Dietary heme and calcium are alleged modulators of colon cancer risk. Little is known about the molecular and cellular changes in the colon epithelium that are induced by consumption of these unabsorbed nutrients. In this nutrigenomics study, we fed rats high- and low-calcium diets with or without heme. In agreement with previous studies, we found that dietary heme increased the cytotoxicity of fecal water in the colon and elevated epithelial proliferation, a risk factor in colon carcinogenesis. Calcium reduced cytotoxicity and inhibits heme-induced effects. Among 365 colon-expressed genes, we could identify 10 diet-modulated genes that show >2-fold altered expression, of which several are related to colon cell turnover and disease. Mucosal pentraxin (Mptx) was the strongest differentially expressed gene, approximately 10-fold down-regulated by dietary heme and 3-fold up-regulated by calcium. cDNA microarray and quantitative PCR analysis show that calcium significantly inhibits the effects of heme, which correlates with the physiological effects. Our results indicate that Mptx expression is related to colonic cell turnover, and that Mptx might be a marker for diet-modulated mucosal integrity. We also show that Mptx expression is restricted to the intestine, and occurs predominantly in the colon.