Colorectal cancer (CRC) mainly affects people in Western society, and global epidemiological and experimental studies have shown that Western dietary habits strongly impact on the susceptibility to develop CRC. Increasing evidence is emerging that this susceptibility is influenced by hostmicrobiome interactions in the gut, indicating that interfering with host-microbiome interactions by diet and pre –and probiotics may be very effective in CRC therapy. We have recently generated the first mouse model which develops invasive colorectal cancer by overexpressing one single Zeb2 oncogene, and could show that pathology is fully dependent on the presence of the intestinal microbiota. Our elegant, fast and fully penetrant CRC mouse model represents a unique platform to study interactions between the intestinal microbiota, host immunity and CRC development, which will help to identify new mechanisms allowing to prevent CRC. We envision that this information can lead to important breakthroughs in the prevention of CRC in high risk patients.