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 Apc Min/+ 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.Nutrients 2020, 12, 544 2 of 35 characterizes these conditions is now recognized as an important factor in CRC due to its involvement in the disruption of the same oncogenic pathways that are disrupted in CRC [5]. The mutation of genes involved in the maintenance of the intestinal mucosal barrier that protects the intestinal wall from bacterial invasion contributes to both Crohn's and UC [6,7].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]. Various molecules are involved in the activation of such pathways, including transcription factors (e.g., NF-κB, and STAT3) and various inflammatory cytokines (e.g., IL-6 and TNF-α), which are normally secreted during an inflammatory response. The resulting compensatory cell regeneration results in increased rates of mitosis that, when chronically active, increase DNA mutation rates [8,9]. Not only can this process promote the disruption of oncogenic pathways, but it can also provide cancerous cells with a nurturing environment due to the increased availability of proliferative and survival signals. This notion is supported by an animal study by Tanaka et al. [10], in which a combined treatment of the chemical carcinogen azoxymethane (AOM) with the inflammatory agent dextran sodium sulfate (DSS) significantly increased intestinal tumorigenesis in CD-1 mice. The AOM + DSS model yields a consistent, reproducible colon cancer outcome ...