Dietary Fiber and the Etiology of Cancers Colon and Rectum

Population Studies

This is one long-standing association that has been surprisingly problematic. Early studies on native Africans who consumed an unrefined diet showed them to have a very low incidence of this cancer.

Although subsequent studies have shown a negative association between greater fiber intake and lowered risk, it has proved to be relatively weak. Indeed, in one US study there was no real association between fiber intake and cancer susceptibility. Some of the loss of significance seen in this evaluation may reflect the lack of allowance for confounding variables. For example, in a 6-year follow-up of women, the association between low fiber intake and the incidence of colon cancer disappeared after adjustment was made for meat intake. In another study of men, low fiber intake was an independent risk factor for the incidence of adenomatous polyps during a 2-year follow-up period.

Fruit and vegetable fiber has been consistently associated with a lower risk of colon cancer, but the relationship with cereal fiber is less clear. However, whole grain cereals appear to be protective—a further anomaly in the relationships between plant foods and disease risk. These discrepancies may be in the process of resolution. First, it seems that the early observational data were confounded by the analytical technologies available, and the perception that native populations consuming unrefined diets had high fiber intakes is incorrect. It seems likely that they ate relatively little fiber but had high intakes of RS. Population studies have shown a protective effect of apparent RS intake and color-ectal cancer risk. The word 'apparent' is pivotal because there is currently no accepted method for RS determination and thus, there are no reliable data on dietary intakes. There are also issues regarding the intakes of dietary fiber and cancer risk. Part of the problem inherent in the study of colonic cancer is that, in contrast to CHD (in which there are easily measurable risk markers such as plasma cholesterol that can be modified by diet), the only indices for colon cancer are not easily measurable: the appearance of aberrant crypts, adenomatous polyps, or the disease itself. Hitherto, animal studies have largely been confined to rodents treated with chemical carcinogens (usually dimethylhydrazine), and they suggest that dietary fiber from wheat bran and cellulose may afford greater protection against the development of colon cancer when associated with a low-fat diet compared with soluble NSPs. These data stand in contrast to observational studies but are supported by interventions in humans with familial adenomatous polyposis. These people are at genetically greater risk of colonic cancer and represent one means of assessing risk modification through dietary intervention and monitoring polyp size and frequency through colonoscopy. In the Australian

Polyp Prevention Trial, subjects consumed 25 g of wheat bran per day and there was a decrease in dysplasia and total adenoma surface area when the diet was also low in fat. This supports epidemiolo-gical studies that show that increased fat and protein intakes increase risk. Other prevention trials have examined the effects of increasing fiber intake on the recurrence of polyps following a polypect-omy. In a Canadian study of 201 men and women, a high-fiber, low-fat diet protected against polyp recurrence in women but in men there was actually an increase. A third trial examined the effects of diet on the prevalence of rectal polyps in 64 people with familial polyposis coli who had a total colect-omy. Those who received and actually took the high-fiber (22.5 g fiber as a breakfast cereal) showed a reduction in polyps. These data are not conclusive but are reasonably consistent with overall knowledge.

Complex Carbohydrates and Colorectal Cancer

An obvious factor for the inconsistent results of the effect of different intakes of dietary fiber on color-ectal cancer is the variation in the analytical methodology used in different studies. There is also increasing evidence that total dietary complex carbohydrates may be as important as fiber. Analysis of stool weight from 20 populations in 12 countries showed that larger stools were correlated with a lower incidence of colon cancer. Intakes of starch and dietary fiber (rather than fiber alone) were the best dietary correlates with stool weight. A subsequent meta-analysis showed that greater consumption of starch (but not of NSPs) was associated with low risk of colorectal cancer in 12 populations. The examination also showed that fat and protein intakes correlated positively with risk. This meta-analysis is probably the first of its kind to suggest a protective role for starch in large bowel cancer and underscores the need to consider complex carbohydrates as fiber equivalents and not just as NSPs and starch. The need for better information on dietary intake data and risk is underscored by the data from the European Prospective Investigation of Cancer and Nutrition, which showed a substantial reduction in risk with increasing fiber intake. This multinational study is important because it has sufficient power (expressed as a range of fiber intakes and individuals observed) to give confidence in the observations. Follow-up of 1939 011 person-years throughout 10 countries showed that a doubling of fiber intake from foods could reduce risk by 40%.

Potential Mechanisms Indicating a Role in the Etiology of Colorectal Cancer

Colorectal tumorigenesis is a multistep process. These steps involve a number of genetic alterations that convert a normal epithelium to a hyperproliferative state and then to early adenomas, later adenomas, and, finally, frank carcinoma and metastasis. Fiber may, and probably does, play a role in all of these stages, and several mechanisms have been proposed by which it could play a role in the etiology of the disease (Table 1).

