Results

CORRELATION ANALYSIS

Table 1 shows that meat, animal fat and total fat had the highest correlation coefficients with CRC. These factors were also highly correlated with each other (r > 0.75). Controlling for meat reduced the correlation with CRC for total fat and for animal fat to negligible levels while that for meat remained after controlling for total fat and animal fat (table1).

REGRESSION ANALYSIS

We excluded olive oil in the first analysis as many studies of diet and CRC have not included it. The stepwise procedure identified first meat, then fish, and finally vegetables as the significant variables to be included in the model (table 2). The addition of fruit, total fat, vegetable oil, animal fat, meat, milk and cereal did not produce any improvement in fit above that found from the three factor model. The backward procedure produced the same model.

When olive oil was added, the stepwise procedure selected four factors that, in increasing order of magnitude of contribution were: meat, olive oil, fish and fruit (table 2). Vegetables did not contribute to the goodness of fit when olive oil was included in the selection list. The associations between CRC and meat, fish, and fruit were positive, while that with olive oil was negative. The model of meat, fish and olive oil accounted for 76% of the variation in CRC incidence between countries. The addition of fruit raised this to 80%. The addition of other food factors did not produce any significant improvement. The backward elimination procedure resulted in the same final models.

We explored the effect of fruit and vegetables further. The effect of vegetables alone was reduced by the addition of olive oil to the model of meat + fish + vegetables (the fitted parameter changed from −0.07, which was significantly different from zero, to −0.02, which was not; table 2). In contrast the addition of vegetables to the model of meat + fish + olive oil had less of an effect on the fitted parameter for olive oil (table 2). Thus the association of olive oil and CRC was not explained by its association with vegetables. Adding olive oil to the model of meat + fish + fruit produced a significant improvement in fit (its fitted parameter changed from −0.01 to 0.07). The addition of fruit to the model of meat + fish + olive oil also improved the fit and increased the apparent effect of olive oil (parameter changed from −0.71 to −1.05). Thus fruit only seemed to have an effect when meat, fish and olive oil were included in the model; but olive oil had an effect irrespective of whether fruit was included. Finally, we compared the effect of olive oil on CRC when both fruit and vegetables were included in the model. The results were basically the same as when fruit and vegetables were considered separately.

Figure 1A–C shows the agreement between the actual CRC rates and those obtained for various fitted models. Figure 1A illustrates the fit of the model with meat alone. Figure 1B shows the fit of the model with meat and fish. It shows that the fitted values for Japan and Norway, both countries with high fish consumption, are now both closer to their observed rates, while those for Greece and Spain were higher than their observed rates. The addition of olive oil to the model of meat + fish (fig 1) improved the fit of the data for Greece and Spain.

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Figure 1

Comparison of observed rates of colorectal cancer (CRC) per 100 000 population with the rates obtained from each of the following three fitted models: models consisting of (A) meat; (B) meat + fish and (C) meat + fish + olive oil.

Discussion

DIETARY FACTORS

Ecological studies consistently find that relatively high levels of risk of CRC are associated with high intakes of meat and fat and low intakes of fibre.6 17 18 COMA reported that the balance of evidence is that fish consumption is not associated with CRC.1 However, there seems to be an additive effect of meat and fish (table 2), which may reflect the overall intake of animal protein and fat.

Vegetarians are generally at lower risk of CRC than meat eaters.19 The apparently protective effect of a vegetarian diet, and specifically of fibre, might be attributable to plant components of diet, perhaps antioxidants, or it might result from lack of exposure to meat and fat. The Working Group on Diet and Cancer of the Committee on Medical Aspects of Food and Nutrition Policy (COMA) reported that the summarised evidence on antioxidants is inconclusive.1 In our study, simple correlation showed an association between high incidence rates of CRC and low levels of cereal and vegetable consumption. However, multivariate modelling showed that high levels of meat consumption rather than low levels of cereal and vegetables were the important factors. Vegetables played a part in our model when olive oil was omitted, but lost significance when it was included.

The association between CRC and fruit in our study, after adjusting for meat, fish and olive oil, was unexpected. This association may be confounded with some aspect of affluence. The COMA report concluded that there is limited and inconsistent evidence about fruit consumption and CRC.1

Olive oil was found to be negatively associated with CRC after allowing for the other dietary factors. The moderating influence of the olive oil effect may be best understood by a consideration of how olive oil and bile salts might interact together.

THE DIAMINE OXIDASE HYPOTHESIS

It is widely believed that bile salts may have some role in the aetiology of CRC.20 It has also been suggested that the enzyme diamine oxidase (DAO) may play a part.21 DAO is a major catabolic enzyme for histamine. It is found in highest concentration in the ileal mucosa, and also in the colon.22 DAO is thought to have a role in colonic mucosal regulation.23 DAO activity is reduced in vitro by detergent and also by glycochenodeoxycholic acid.24 25

The role of secondary bile acids, including deoxycholic acid, in the development of colorectal carcinoma has been well documented.5 6 Deoxycholic acid appears to be reduced in vegetarians.19 26 The inhibition of DAO by deoxycholic acid is as yet speculative but possible, in view of in vitro inhibition of DAO by glycochenodeoxycholic acid.25There seems to be a significant reduction in the cholic acid and chenodeoxycholic acid pool in rats given an olive oil diet.27 In discussing the role of meat in CRC development, Owen and Hill have suggested that meat, too, may influence deoxycholic acid5 6 with higher levels of faecal bile acid in populations with a normal western mixed diet. Increases in faecal steroid levels seem to be associated with higher mucosal proliferation rates or colonic adenomas.28-30

If meat increases deoxycholic acid in the human colon and rectum, it might be expected that meat could increase CRC incidence because of the inhibition of DAO. If functional DAO is necessary for in vivo control of mucosal proliferation, and if olive oil reduces deoxycholic acid in the human colon and rectum, then it might be expected that olive oil would have a protective effect on CRC incidence because of the greater availability of DAO. It is therefore noteworthy that, in two human studies of the relation between olive oil and CRC, high consumption of olive oil was associated with a decrease in cancer risk.31 32

In summary, the DAO hypothesis is that deoxycholic acid, which may be increased by meat consumption and reduced by olive oil consumption, may influence polyamine metabolism in the colorectal mucosa leading to changes in mucosal turnover, polyp formation and the adenoma/carcinoma sequence.

In conclusion, we provide some further ecological support for the involvement of meat in the development of CRC and we show new evidence supporting the hypothesis that olive oil may protect against CRC. We appreciate that the mechanism we have suggested is speculative and also that ecological studies are limited. We suggest that further study is merited, including studies of DAO activity in the colorectal mucosa of people who develop CRC, and further epidemiological studies of CRC and olive oil.