Objective: To investigate the risk of colorectal cancer and its relationship with colonic flora and microenvironment under high-fat and high-calorie diet. Methods: Wistar rats were used to study, and they were given normal diet, high-fat diet, and dimethyl hydrazine (DMH) to induce the occurrence of colorectal cancer. Then observe the difference in tumor formation and the relationship among microbial community, inflammatory factors and metabolism. Results: No tumors were found in the normal diet group (G1) and the high-fat diet group (G3). Four nodules were found in the four rats in the normal diet + DMH group (G2) and 8 cancerous nodules were formed in 7 rats (70%) from high-fat diet + DMH group (G4). Cholesterol and TNF-α increased, IL-1, IL-6 and LEP decreased in the high-fat diet group. The difference was statistically significant. In the cancer-inducing group, only the difference in cholesterol was statistically significant. Compared with the normal diet group (G1) and the high-fat diet group (G3), the rat's gut bacterial abundance was not significantly different, but the gut flora structure was significantly changed. The content of Candida in the intestinal tract of rats in the high-fat diet group was reduced (P = 0.015), while the content of Verrucomicrobia increased (P = 0.035); In the comparison of genus content, Ruminococcus, Candida, Saccharibacteria genera incertae sedis, Enterobacter, Clostridium IV, Enterococcus, Enterorhabdus, Acetivibrio, Adlercreutzia, Lactococcus, etc., decreased significantly, while Akkermansia, Warthococcus, Staphylococcus, Butyricimonas, Clostridium XVIII, etc. increased significantly. Conclusion: This study found that high-fat, high-calorie diet can increase the susceptibility of the intestine to carcinogenic factors. The reason may be that the high-fat diet causes the body to appear inflammatory states and microbial community imbalance, especially rumenococcus, candida, Saccharomyces, Enterobacter, Clostridium IV, Enterococcus, Enterobacter, Vibrioaceticus and other genus reduction are important links. Exploring ways to improve these floras is an important factor to improve the resistance of the intestinal tract to cancer-inducing agents.