Colorectal cancer (CRC) is a frequently lethal disease with very heterogeneous outcomes and drug responses. We recently developed a new, fast and fully penetrant in vivo mouse model of spontaneous CRC based on the lEC-specific mono-allelic expression of the EMT transcription factor ZEB2. ZEB2, an E-box binding transcription factor, is a crucial driver of epithelial-to-mesenchymal transition (EMT). ZEB2 was initially described as a factor that interacts with SMAD proteins playing a role in the TGF-p signalling pathway. ZEB2 activation was also shown to induce tumor cell invasion in epithelial cells, leading to a rapid breakdown of cell polarity, cell-cell adhesion and induction of cellular motility. Importantly, its expression in human epithelial cancers is linked to poor prognosis. To study the specific role of ZEB2 in the intestine we generated Intestinal epithelial cell (lEC)-specific transgenic mice by crossing a Rosa26-driven ZEB2-over-expression mouse model with a Villin-Cre transgenic line. IEC-ZEB2 transgenic mice all develop an invasive mucinous carcinoma, specifically in the colon, while no defects are observed in the small intestine. Endoscopy revealed that from early age, IEC-ZEB2 transgenic mice exhibit changes in their colonic mucosa which develop into multiple nodules obstructing the intestinal lumen and invading into the lamina propria and tunica muscularis. As a result, IEC-ZEB2 transgenic mice all die before the age of 45 weeks. In the oldest mice, we have been able to detect potential sites of metastases, identifying ZEB2 as a potent driver of invasive carcinoma. Tumor tissue analysis revealed high expression levels of pro-inflammatory cytokines and FITC-dextran treatment indicated intestinal barrier permeability in our model. Surprisingly, antibiotic-treated mice are completely protected from cancer development Our data indicate that over-expression of ZEB2 induces hyper-proliferative intestinal epithelium, breakdown of intestinal barrier, and allows translocation of microbiota, driving the development of colon cancer