Colorectal cancer (CRC) progression is marked by a series of sequential driver mutations, however, the factors driving this process remain misunderstood. P53 and SMAD4 mutations result in a substantially hampered treatment response and promote the pathogenesis of CRC. While gut dysbiosis is known to promote CRC carcinogenesis and inflammation, the connection between the microbiome in and CRC mutagenesis remains unclear. To understand how sequential driver mutations influence microbiome composition, we have used a mouse orthotopic organoid model to compare longitudinal microbiome alterations in APC, KRAS, P53 (AKP) and APC, KRAS, P53, SMAD4 (AKPS) tumors. Within AKP and AKPS tumors, we found that the microbiome composition was altered longitudinally. CRC progression is marked by longitudinal alterations in microbiota abundance and composition for both AKP and AKPS tumors. Our results indicate that the addition of a SMAD4 mutation modulates the balance of the intestinal microbiota towards a pro-inflammatory and immunosuppressive state. These findings help elucidate the role of the microbiome in CRC mutagenesis and reveal potential targets to hamper the progression of CRC.
