Emerging data have linked the gut microbiome to colorectal adenomas, the established early lesions in colorectal cancer (CRC) and de facto targets during screening colonoscopy. However, deficit in our knowledge of the basic science of the gut microbiome and the specific driver mechanisms for inducing adenoma formation and progression has impeded translation. We hypothesize that the microbiome is an adenoma nonautonomous inducer of colorectal “priming,” the term we use in this application to refer to molecular/cellular alterations critical for adenoma formation and progression. The near-term objective of this proposal is to define whether and how the microbiome and the primed colon act in concert to drive adenoma formation. The long-term objective of this proposal is to develop microbiome-based strategies for precision prevention of adenomas and ultimately CRC.