease was first suggested almost 40 years ago when T. L. Cleave, a British naval surgeon, proposed that the processing of food and the elimination of fiber from the diet was responsible for many of the ills of industrialized societies.4*5 However, it was the observations of Burkitt in Africa, where the incidence of colon cancer is low, that framed the hypothesis that diets characterized by high fiber were protective against the development of colon cancer.” Since Burkitt’s hypothesis, a number of epidemiological studies have attempted to correlate the relationship between fiber intake and colon cancer. At least 17 studies (only two of which were case control studies) have found an inverse relationship between fiber intake and colon cancer,7 and a recent meta-analysis of epidemiologic studies on this topic provided an estimated combined odds ratio of 0.57 (95% confidence interval = 0.50-0.64) for colon cancer when comparing the highest and lowest quantiles of fiber intake.’ However, at least four studies (three of which were case control studies) have found no correlation between colon cancer and fiber intakee7 Furthermore, most of these studies have failed to consider the effects of animal fat and caloric intake, which may in fact be the independent variables that would explain the observed differences in risk. The Nurses’ Health Study, a case control study involving more than 80,000 women in the United States, found that women with the highest animal fat intake and the lowest crude fiber intake had the highest risk of colon cancer. However, a greater correlation with colon cancer risk was found for a high fat intake than a low-fiber diet9 How might dietary fiber reduce the risk of colorectal cancer? As just acknowledged, the benefits of fiber may simply lie in the displacement of dietary components such as fat or calories. These agents are most likely deleterious by virtue of their ability to enhance cell proliferation, thereby increasing the
December 1992
chances for mutagenic events. Specifically, high dietary fat has been associated with an increase in intraluminal bile acids that appear to enhance epithelial proliferation.‘O*” Another mechanism by which fiber may be protective is its ability to decrease the colonic transit time and bind a wide variety of reactive compounds, thereby reducing the contact between intraluminal carcinogens and colonic epithelium. However, it remains to be shown whether any of these mechanisms influences the development of colorectal cancer in humans. A final factor to consider is that the dietary sources of fiber, which often include fruits and vegetables, may contain increased amounts of micronutrients that may provide the protective effects that have been attributed to fiber. Animal models of colon carcinogenesis have been useful to examine the components and potential mechanisms afforded by dietary fiber. The term dietary fiber encompasses several groups of nonstarch polysaccharides (NSP) that vary in their ability to influence the development of cancer. Cellulose has been shown to protect against experimental colonic neoplasia in rats treated with the carcinogen 1,2-dimethylhydrazine, whereas similar doses of purified pectin did not.‘2*‘3 It has also been shown that oat bran, pectin, and guar all have different effects on stimulating mucosal growth in the rat colon.‘4 Interestingly, human colon cancer cell lines grown in the subcutaneous tissues of athymic mice show enhanced growth when the animals are fed a high-fat diet, and this effect may be attenuated by the addition of fiber, even though the tumors are isolated from the gastrointestinal tract.15 To confuse matters further, it should also be noted that some studies using animal models have shown the addition of large doses of fiber to be deleterious. When a 20% wheat bran diet was given during the period of carcinogen administration, a threefold increase in colon tumors was noted relative to contro1s.‘6 Thus, if fiber does provide a protective role against the development of colorectal cancer, population studies will likely need to consider the amounts and sources for fiber in their analysis. With this background in mind, what new insights have Cummings and his group brought to the issue of fiber and colorectal cancer? The authors report a significant correlation between stool weight and dietary intake of NSP (r = 0.84) based on data collected from a variety of published works on stool weight and NSP intake from XI different populations in 12 countries. They correlated the average stool weight in each population with cancer registry data for the incidence of colon cancer in each population and found a significant inverse relationship (r = 0.78). Based on their analysis, they determined that diets
