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Nutrition and Disease

Western-Style Diets Induce Oxidative Stress and Dysregulate Immune Responses in the Colon in a Mouse Model of Sporadic Colon Cancer^1–3,

⁴ Department of Medicine, Weill Cornell Medical College, New York, NY 10021; ⁵ Hospital Informatics, ⁶ Laboratory Animal Research Center, and ⁷ Laboratory of Biochemical Genetics and Metabolism, The Rockefeller University, New York, NY 10065; ⁸ Department of Medicine, Montefiore Medical Center, Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, NY 10467; and ⁹ Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595

A Western-style diet (WD), defined by high-fat, low-calcium, and vitamin D content, is associated with increased risk of human colorectal cancer. Understanding molecular mechanisms altered by the WD is crucial to develop preventive and therapeutic strategies. Effects of a WD on the colonic transcriptome of C57Bl/6J mice, a model for sporadic colon cancer, were studied at endpoints before tumors occur. To assess whether a WD induces inflammatory changes, expression profiles of a broad spectrum of inflammatory proteins were performed and numbers of lamina propria macrophages were determined with semiquantitative morphometry. Transcriptome changes were translated into molecular interaction network maps and pathways. Pathways related to oxidative stress response; lipid, glutathione, and xenobiotic metabolism; and the immune response were perturbed by the WD. Several nuclear factor-erythroid 2-related factor 2- and aryl hydrocarbon receptor-dependent genes, including those coding for enzymes involved in phase 1 and 2 drug metabolism and oxidative stress responses, were induced. Oxidative stress was demonstrated by measurements of endogenous colonic redox-sensitive compound concentrations. Perturbations in immune response-related pathways, expression of inflammatory proteins, and increased numbers of lamina propria macrophages showed that the WD significantly alters the local colonic immune response. Collectively, these data suggest that consumption of a WD interferes with networks of related biological response pathways involving colonic lipid metabolism, oxidative stress, and the immune response. These new findings impact our understanding of links between consumption of WD and colon carcinogenesis, providing additional information for developing preventive means for decreasing colorectal cancer risk.

^* To whom correspondence should be addressed. E-mail: holtp{at}rockefeller.edu.

Manuscript received 30 December 2008. Initial review completed 11 February 2009. Revision accepted 18 August 2009.

Published online 16 September 2009.