The current standard of care for colorectal cancer (CRC) involves chemotherapies developed more than 50 years ago. Although the 5-year survival rate has been rising over the past few decades, it is still low at about 65%. And most of the improvement in survival is due to increased screening, which has identified more cases of CRC in earlier stages. In the past decade, with the advancement of high-throughput “omics” technologies, it has become clear that the microbiome plays an essential role in driving the pathogenesis of CRC; however, the mechanisms that underlie host-microbiome interactions in CRC have yet to be elucidated. Part of the reason is the complex interplay between the colon epithelium, the microbiome, and the immune system. Previous publications have elucidated how the microbiome could affect miRNA expression in CRC, but how CRC could affect the microbiome is not yet understood, even though host genetics is known to shape the microbiome. In light of these evidence, we are testing the hypothesis that a positive feedback loop exists in CRC in which preexisting dysbiosis initially drives the expression of certain miRNAs in the colon epithelium, which are then released into the colon lumen and in turn affect the composition of the gut microbiome, leading to additional dysbiosis. Results from this study will elucidate the underlying mechanisms of host-microbiome interactions in CRC and will provide insights into the development of novel treatment strategies.