LINKS BETWEEN CANCER AND CARBOHYDRATE INTAKE
10.3 LINKS BETWEEN CANCER AND CARBOHYDRATE INTAKE
10.3.1 S UGARS AND D IGESTIBLE C ARBOHYDRATES
Digestible carbohydrate intake is positively linked to cancer risk because of its role in promotion of obesity. Excess energy intake and obesity are related to higher incidences of many cancers, so it is difficult to isolate the adverse effects of any macronutrient source. Total sucrose intake and glycemic index were linked to
increased risk of lung cancer in a case-control study in Uruguay. 8 Augustin et al. 9 reported a direct association between glycemic index and endometrial cancer in a case-control study. Ovarian cancer risk was also linked to glycemic index and glycemic load in an Italian case-control study. 10
Results with breast cancer and sugar intake have been conflicting and not sufficient to determine a link. 11 Augustin et al. 12 reported that glycemic index and glycemic load were linked to increased breast cancer risk. Jonas et al. 13 found no
Dietary Carbohydrates and Risk of Cancer
association between postmenopausal breast cancer risk and dietary glycemic index and load among 63,307 U.S. women in the Cancer Prevention Study II Nutrition Cohort. Insulin resistance and insulin-like growth factors may play a role in
development of breast cancer. Cho et al. 14 reported that associations between carbohydrate intake or glycemic load and breast cancer risk among young adult women differed by body weight, with more risk in women with a larger body mass index. The Health-Professional Follow-Up Study found a reduced risk of
advanced prostate cancer with increased fructose intake. 15 A diet high in glycemic load may increase the risk of pancreatic cancer in women who already have an underlying degree of insulin resistance. 16
More data have been published on the relationship between sugar consumption and digestive cancers. Augustin et al. 17 reported that high dietary glycemic index and glycemic load were associated with cancers of the upper aerodigestive tract. The World Cancer Research Fund and the American Institute for Cancer Research 18 reported an increase in colorectal polyps and colorectal cancer risk across intakes
of sugar and sugar-rich foods. Satia-Abouta et al. 19 found that total energy intake was consistently associated with colon cancer risk, but associations with individual macronutrients varied by race and by adjustment for energy intake in a North Carolina case-control study. A Canadian prospective cohort study in women found no relationship between diets high in glycemic load, carbohydrates, or sugar and colorectal cancer risk. 20
10.3.2 D IETARY F IBER
Dietary fiber has physiological effects throughout the gastrointestinal tract that may explain its protectiveness against cancer. Although we generally think of dietary
fiber as most active in the large intestine, it is known that fiber affects hormones in the upper digestive tract. These changes may alter satiety, slow digestion, and aid
in weight maintenance. Additionally, insulin response has been considered most relevant in diabetes prevention, although it also has been linked to risk of colon cancer and breast cancer.
Potential mechanisms for the protective nature of dietary fiber against colon cancer are listed in Table 10.1. The fermentation of dietary fiber in the gut is considered its most important physiological effect. Fermentation of carbohydrate in the colon produces short-chain fatty acids (SCFAs) that help maintain the
integrity of the gut. 21 More than 75% of dietary fiber in an average diet is broken down in the large intestine, resulting in the production of carbon dioxide, hydrogen, methane, and short-chain fatty acids, including butyrate, propionate, and acetate. Propionate and acetate are metabolized in colonic epithelial cells or peripheral tissue. Butyrate may regulate colonic cell proliferation and serve as an energy source for colonic cells. Propionate is transported to the liver and may suppress cholesterol synthesis, a potential explanation for how soluble dietary fiber lowers serum cholesterol.
According to calculations by Cummings and MacFarlane, 22 if approximately 20
g of fiber is fermented in the colon each day, approximately 200 mM SCFAs will
be produced, of which 62% will be acetate, 25% propionate, and 16% butyrate.