EDITORIALS 1965
characterized by NSP intakes of >18 g/day would be associated with average stool weights of >15O g/day, which should be protective against bowel cancer. Several issues are worth noting regarding the authors’ data and conclusions. The first point pertains to the use of average stool weights for a given population. The authors collected stools from 220 healthy British adults and reported that the mean daily stool weight was 117 + 3.8 (SEM) g/day with a range of stool weights that varied from 19-450 g/day! If dietary fiber plays the important role that the authors suggest, it should be possible to identify subgroups at variable risks for cancer within this population. These variable risk subgroups may be overlooked when average stool weights from a variety of populations are plotted against the incidence of colorectal cancer. If such a relationship cannot be shown, confounding variables should be sought. The second point concerns the notable exceptions to the list of countries where daily fecal weight and colon cancer incidence are inversely correlated (Table 2). For example, a relatively low incidence of colon cancer is observed in the Maori of New Zealand despite a relatively low daily fecal weight. In the study reported by this group on a Japanese population, the average intake of NSP did not exceed 13 g/day, which corresponds to British levels of intake, in spite of the well-documented low incidence of colon cancer in Japan.17 Similarly, colon cancer is relatively prevalent among the populations of Helsinki, Finland, and the urban Chinese community of Malaysia despite relatively high fecal weights. These variances again suggest the presence of important confounding variables that are worthy of attention. Neither dietary fat intake or the source of dietary fiber were addressed in this analysis and, as mentioned earlier, these may be important factors in coionic carcinogenesis. A third point refers to the discordance in stool weights that was observed between men and women. Although the stool weight in women was not corrected for total body weight, it differed significantly between men and women (122 + 5.9 g/day vs. 102 + 5.4 g/day, P = 0.02). If stool weight were predictive of colon cancer risk, one would expect to see gender differences in the incidence of colon cancer. However, the incidence of colon cancer is similar between men and women in North America and greater in men in many other regions.” These relationships are multifactorial and are related to tumor sites in the colon, age, and menopause as discussed by the authors. This complex relationship remains to be fully understood. Finally, by what mechanism might dietary fiber protect against cancer in the colon but not the rec-
1966
GASTROENTEROLOGY Vol. 103, No. 6
EDITORIALS
turn? Perhaps the fermentation of fiber has more prominent effects in the proximal colon. Are there currently undetected “systemic effects” of a highfiber diet? Prior studies have suggested an inverse relationship between fiber intake and cancers of the esophagus, mouth, pharynx, stomach, breast, endometrium, and ovary.” Of interest, genetic damage is significantly more prominent in tumors of the distal colon than the proximal colon, suggesting that the luminal milieu may be more hostile distally.” The mechanism accounting for the differences in mutation and chromosomal instability have not yet been explored in vivo. Although it is not clear how the protective effects of fiber might be limited to that portion of the gastrointestinal tract between the ileocecal valve and rectosigmoid junction, it is often a piece of epidemiological evidence such as this that leads to the development of new mechanistic concepts in the laboratory. The authors conclude that diets characterized by a high fiber content will be expected to be protective against the development of colon cancer. Furthermore, they suggest, with some justification, a target level of at least 18 g/day of NSP. However, it has yet to be shown that such dietary changes in a given population will decrease the incidence of colon cancer. This requires a prospective analysis and may be rather difficult to confirm. Unlike certain habits such as cigarette smoking or alcohol consumption, from which a large segment of the population abstains, fiber and fat are components of virtually all diets. If subjects were simply to add fiber to their diet without altering fat or caloric intake, would a reduction in risk for colorectal cancer be expected? Would a relatively pure fiber supplement afford the same protection as the fiber found in fruits, vegetables, and grains? Prospective interventional studies are required to determine whether dietary intervention can modify the incidence of colorectal cancer. If one were to use the development of cancer as the end point in an observational study, it would require several decades to reach any conclusions. Therefore, reliable “intermediate biomarkers” must be used to assess the impact of intervention on cancer risk. One example of this application is the study by Alberts et al., which showed that dietary supplementation with wheat bran fiber for 2 months significantly decreased proliferation indices in colonic biopsies.