Consumption of the Total Western Diet Promotes Colitis and Inflammation-Associated Colorectal Cancer in Mice

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 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 ...

The Western Dietary Pattern Combined with Vancomycin-Mediated Changes to the Gut Microbiome Exacerbates Colitis Severity and Colon Tumorigenesis

“…Significant main effects of both diet and antibiotic treatm were evident for both tumor multiplicity and tumor burden (Figure 4a,c). As has previously observed in this model [30], mice fed the TWD had a greater number of tum and higher tumor burden (main effect of diet, p = 0.0019 and p = 0.0017, respectiv Interestingly, combining TWD with vancomycin significantly exacerbated tumor m plicity by 2-fold (p = 0.0017) and tumor burden by 2.3-fold (p = 0.0241) compared to T fed mice with no antibiotic treatment (Figure 4a,c). The average tumor size was unaffe by either diet (main effect p = 0.4545) or vancomycin treatment (main effect p = 0.6 ( Figure 4c).…”

“…The colitis DAI was assessed on day 24 during active colitis immediately following DSS exposure and 14 days later on day 38 during recovery from gut injury (Figure 2a). Significant main effects of both diet (p < 0.0001) and vancomycin (p = 0.0028) were noted at the first time point, with the TWD diet markedly exacerbating colitis symptoms as has been observed repeatedly in this model [30]. Interestingly, vancomycin exposure compounded this effect, with the most severe colitis symptoms noted for mice fed TWD with vancomycin.…”

“…Similarly, another group [45] using the TWD demonstrated that A/J mice fed 100 mg/kg of the foodborne carcinogen 2amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) had increased ACF relative to mice fed the AIN93G diet suggesting that the carcinogenic phenotype elicited by feeding the TWD is not exclusive to the AOM induction model. Benninghoff et al [30] demonstrated that mice fed the TWD had altered colon mucosa gene expression related to interferon response, inflammation, innate immunity, adaptive immunity, and antigen processing pathways relative to cohorts fed the AIN93G diet. These gene expression patterns were also accompanied by increased colitis disease activity, delayed recovery and enhanced colon tumorigenesis.…”

Dietary Supplementation of Foxtail Millet Ameliorates Colitis-Associated Colorectal Cancer in Mice via Activation of Gut Receptors and Suppression of the STAT3 Pathway

“…After being fixed in 10% formalin solution for 24 h, the distal colon tissues (5 mm) were paraffin-embedded, sectioned and stained using hematoxylin and eosin (H&E) [27]. Three random fields of views were photographed at 100× magnification with a microscope for each colon sample.…”

Onion bulb extract can both reverse and prevent colitis in mice via inhibition of pro-inflammatory signaling molecules and neutrophil activity

“…For example, soft drink consumption and sucrose or red meat intake were associated with increased risk of ulcerative colitis (UC) development [ 34 – 36 ]. In addition, western type-, high salt-type, and carrageenan-free-type of diet was linked with increased colitis severity in mice [ 37 , 38 ] and in IBD patients [ 39 , 40 ]. Zinc deficiency was also linked with increased intestinal barrier permeability and colitis exacerbation in IBD patients [ 41 ].…”