Functional Food Carbohydrates
TABLE 10.1 List of Mechanisms by which Fiber Can Protect against the Development of Cancer
• Increased stool bulk Decrease of transit time Dilution of carcinogens
• Binds with bile acids or other potential carcinogens • Lower fecal pH
Inhibition of bacterial degradation of normal food constituents to potential carcinogens • Changes in microflora • Fermentation by fecal flora to short-chain fatty acids
Decrease in colonic pH Inhibition of carcinogens
• Increase in lumenal antioxidants • Peptide growth factors • Alteration of sex hormone status • Change in satiety resulting in lowered body weight • Alterations in insulin sensitivity and glucose metabolism
Colonic absorption of SCFAs is concentration dependent with no evidence of a saturable process. The mechanism by which SCFAs cross the colonic mucosa is thought to be passive diffusion of the unionized acid into the mucosa cell. SCFAs are respiratory fuels for the colonic mucosa. In isolated human colonocytes, butyrate
is actively metabolized to both CO 2 and ketone bodies, which accounts for about 80% of the oxygen consumption of colonocytes. Butyrate is almost completely consumed by the colonic mucosa, while acetate and propionate enter the portal circulation, extending the effects of dietary fiber beyond the intestinal tract.
Butyrate may be an important protective agent in colonic carcinogenesis. 23 Trophic effects on normal colonocytes in vitro and in vivo are induced by butyrate. In contrast, butyrate arrests the growth of neoplastic colonocytes and inhibits the preneoplastic hyperproliferation induced by some tumor promoters in vitro. Butyrate induces differentiation of colon cancer cell lines and regulates the expression of molecules involved in colonocyte growth and adhesion.
The effects of butyrate on colonic tumor cell lines in vitro seem to contradict what has been shown in vivo. 24 Butyrate appears to have two contrasting effects. It serves as the primary energy source for normal colonic epithelium and stimulates growth of colonic mucosa, yet in colonic tumor cell lines it inhibits growth and induces differentiation and apoptosis. Since SCFAs are volatile, they are quickly absorbed from the lumen. SCFAs acidify the gut, which may affect development of colon cancer because changes in gut pH will affect solubility of metabolites and activities of bacterial enzymes. 25
Other mechanisms through which dietary fiber affects colon cancer have been examined in animal models. Reddy et al. 26 reported that the concentration of fecal
secondary bile acids and fecal mutagenic activity were significantly lower during
Dietary Carbohydrates and Risk of Cancer
wheat bran supplementation compared to the control, whereas an oat bran diet supplemented at a level to achieve the same level of fiber had no impact on these
measures. Other studies have examined fiber’s ability to increase fecal bulk and speed
intestinal transit. Dietary fibers differ in their ability to hold water and their resistance to bacterial degradation in the gut. Pectin is effective in holding water,
but is quickly fermented in the gut and cannot be found in feces. Wheat bran consistently has been found to have the most effect on stool bulk, probably because it is slowly fermented and survives transit through the gut. Milling of wheat bran may affect the laxative properties of the bran, with larger particle sizes causing larger increases in fecal weight.
Dietary fiber sources such as wheat bran are complex matrices, and attempts have been made to isolate the effects of chemical components of wheat bran. In an
animal study, rats were fed wheat bran, dephytinized wheat bran, and phytic acid alone, and aberrant crypt foci were measured after treatment with azoxymethane. 27 Wheat bran without phytic acid was less protective than intact wheat bran, suggesting that the protective effects of wheat bran include fiber and phytic acid. Certain components of dietary fiber are more protective against colorectal cancer. Insoluble fibers have consistently been found to decrease cell proliferation, while soluble fibers
may increase cell proliferation. Lu et al. 28 found that lignin, a component of insoluble dietary fiber, is a free radical scavenger. They suggest that the ability of dietary fiber
to protect against colorectal cancer may be determined by the amount of lignin in dietary fiber as well as the free radical-scavenging ability of the lignin.
A usual criticism of animal studies in this area is the large amount of dietary fiber that is fed. Dietary fibers have been fed at levels of 30% of the diet and more.
These levels of intake have no bearing on typical or recommended intakes in humans. Yet animal studies allow investigators to screen a wide range of different dietary fibers at many doses.