‘* This group used a diet containing wheat fiber (2 g/ day) during the control period and intervened with 1.5 oz of All Bran cereal (13.5 g of wheat bran fiber; Kellogg Company, Battle Creek, MI) daily for 8 weeks. g
The half cup of cereal
NSP suggested by Cummings
provided
75% of the 18
et al., which supports
the feasibility of this type of dietary intervention. Further work into the molecular mechanisms of colorectal carcinogenesis may lead to identification of useful biomarkers that characterize early developmental events in colonic neoplasia. These biomarkers will allow us to measure the impact of dietary interventions as well as focus our efforts at surveillance screening in those at greatest risk. One might anticipate that similar approaches could be used to determine the impact of fat and fiber intake on tumor progression in the colon. In conclusion, Cummings’ group has used the simplest of all possible techniques to add to our knowledge of the genesis of colon cancer. The “weight of the evidence” implicates a protective effect of a diet characterized by high fiber (>18 g/day of NSP). There would appear to be relatively little risk to such a diet, but it is not clear that this protective association can be separated from other components of the diet, most prominently the effects of fat and calories. In any event, this work should stimulate discussion over breakfast and in the laboratories. C. RICHARD BOLAND JOSEPH C. KOLARS Gastroenterology Section
Veterans Administration Medical Center and the Gastroenterology Division Department of Internal Medicine University of Michigan Medical School Ann Arbor, Michigan
References 1. Boring CC, Squires TS, Tong T. Cancer Statistics,
1992.Ca-A CancerJPhys 1992;42:19-38. 2. Dunlop MG. Colorectal cancer genetics. Semin Cancer Biol 1992;3:131-140. 3. Thomas DB, Karagas MR. Cancer in first and second generation Americans. Cancer Res 1987;47:5771-5776. 4. Cleave TL. The neglect of natural principles in current medical practice. J R Nav Med Serv 1956;42:55-83. 5. Cleave TL. Peptic ulcer. Bristol, UK: John Wright and Sons, 1962. as a clue to causation. Lancet 6. Burkitt DP. Relationship 1970;2:1237-1240. 7. Greenwald P, Lanza E. Role of dietary fiber in the prevention of cancer. In: DeVita VT, Hellman S, Rosenberg SA, eds. Important advances in oncology. Philadelphia: Lippincott, 1986:37-54. 8. Track B, Lanza E, Greenwald P. Dietary fiber, vegetables, and colon cancer: critical review and meta-analysis of the epidemiologic evidence. J Nat1 Cancer Inst 1990;82:650-661. 9. Willett WC, Stampfer MJ, Colditz GA, Rosner BA, Speizer FE. Relation of meat, fat, and fiber intake to the risk of colon cancer in a prospective study among women. N Engl J Med 1990;323:1664-1672. 10. Cummings JH, Wiggins HS, Jenkins DJA, Houston H, Jivraj T, Drasar BS, Hill MJ. Influence of diets high and low in animal fat on bowel habit, gastrointestinal transit time, fecal micro-
December
11.
12.
13.
14.
15.
16.
17.
1992
flora, bile acid, and fat excretion. J Clin Invest 1978;61:953963. Craven PA, Pfanstiel J, DeRubertis FR. Role of reactive oxygen in bile salt stimulation of colonic epithelial proliferation. J Clin Invest 1986;77:850-859. Freeman HJ, Spiller GA, Kim YS. A double-blind study on the effect of purified cellulose dietary fiber on 1,2-dimethylhydrazine-induced rat colonic neoplasia. Cancer Res 1978; 38:2912-2917. Freeman HJ, Spiller GA, Kim YS. A double-blind study on the effects of differing purified cellulose and pectin fiber diets on 1,2-diemthylhydrazine-induced rat colonic neoplasia. Cancer Res 1980;40:2661-2665. Jacobs LR, Lupton JR. Effect of dietary fibers on rat large bowel mucosal growth and cell proliferation. Am J Physiol 1984;246:G378-G385. McGarrity TJ, Peiffer LP, Kramer ST, Smith JP. Effects of fat and fiber on human colon cancer xenografted to athymic nude mice. Dig Dis Sci 1991;36:1606-1610. Jacobs LR. Enhancement of rat colon carcinogenesis by wheat bran consumption during the stage of 1,2-dimethylhydrazine administration. Cancer Res 1983;43:4057-4061. Kuratsune M, Honda T, Englyst HN, Cummings JH. Dietary
EDITORIALS
18.
19. 20.
21.
