Heme iron amplifies azoxymethane initiating effect on rat colon preneoplastic lesions

Objective: Colorectal cancer is a major public health issue for which dietary factors such as red and processed meat consumption seem to play a prominent role. Heme iron, which is present in important concentration in those food products, was reported to play a role in colorectal cancer promotion in animal studies. However, its role in colorectal cancer initiation remains to be established. Methods: Male Fischer 344 rats were given experimental diets (control diet, ferric citrate-supplemented diet or hemin-supplemented diet) for 2 weeks before being initiated for colon cancer with azoxymethane. Rats were then fed a control diet for 8 weeks. Preneoplastic lesions, lipid peroxidation, genotoxicity and oxidative stress markers, together with gut microbiota, were analyzed. Results: Heme iron, given in the rat diet for only 2 weeks before the colorectal cancer initiating event, increased two types of preneoplastic lesions in the rat colon, namely aberrant crypt foci and mucin-depleted foci, when compared to a control diet containing the same amount of iron in a non-heminic form. This heme iron concentration in the diet, representative of human consumption, induced at the same time a huge increase in luminal lipid peroxidation, a significant increase in RNA/DNA oxidative damage and an increase in the expression of antioxidant defenses in colon mucosa, accompanied by epithelial cell proliferation together with a reduction in colon mucus cells, and a gut dysbiosis. Conclusion: These results, obtained in an animal model, suggest that iron, only in its heminic form, has a co-initiating effect on colorectal carcinogenesis.