Two analyses, conducted as meta-analyses, have summarized the observational and case-control epidemiologic studies on dietary fiber and colorectal cancer. Trock
et al. 29 analyzed 37 epidemiologic studies that examined the relationship between colorectal cancer and fiber, vegetables, grains, and fruits, either alone or in combi-
nation. Overall, 80% of the studies reported up to that time supported the protective role of dietary fiber in colorectal cancer. Howe et al. 30 conducted a combined analysis
of data from 13 case-control studies in populations with different colorectal cancer rates and dietary practices. The risk of colorectal cancer decreased incrementally as dietary fiber intake increased. Consumption of more than 31 g of fiber/day was associated with a 50% reduction in risk of colorectal cancer compared to a diet incorporating <11 g/day. The authors estimate that the risk of colorectal cancer in the U.S. population could be reduced by about 31% from an average increase in
fiber intake from food sources of about 13 g/day. In contrast, Giovannucci 31 recently concluded that more recent epidemiologic studies have not supported a strong
influence of dietary fiber or fruits and vegetables on colorectal cancer. Le Marchand et al. 32 report a protective role of fiber from vegetables against
colorectal cancer that appears to be independent of its water solubility property and of the effects of other phytochemicals. High intake of vegetables, fruits, and grains
Functional Food Carbohydrates
was associated with a decreased risk of polyps in a case-control study. 33 Lubin et al. 34 found no significant protection against adenomatous polyps in a case-control study. They did find a significant interaction between water and fiber intake. They suggest that fiber and water increase the volume of colonic contents, as well as dilute and adsorb exogenous and endogenous toxic compounds present in the colonic contents. Also, the increased volume of bowel contents promotes peristalsis, reducing the duration of the contact of colonic contents with the mucosa.
Slattery et al. 35 examined eating patterns and risk of colon cancer in a population- based case-control study. The prudent patterns, which included vigorous exercise, smaller body size, and higher intakes of dietary fiber and folate, were associated with a lower risk of colon cancer. In contrast, the Western style was associated with
increased risk of colorectal cancer. Mai et al. 36 reported that within a cohort of older women characterized by a relatively low fiber intake, there was little evidence that
dietary fiber intake lowered the risk of colorectal cancer. Peters et al. 37 assessed the relation of fiber intake and frequency of colorectal
adenoma within the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screen- ing Trial. High intakes of dietary fiber were associated with lower risk of colorectal
adenoma. In this case-control study of over 38,000 subjects, subjects with the highest amounts of fiber in their diets (36 g/day) had the lowest incidence of colon adenomas.
Their risk of having an adenoma detected by sigmoidoscopy was 27% less than that of the people who ate the least amount of fiber (12 g/day). Fiber from fruits and
grain/cereals was significantly associated with lower adenoma risk, while fiber from vegetables and legumes was not.
The data from large cohort studies are not consistent. In the Health Professional Follow-up Study, 38 dietary fiber was inversely associated with risk of colorectal adenoma in men. All sources of fiber (vegetables, fruits, and grain) were associated with a decreased risk of adenoma. The Nurses’ Health Study found no protective
effect of dietary fiber on the development of colorectal cancer in women. 39 In the Iowa Women’s Health Study, a weak and statistically nonsignificant inverse associ- ation was found between dietary fiber intake and risk of colon cancer. 40
The European Prospective Investigation into Cancer and Nutrition (EPIC) is a prospective cohort study comparing the dietary habits of more than a half-million people in 10 countries with colorectal cancer incidence. 41 It found that people who ate the most fiber (those with total fiber from food sources averaging 33 g/day) had
a 25% lower incidence of colorectal cancer than those who ate the least fiber (12 g/day). The investigators estimated that populations with low average fiber consump- tion could reduce colorectal cancer incidence by 40% by doubling their fiber intake.
Few epidemiologic studies have collected biomarkers of dietary fiber intake. Cummings et al. 42 collected data from 20 populations in 12 countries and found that
average stool weight varied from 72 to 470 g/day and was inversely related to colon cancer risk. Dukas et al. 43 reported that in the Nurses’ Health Study, women in the highest quintile of dietary fiber intake (median intake, 20 g/day) were less likely to experience constipation than women in the lowest quintile (median intake, 7 g/day).
It is known that different dietary fibers have different effects on stool weight. As summarized by Cummings, 7 wheat bran is most effective in increasing stool
weight, with each gram of fiber fed as wheat bran increasing stool weight by 5.4 g.
Dietary Carbohydrates and Risk of Cancer
In contrast, soluble fibers like pectin only increase stool weight by 1.2 g/g of fiber fed as pectin. Yet psyllium, a fiber that is at least 70% soluble, increases stool weight by 4.0 g/g of fiber fed as psyllium. Thus, the laxation properties of a fiber source cannot be predicted based on the solubility of the fiber. The relationship between stool weight and protection from colorectal cancer could be strong while the rela- tionship between dietary fiber intake and colorectal cancer is weak because of all these inconsistencies in fiber measurement and physiological effect.