1967
fiber in the Japanese diet as investigated in connection with colon cancer risk. Jpn J Cancer Res 1986;77:736-738. Parkin DM, Laara E, Muir CS. Estimates of the worldwide frequency of sixteen major cancers in 1980. Int J Cancer 1988;41:184-197. Shankar S, Lanza E. Dietary fiber and cancer prevention. Hematol Oncol Clin North Am 1991;5:25-41. Delattre 0, Olschwang S, Law DJ, Melot T, Remvikos Y, Salmon RJ, Sastre X, Validire P, Feinberg AP, Thomas G. Multiple genetic alterations in distal and proximal colorectal cancer. Lancet 1989;2:353-356. Alberts DS, Einspahr J, Rees-McGee S, Ramanujam P, Buller MK, Clark L, Ritenbaugh C, Atwood J, Pethigal P, Earnest D, Villar H, Phelps J, Lipkin M, Wargovich M, Meyskens FL, Jr. Effects of dietary wheat bran fiber on rectal epithelial cell proliferation in patients with resection for colorectal cancers. J Nat1 Cancer Inst 1990;82:1280-1285.
Address requests for reprints to: C. Richard Boland, M.D., Chief, Gastrointestinal Section (lllD), Veterans Affairs Medical Center, 2215 Fuller Road, Ann Arbor, Michigan 48105. 0 1992 by the American Gastroenterological Association
Pacing the Gut The smooth muscle cells in the tunica muscularis of the human stomach exhibit spontaneous cyclical changes in membrane potential, detected readily by intracellular electrodes. When groups of these cells oscillate together, they create a change in tissue potential now detectable with extracellular electrodes. Such electrodes applied at operation to the corpus and antrum of the human stomach pick up these tissue potentials, called pacesetter potentials or slow waves. They have a regular, steady rhythm at a single frequency of about three cycles per minute.’ The potentials, however, are not detected in the gastric fundus. The findings are consistent with the hypothesis that the corpus and antrum of the human stomach are driven by a single dominant pacemaker located in the orad corpus. This region acts as pacemaker, because its cells oscillate at the fastest frequency and drive the more slowly beating distal cells to its faster rate. As the pacesetter potentials spread distally along the gastric wall, they may phase the onset of a second electrical phenomenon, called action potentials. Action potentials are spike-shaped, rapid changes in electrical potential superimposed on the pacesetter potentials. They are brought about by the action of stimulating neurotransmitters and hormones on gastric smooth muscle cells, stimulators such as acetylcholine and gastrin. Action potentials trigger the onset of contractions. As the amplitude and frequency
of the action potentials increase, so does the strength of the contractions. Without action potentials, few or no contractions are present and gastric emptying is slow or absent. Because the pacesetter potentials phase the onset of action potentials and contractions, they clearly set the frequency of the gastric peristaltic waves and determine their velocity and their direction of spread, hence, the term “pacesetter” potentials. Pacing the human stomach, like pacing the human heart, seems like a good idea. By driving the gastric pacesetter potentials faster,2 one might expect to speed gastric emptying. Tests in dogs with healthy stomachs, however, have shown that gastric emptying is not speeded by pacing the stomach fastere3 This may be because the rate of gastric emptying is already optimal in a healthy subject. Only as much thyme is discharged into the small intestine as can be efficiently digested and absorbed by that organ, Any influence, such as pacing which increases the frequency of peristaltic waves and so might speed emptying and upset the balance between emptying, digestion, and absorption, is resisted by neurohormonal controls that act to decrease the incidence of action potentials, weaken contractions, and prevent the change. When gastric emptying is slower or faster than is optimal, however, would pacing then have a role? Hocking et al. have explored this question in a report
EDITORIALS
Fiber and Colon Cancer: The Weight of the Evidence Cancers of the colon and rectum are major public health concerns throughout the world, particularly in North America and Western Europe. Approximately 156,000new cases of large bowel malignancy and more than 58,000 deaths from this disease are expected in the United States in 1992.’ Over the past 8 years, spectacular progress has been made in understanding the molecular events that occur during the transformation of normal colonic epithelium to a focus of adenocarcinoma. Studies by Vogelstein and others have shown that colon cancer develops as a result of an accumulation of genetic lesions that regulate cell growth and proliferation.’ Further research into these basic mechanisms may ultimately provide us with biomarkers that will allow us to focus our surveillance strategies on those individuals at greater risk of colonic malignancies. Understanding these fundamental mechanisms may also allow us to identify the environmental risk factors associated with colorectal cancer in hopes that changes in behavior will reduce the incidence of this disease. In the meantime, it is widely accepted that a diet generous in crude dietary fiber will result in gastrointestinal bliss and perhaps even help prevent colorectal cancer. The study in this issue by Cummings et al., which addresses the relationship between dietary fiber intake and colon cancer throughout the world, contributes to the growing body of literature that supports this belief. What is the evidence that dietary components alter the risk for colorectal cancer? Perhaps the strongest data supporting this concept came from epidemiologic studies in Japan, a country with a relatively low incidence of colorectal cancer. When Japanese individuals immigrated to countries with higher incidences of colorectal cancer, they assumed the increased risk endogenous to that country, presumably due to changes in diet. Other studies of immigrating populations showed the same shifts in cancer incidence.3 The specific dietary components associated with the changes in disease patterns have been difficult to elucidate. Population studies have implied that diets high in animal fat and calories and low in crude dietary fiber are risk factors for the development of colon cancer. Unfortunately, few studies have been
able to isolate the independent effects of these variables. It is important to consider the fact that diets low in fiber are often high in animal fat and calories. Nonetheless, dietary fiber content has enjoyed the greatest popularity as an important modifier of one’s risk for colorectal cancer. The role of a low-fiber diet in the genesis of gastrointestinal disease was first suggested almost 40 years ago when T. L. Cleave, a British naval surgeon, proposed that the processing of food and the elimination of fiber from the diet was responsible for many of the ills of industrialized societies.4*5 However, it was the observations of Burkitt in Africa, where the incidence of colon cancer is low, that framed the hypothesis that diets characterized by high fiber were protective against the development of colon cancer.” Since Burkitt’s hypothesis, a number of epidemiological studies have attempted to correlate the relationship between fiber intake and colon cancer. At least 17 studies (only two of which were case control studies) have found an inverse relationship between fiber intake and colon cancer,7 and a recent meta-analysis of epidemiologic studies on this topic provided an estimated combined odds ratio of 0.57 (95% confidence interval = 0.50-0.64) for colon cancer when comparing the highest and lowest quantiles of fiber intake.’ However, at least four studies (three of which were case control studies) have found no correlation between colon cancer and fiber intakee7 Furthermore, most of these studies have failed to consider the effects of animal fat and caloric intake, which may in fact be the independent variables that would explain the observed differences in risk. The Nurses’ Health Study, a case control study involving more than 80,000 women in the United States, found that women with the highest animal fat intake and the lowest crude fiber intake had the highest risk of colon cancer. However, a greater correlation with colon cancer risk was found for a high fat intake than a low-fiber diet9 How might dietary fiber reduce the risk of colorectal cancer? As just acknowledged, the benefits of fiber may simply lie in the displacement of dietary components such as fat or calories. These agents are most likely deleterious by virtue of their ability to enhance cell proliferation, thereby increasing the
December 1992
chances for mutagenic events. Specifically, high dietary fat has been associated with an increase in intraluminal bile acids that appear to enhance epithelial proliferation.‘O*” Another mechanism by which fiber may be protective is its ability to decrease the colonic transit time and bind a wide variety of reactive compounds, thereby reducing the contact between intraluminal carcinogens and colonic epithelium. However, it remains to be shown whether any of these mechanisms influences the development of colorectal cancer in humans. A final factor to consider is that the dietary sources of fiber, which often include fruits and vegetables, may contain increased amounts of micronutrients that may provide the protective effects that have been attributed to fiber. Animal models of colon carcinogenesis have been useful to examine the components and potential mechanisms afforded by dietary fiber. The term dietary fiber encompasses several groups of nonstarch polysaccharides (NSP) that vary in their ability to influence the development of cancer. Cellulose has been shown to protect against experimental colonic neoplasia in rats treated with the carcinogen 1,2-dimethylhydrazine, whereas similar doses of purified pectin did not.‘2*‘3 It has also been shown that oat bran, pectin, and guar all have different effects on stimulating mucosal growth in the rat colon.‘4 Interestingly, human colon cancer cell lines grown in the subcutaneous tissues of athymic mice show enhanced growth when the animals are fed a high-fat diet, and this effect may be attenuated by the addition of fiber, even though the tumors are isolated from the gastrointestinal tract.15 To confuse matters further, it should also be noted that some studies using animal models have shown the addition of large doses of fiber to be deleterious. When a 20% wheat bran diet was given during the period of carcinogen administration, a threefold increase in colon tumors was noted relative to contro1s.