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Epidemiological data indicate that colon cancer incidence is associated mainly with high dietary fat intake. Studies in metabolic epidemiology have shown a strong association between dietary fat intake, level of fecal bacteria, fecal acid, and neutral sterols, and the risk of colon cancer among different populations. Current concepts visualize that colonic bile acids and cholesterol metabolites play a modifying role in large bowel carcinogenesis, and that these compounds are derived from dietary factors, directly or indirectly, and subsequently are modified by the intestinal bacteria. In animal models, lithocholic acid and deoxycholic acid, which are present in high concentration in the large bowel of man, acted as promoters of colon carcinogenesis. The carcinogenic effect of azoxymethane in rats was enhanced by the increase of bile salts in the colon induced by surgical means. Animals fed a high fat diet were more susceptable to colon tumor induction by dimethylhydrazine compared with rats fed a normal fat diet. Our data also demonstrate that the intestinal microflora played a modifying role in accelerating colon tumor production by dimethylhydrazine.

The distribution of cancer of the colon, particularly its infrequency in Japan, its increase among Japanese immigrants to the United States and the high rate of this disease among Americans and most Western Europeans, indicates that environmental factors are of etiologic significance in the development of this disease. Available evidence suggests that this factor is dietary in nature and is likely to be related to dietary fat intake. Studies in metabolic epidemiology have shown a correlation between dietary intake and the makeup of fecal bacteria, and between bile acids and cholesterol metabolism in the feces. A strong association has also been established between the level of anaerobic bacteria, metabolized bile acids, and degraded cholesterol and the risk of colon cancer among different populations. It remains to be shown whether this established association is causative in nature.

The dietary pattern and fecal constituents of two populations with distinct risk for the development of colon cancer, a high-risk population in New York Metropolitan area and a low-risk population in rural Kuopio, were studied. The average daily intake of dietary fat and protein was the same in the two groups, but the sources of fat were different, a greater portion coming from dairy products in rural Kuopio and from meat in the New York Metropolitan area. Not only the frequency of bowel movements was higher, but also the daily total stool output as well as the fecal fiber excretion were greater in Kuopio compared with New York due to high dietary intake in rural Kuopio of cereal products rich in fiber. The concentration of fecal secondary bile acids and bacterial β-glucuronidase activity was lower in rural Kuopio, but the total daily excretion of these constituents was the same in two populations. The daily fecal excretion of bacterial nuclear dehydrogenase activity and of neutral sterols was higher in rural Kuopio, and the concentration of these constituents was the same in the two groups. The high daily excretion of cholesterol metabolites in Kuopio might be due to high dietary intake of dairy products. The data suggest that one of the factors contributing to the low-risk of large bowel cancer in Finland, in spite of high dietary intake of fat, appears to be the fact that a high dietary fiber leads to an increase in stool bulk, thus diluting bile acids, which have promoting activity. Cancer 42:2832–2838, 1978.

Fecal neutral steroids and bile acids were measured in patients with familial polyposis, family controls who are immediate relatives of patients, and controls other than relatives. All subjects were consuming a mixed Western diet at the time of collection of stool specimens. Although the total fecal neutral sterol concentrations were not different between the groups, the patients with familial polyposis excreted a high amount of cholesterol and low levels of coprostanol and coprostanone compared with other groups. Patients with familial polyposis excreted levels of total bile acids in their feces comparable to those excreted by controls; lithocholic acid excretion was decreased in patients with familial polyposis. These findings suggest that analysis of stools for cholesterol and its metabolites be useful in screening the siblings of polyposis families for latent disease.

Epidemiological data demonstrate that colon cancer incidence is associated mainly with high dietary fat consumption. Studies in metabolic epidemiology indicate that high fat intake influences both the amount and type of bile acids and neutral sterols and intestinal microflora acting on these compounds which may contain tumorigenic activity for the colon. This is compatible with the results of studies comparing populations with high or low risk for the colon cancer and patients with colon cancer.

There is a general agreement that dietary factors, particularly dietary fat, significantly influence the pathagenesis of large bowel cancer. The following hypotheses on the etiology of colon cancer are suggested: 1)conversion of cholesterol and δ5−7-dehydrocholesterol, which are normally present in colonic contents and mucosa, to reactive metabolites that act as carcinogens, may be an important step in colon carcinogenesis; 2)dietary fat changes the concentration of bile acids and also the metabolic activity of colonic bacteria, which may produce tumorigenic compounds from bile acids; 3) mucosal and/or luminal conversion of cholesterol to its epoxide may be of etiologic significance; and 4) diet also influences mixed-function oxidases, which could play a role in modifying colon carcinogenesis. Today's challenges to biomedical scientists and clinical investigators involved in colon cancer are as follows: 1) the animal experimentor should design and effectively relate animal models to the human setting; 2) it should be found whether it is possible for the fecal constituents of an individual on an American diet to be made similar to those of individuals on a Japanese diet, and, if so, what degree of dietary modification is required?; 3) it should be found whether solitary polyps could be reduced in size by strict dietary modification; 4) regarding managerial preventive medicine, it should be decided whether it is recommended to reduce the fat and cholesterol content of our staple diet; and 5) with regard to individual preventive medicine, people should be aware of calorie excesses, and of the fat and cholesterol content of their diet from early in life onward.

Evidence from epidemiology and geographic pathology indicates that colon cancer is an environmental disease. Large bowel cancer currently has the highest incidence of all human neoplastic diseases in the United States. In other Western countries it has similarly high incidences, while in countries on the African continent, in Central and Western Latin America, and in Japan, it has a low incidence. In low incidence countries, the incidence of the disease is inversely related to level of socioeconomic group; such a distinction is not observed in the Western world. High intake of dietary fat is considered the key element associated with higher risk. Dietary fiber content has been implicated but requires validation. Studies in metabolic epidemiology have shown that individuals on high fat diets have slightly different intestinal microflora. However, in both high and low risk individuals significantly different levels of certain key bacterial enzymes in the flora are even more important. There are appreciable differences in neutral sterols and bile acids, the high risk population having higher levels in their stools. Reliable modalities for the induction of large bowel cancer in animal models include the administration to rodents of derivatives of: 1) 3-methyl-4-aminobiphenyl; 2) compounds related to the natural plant product cycasin or methylazoxymethanol β-glucoside, namely methylazoxymethanol acetate, azoxymethane (AOM), and 1,2-dimethylhydrazine (DMH); 3) intrarectal administration of direct-acting carcinogens such as methylnitro-nitrosoguanidine (MNNG), methylnitrosourea, and methylazoxymethanol acetate; and 4) in select hamster strains, oral administration of large amounts of 3-methylcholanthrene. Some of these chemicals, specifically intrarectal MNNG or AOM, are at least as carcinogenic in germ-free rats as in conventional rats, but 1,2-dimethylhydrazine is less active in the germ-free system. A high fat diet, similar to that of a high risk human population, yields more induced colon cancer compared with a low fat diet. Animals on a high fat diet excrete more neutral sterols and bile acids than controls. Colon cancer induced by DMH in animals can be inhibited with drugs such as disulfiram, which alter the metabolic fate of the carcinogen. Bile acids exert a promoting effect in colon carcinogenesis in animal models, thus outlining the possible role of bile acids in human cancer development.