Abstract
Consumption of a Western type diet is a known risk factor for colorectal cancer. Our group previously developed the total Western diet (TWD) for rodents with energy and nutrient profiles that emulate a typical Western diet. In this study, we tested the hypothesis that consumption of the TWD would enhance colitis, delay recovery from gut injury and promote colon tumorigenesis. In multiple experiments using the azoxymethane + dextran sodium sulfate or ApcMin/+ mouse models of colitis-associated colorectal carcinogenesis (CAC), we determined that mice fed TWD experienced more severe and more prolonged colitis compared to their counterparts fed the standard AIN93G diet, ultimately leading to markedly enhanced colon tumorigenesis. Additionally, this increased tumor response was attributed to the micronutrient fraction of the TWD, and restoration of calcium and vitamin D to standard amounts ameliorated the tumor-promoting effects of TWD. Finally, exposure to the TWD elicited large scale, dynamic changes in mRNA signatures of colon mucosa associated with interferon (IFN) response, inflammation, innate immunity, adaptive immunity, and antigen processing pathways, among others. Taken together, these observations indicate that consumption of the TWD markedly enhanced colitis, delayed recovery from gut injury, and enhanced colon tumorigenesis likely via extensive changes in expression of immune-related genes in the colon mucosa.
Highlights
Colorectal cancer (CRC) is the third leading cause of cancer death and the third most commonly diagnosed cancer in men and women in the United States [1]
Our observations indicate that consumption of the total Western diet (TWD) markedly enhanced
Our observations indicate that consumption of the TWD markedly enhanced colitis, delayed recovery from gut injury, and promoted colon tumorigenesis
Summary
Colorectal cancer (CRC) is the third leading cause of cancer death and the third most commonly diagnosed cancer in men and women in the United States [1]. Dysfunction of the intestinal mucosal barrier leads to sustained damage of gut epithelial cells. This chronic injury to the gut triggers a compensatory immune response characterized by the up-regulation of cell proliferation and anti-apoptotic pathways that promote cell survival [8]. The resulting compensatory cell regeneration results in increased rates of mitosis that, when chronically active, increase DNA mutation rates [8,9]. Can this process promote the disruption of oncogenic pathways, but it can provide cancerous cells with a nurturing environment due to the increased availability of proliferative and survival signals
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