‘6 Thus, if fiber does provide a protective role against the development of colorectal cancer, population studies will likely need to consider the amounts and sources for fiber in their analysis. With this background in mind, what new insights have Cummings and his group brought to the issue of fiber and colorectal cancer? The authors report a significant correlation between stool weight and dietary intake of NSP (r = 0.84) based on data collected from a variety of published works on stool weight and NSP intake from XI different populations in 12 countries. They correlated the average stool weight in each population with cancer registry data for the incidence of colon cancer in each population and found a significant inverse relationship (r = 0.78). Based on their analysis, they determined that diets
EDITORIALS 1965
characterized by NSP intakes of >18 g/day would be associated with average stool weights of >15O g/day, which should be protective against bowel cancer. Several issues are worth noting regarding the authors’ data and conclusions. The first point pertains to the use of average stool weights for a given population. The authors collected stools from 220 healthy British adults and reported that the mean daily stool weight was 117 + 3.8 (SEM) g/day with a range of stool weights that varied from 19-450 g/day! If dietary fiber plays the important role that the authors suggest, it should be possible to identify subgroups at variable risks for cancer within this population. These variable risk subgroups may be overlooked when average stool weights from a variety of populations are plotted against the incidence of colorectal cancer. If such a relationship cannot be shown, confounding variables should be sought. The second point concerns the notable exceptions to the list of countries where daily fecal weight and colon cancer incidence are inversely correlated (Table 2). For example, a relatively low incidence of colon cancer is observed in the Maori of New Zealand despite a relatively low daily fecal weight. In the study reported by this group on a Japanese population, the average intake of NSP did not exceed 13 g/day, which corresponds to British levels of intake, in spite of the well-documented low incidence of colon cancer in Japan.17 Similarly, colon cancer is relatively prevalent among the populations of Helsinki, Finland, and the urban Chinese community of Malaysia despite relatively high fecal weights. These variances again suggest the presence of important confounding variables that are worthy of attention. Neither dietary fat intake or the source of dietary fiber were addressed in this analysis and, as mentioned earlier, these may be important factors in coionic carcinogenesis. A third point refers to the discordance in stool weights that was observed between men and women. Although the stool weight in women was not corrected for total body weight, it differed significantly between men and women (122 + 5.9 g/day vs. 102 + 5.4 g/day, P = 0.02). If stool weight were predictive of colon cancer risk, one would expect to see gender differences in the incidence of colon cancer. However, the incidence of colon cancer is similar between men and women in North America and greater in men in many other regions.” These relationships are multifactorial and are related to tumor sites in the colon, age, and menopause as discussed by the authors. This complex relationship remains to be fully understood. Finally, by what mechanism might dietary fiber protect against cancer in the colon but not the rec-
1966
GASTROENTEROLOGY Vol. 103, No. 6
EDITORIALS
turn? Perhaps the fermentation of fiber has more prominent effects in the proximal colon. Are there currently undetected “systemic effects” of a highfiber diet? Prior studies have suggested an inverse relationship between fiber intake and cancers of the esophagus, mouth, pharynx, stomach, breast, endometrium, and ovary.” Of interest, genetic damage is significantly more prominent in tumors of the distal colon than the proximal colon, suggesting that the luminal milieu may be more hostile distally.” The mechanism accounting for the differences in mutation and chromosomal instability have not yet been explored in vivo. Although it is not clear how the protective effects of fiber might be limited to that portion of the gastrointestinal tract between the ileocecal valve and rectosigmoid junction, it is often a piece of epidemiological evidence such as this that leads to the development of new mechanistic concepts in the laboratory. The authors conclude that diets characterized by a high fiber content will be expected to be protective against the development of colon cancer. Furthermore, they suggest, with some justification, a target level of at least 18 g/day of NSP. However, it has yet to be shown that such dietary changes in a given population will decrease the incidence of colon cancer. This requires a prospective analysis and may be rather