Consumption of the total Western diet (TWD) enhanced and sustained colonic inflammation and promoted colon tumorigenesis in mice, which led to marked changes in the composition of the gut microbiome in mice

To improve translation of preclinical rodent nutrition studies to human trials, our research team developed the new Total Western Diet (TWD) for rodents with energy and nutrient profiles that emulate a typical Western diet. A series of pre‐clinical studies was preformed using different models of colon cancer to compare TWD to the AIN93G diet, a standard basal diet designed to promote animal health. Consumption of TWD 1) increased number of aberrant crypt foci in A/J mice initiated with azoxymethane (AOM), 2) significantly enhanced tumorigenesis in C57BL/6J mice initiated with AOM and provided dextran sodium sulfate (DSS) to promote colonic inflammation and 3) enhanced colon tumorigenesis in APC Min/+ mice provided DSS. Using the AOM/DSS model of CAC, we assessed the impact of TWD on the colitis disease activity index, colon tissue histopathology and composition of the gut microbiome by 16S sequencing over the course of disease development (pre‐initiation, colitis, recovery and terminal). We determined that TWD consumption markedly enhanced colitis activity (40‐fold increase) compared to mice fed AIN93G. Moreover, TWD‐fed mice had significantly higher histopathology scores for inflammation and mucosal injury during the period of colitis and, importantly, during the recovery phase of this disease model. Colonic inflammation in TWD‐fed mice persisted to the end of the study (day 105), whereas mucosal injury (save for sites of neoplasia) had resolved. Prior to initiation with AOM/DSS, the gut microbiome compositions of AIN93G‐ and TWD‐fed mice were very similar. As colitis progressed, the populations became more distinct, especially so by the recovery stage (day 45), which was also typified by sustained colonic inflammation and mucosal injury in TWD‐fed mice. By the study end (day 105), separation between the fecal microbiomes for the different diet groups was evident. Finally, examination of the terminal fecal microbiome revealed distinct gut microbiota profiles for TWD‐fed animals initiated with AOM/DSS compared to sham mice, whereas a distinction was not evident for those fed AIN93G. Collectively, these data show that the TWD markedly enhanced colorectal tumorigenesis in repeated experiments and multiple animal models. Moreover, enhanced and sustained inflammation of the colon epithelium is a probable mechanism for promotion of CAC by TWD. Finally, mice with pronounced colitis‐associated colorectal cancer, induced by dietary exposure to TWD, harbored microbiomes distinct from their counterparts fed healthy diets. Support or Funding Information Utah Agricultural Experiment Station, Project UTA‐1178; USDA NIFA/AFRI Grant No. 2014‐67017‐21755