A number of agents may induce genetic damage in the colonocyte, including mono- and diacylgly-cerols, nonesterified fatty acids, secondary bile acids, aryl hydrocarbons and other pyrrolytic products of high-temperature cooking, and ammonia and amines and other products of large bowel bacterial protein degradation. One of the simplest protective mechanisms for dietary fiber is purely physical. By increasing fecal bulk, fiber could produce a more rapid transit time as well as act as a diluent and thus reduce exposure to potential mutagenic agents. It is also possible that fiber components could bind mutagens. However, because this appears to be unlikely for bile acids, the same may apply to other carcinogens.

Table 1 Effects of dietary fiber and resistant starch that could impact on the etiology of colorectal cancer

Increased stool bulk (mainly insoluble NSPs)

Decreases transit time, minimizing contact between colonocytes and luminal carcinogens Reduces exposure through dilution of carcinogens

Binding of bile acids and other potential carcinogens (mainly insoluble NSPs)

Lowers free concentrations of mutagens

Modifying fecal flora and increasing bacterial numbers

(soluble and insoluble NSPs and RS) Decreases secondary bile acids, which are potential carcinogens Lowers colonic NH3 (a cytotoxic agent) by fixing nitrogen in the bacterial mass

Lowering fecal pH through SCFA production (NSPs but mainly RS)

Inhibits growth of pH-sensitive, potentially pathogenic species, which may degrade food constituents, and endogenous secretions to potential carcinogens Lowers absorption of toxic alkaline compounds (e.g., amines) Lowers solubility of secondary bile acids

Fermentation to SCFAs (NSPs but mainly RS)

Depending on source, raises butyrate which is a preferred substrate for normal colonocytes, and (in vitro) promotes a normal cell phenotype, retards the growth of cancer cells, and facilitates DNA repair

NSPs, nonstarch polysaccharides; RS, resistant starch; SCFAs, short-chain Fatty acids.

Production of SCFAs by the resident microflora induces a number of general changes in the colonic environment, including a lowering of pH. Case-control studies show that pH is higher in patients with cancer compared to controls but this may reflect altered dietary habits rather than long-term risk. However, at lower pH, basic toxins are ionized while secondary bile acids are less soluble so that the absorption of both would be reduced. The activities of both of the enzymes 7a-dehydroxylase and glucuronidase are decreased at lower pH. These changes would diminish the conversion of primary to secondary bile acids and the hydrolysis of glucur-onide conjugates, respectively and thus limit their carcinogenic potential. However, there is consensus that the effects of SCFAs may be rather more specific and mediated through one acid—butyrate. Butyrate is a preferred substrate for normal colonocytes and numerous studies in vitro have shown that it has several actions that promote a normal cell phenotype. Cell studies show that butyrate induces hyperacyla-tion of histones, leading to downregulation of gene expression and arrest of proliferation. Other actions include DNA hypermethylation which would have similar effects on tumor cell growth. Butyrate also has favorable effects on apoptosis so that a normal program of cell death is maintained. One marker of a differentiated colonocyte is its ability to produce alkaline phosphatase and butyrate is a powerful promoter of alkaline phosphatase in vitro. There is reciprocal downregulation of various oncogenes in colorectal cancer cell lines. These data are very promising for a direct role of butyrate in protecting against colonic cancer but there is an emerging paradox. In the presence of butyrate, there is either increased proliferation or no effect in normal cells but the proliferation of neoplastic cells is reduced. The differentiation of the normal cells is unchanged or suppressed with butyrate but is induced in cancer cells. These differing effects may be explained by neoplastic alterations (perhaps as a result of mutations in oncogenes) in cell signal systems.

It must be emphasized that none of the effects of butyrate in vitro have been duplicated in vivo, but they are of great promise and supportive evidence continues to accumulate. This is especially true for RS which appears to produce relatively more buty-rate than other nondigestible carbohydrates. However, consideration may also need to be given to the existence of interindividual differences in the fermentative capacity of the microflora, the fact that RS from different sources may be fermented to different extents, and the actual colonic site at which fermentation takes place (i.e., whether in the proximal or distal colon).

Inter alia, the data suggest that protection against colorectal cancer is due to several mechanisms and that these can interact. One factor of considerable importance is the issue of overweight which is an independent risk factor for colorectal cancer. Obesity may have to be taken into account much more than has been the case in earlier studies. It appears that some of the effect may be mediated through raised plasma insulin and insulin-like growth factors (which may well be influenced by dietary carbohydrates).

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