difficult to confirm. Unlike certain habits such as cigarette smoking or alcohol consumption, from which a large segment of the population abstains, fiber and fat are components of virtually all diets. If subjects were simply to add fiber to their diet without altering fat or caloric intake, would a reduction in risk for colorectal cancer be expected? Would a relatively pure fiber supplement afford the same protection as the fiber found in fruits, vegetables, and grains? Prospective interventional studies are required to determine whether dietary intervention can modify the incidence of colorectal cancer. If one were to use the development of cancer as the end point in an observational study, it would require several decades to reach any conclusions. Therefore, reliable “intermediate biomarkers” must be used to assess the impact of intervention on cancer risk. One example of this application is the study by Alberts et al., which showed that dietary supplementation with wheat bran fiber for 2 months significantly decreased proliferation indices in colonic biopsies.‘* This group used a diet containing wheat fiber (2 g/ day) during the control period and intervened with 1.5 oz of All Bran cereal (13.5 g of wheat bran fiber; Kellogg Company, Battle Creek, MI) daily for 8 weeks. g
The half cup of cereal
NSP suggested by Cummings
provided
75% of the 18
et al., which supports
the feasibility of this type of dietary intervention. Further work into the molecular mechanisms of colorectal carcinogenesis may lead to identification of useful biomarkers that characterize early developmental events in colonic neoplasia. These biomarkers will allow us to measure the impact of dietary interventions as well as focus our efforts at surveillance screening in those at greatest risk. One might anticipate that similar approaches could be used to determine the impact of fat and fiber intake on tumor progression in the colon. In conclusion, Cummings’ group has used the simplest of all possible techniques to add to our knowledge of the genesis of colon cancer. The “weight of the evidence” implicates a protective effect of a diet characterized by high fiber (>18 g/day of NSP). There would appear to be relatively little risk to such a diet, but it is not clear that this protective association can be separated from other components of the diet, most prominently the effects of fat and calories. In any event, this work should stimulate discussion over breakfast and in the laboratories. C. RICHARD BOLAND JOSEPH C. KOLARS Gastroenterology Section
Veterans Administration Medical Center and the Gastroenterology Division Department of Internal Medicine University of Michigan Medical School Ann Arbor, Michigan
References 1. Boring CC, Squires TS, Tong T. Cancer Statistics,
1992.Ca-A CancerJPhys 1992;42:19-38. 2. Dunlop MG. Colorectal cancer genetics. Semin Cancer Biol 1992;3:131-140. 3. Thomas DB, Karagas MR. Cancer in first and second generation Americans. Cancer Res 1987;47:5771-5776. 4. Cleave TL. The neglect of natural principles in current medical practice. J R Nav Med Serv 1956;42:55-83. 5. Cleave TL. Peptic ulcer. Bristol, UK: John Wright and Sons, 1962. as a clue to causation. Lancet 6. Burkitt DP. Relationship 1970;2:1237-1240. 7. Greenwald P, Lanza E. Role of dietary fiber in the prevention of cancer. In: DeVita VT, Hellman S, Rosenberg SA, eds. Important advances in oncology. Philadelphia: Lippincott, 1986:37-54. 8. Track B, Lanza E, Greenwald P. Dietary fiber, vegetables, and colon cancer: critical review and meta-analysis of the epidemiologic evidence. J Nat1 Cancer Inst 1990;82:650-661. 9. Willett WC, Stampfer MJ, Colditz GA, Rosner BA, Speizer FE. Relation of meat, fat, and fiber intake to the risk of colon cancer in a prospective study among women. N Engl J Med 1990;323:1664-1672. 10. Cummings JH, Wiggins HS, Jenkins DJA, Houston H, Jivraj T, Drasar BS, Hill MJ. Influence of diets high and low in animal fat on bowel habit, gastrointestinal transit time, fecal micro-
December
11.
12.
13.
14.
15.
16.
17.
1992
flora, bile acid, and fat excretion. J Clin Invest 1978;61:953963. Craven PA, Pfanstiel J, DeRubertis FR. Role of reactive oxygen in bile salt stimulation of colonic epithelial proliferation. J Clin Invest 1986;77:850-859. Freeman HJ, Spiller GA, Kim YS. A double-blind study on the effect of purified cellulose dietary fiber on 1,2-dimethylhydrazine-induced rat colonic neoplasia. Cancer Res 1978; 38:2912-2917. Freeman HJ, Spiller GA, Kim YS. A double-blind study on the effects of differing purified cellulose and pectin fiber diets on 1,2-diemthylhydrazine-induced rat colonic neoplasia. Cancer Res 1980;40:2661-2665. Jacobs LR, Lupton JR. Effect of dietary fibers on rat large bowel mucosal growth and cell proliferation. Am J Physiol 1984;246:G378-G385. McGarrity TJ, Peiffer LP, Kramer ST, Smith JP. Effects of fat and fiber on human colon cancer xenografted to athymic nude mice. Dig Dis Sci 1991;36:1606-1610. Jacobs LR. Enhancement of rat colon carcinogenesis by wheat bran consumption during the stage of 1,2-dimethylhydrazine administration. Cancer Res 1983;43:4057-4061. Kuratsune M, Honda T, Englyst HN, Cummings JH. Dietary
EDITORIALS
18.
19. 20.
21.
1967
fiber in the Japanese diet as investigated in connection with colon cancer risk. Jpn J Cancer Res 1986;77:736-738. Parkin DM, Laara E, Muir CS. Estimates of the worldwide frequency of sixteen major cancers in 1980. Int J Cancer 1988;41:184-197. Shankar S, Lanza E. Dietary fiber and cancer prevention. Hematol Oncol Clin North Am 1991;5:25-41. Delattre 0, Olschwang S, Law DJ, Melot T, Remvikos Y, Salmon RJ, Sastre X, Validire P, Feinberg AP, Thomas G. Multiple genetic alterations in distal and proximal colorectal cancer. Lancet 1989;2:353-356. Alberts DS, Einspahr J, Rees-McGee S, Ramanujam P, Buller MK, Clark L, Ritenbaugh C, Atwood J, Pethigal P, Earnest D, Villar H, Phelps J, Lipkin M, Wargovich M, Meyskens FL, Jr. Effects of dietary wheat bran fiber on rectal epithelial cell proliferation in patients with resection for colorectal cancers. J Nat1 Cancer Inst 1990;82:1280-1285.
Address requests for reprints to: C. Richard Boland, M.D., Chief, Gastrointestinal Section (lllD), Veterans Affairs Medical Center, 2215 Fuller Road, Ann Arbor, Michigan 48105. 0 1992 by the American Gastroenterological Association
Pacing the Gut The smooth muscle cells in the tunica muscularis of the human stomach exhibit spontaneous cyclical changes in membrane potential, detected readily by intracellular electrodes. When groups of these cells oscillate together, they create a change in tissue potential now detectable with extracellular electrodes. Such electrodes applied at operation to the corpus and antrum of the human stomach pick up these tissue potentials, called pacesetter potentials or slow waves. They have a regular, steady rhythm at a single frequency of about three cycles per minute.’ The potentials, however, are not detected in the gastric fundus. The findings are consistent with the hypothesis that the corpus and antrum of the human stomach are driven by a single dominant pacemaker located in the orad corpus. This region acts as pacemaker, because its cells oscillate at the fastest frequency and drive the more slowly beating distal cells to its faster rate. As the pacesetter potentials spread distally along the gastric wall, they may phase the onset of a second electrical phenomenon, called action potentials. Action potentials are spike-shaped, rapid changes in electrical potential superimposed on the pacesetter potentials. They are brought about by the action of stimulating neurotransmitters and hormones on gastric smooth muscle cells, stimulators such as acetylcholine and gastrin. Action potentials trigger the onset of contractions. As the amplitude and frequency
of the action potentials increase, so does the strength of the contractions. Without action potentials, few or no contractions are present and gastric emptying is slow or absent. Because the pacesetter potentials phase the onset of action potentials and contractions, they clearly set the frequency of the gastric peristaltic waves and determine their velocity and their direction of spread, hence, the term “pacesetter” potentials. Pacing the human stomach, like pacing the human heart, seems like a good idea. By driving the gastric pacesetter potentials faster,2 one might expect to speed gastric emptying. Tests in dogs with healthy stomachs, however, have shown that gastric emptying is not speeded by pacing the stomach fastere3 This may be because the rate of gastric emptying is already optimal in a healthy subject. Only as much thyme is discharged into the small intestine as can be efficiently digested and absorbed by that organ, Any influence, such as pacing which increases the frequency of peristaltic waves and so might speed emptying and upset the balance between emptying, digestion, and absorption, is resisted by neurohormonal controls that act to decrease the incidence of action potentials, weaken contractions, and prevent the change. When gastric emptying is slower or faster than is optimal, however, would pacing then have a role? Hocking et al. have explored this question in a report
