A Microfluidic Model to Study Host-Microbiota Interactions in the Colorectal Tumor Microenvironemnt

Abstract

The colonic microbiota has been identified as a key player in the development of colorectal cancer. While changes in microbiota composition and function correlate with disease progression and treatment outcome, the mechanism through which different bacterial species either predispose or protect the host from cancer in the colon are still not fully understood. This is partly due to a lack of models in vitro that permit the study of host microbiota interaction in a microenvironment relevant to colorectal cancer. In this dissertation, we developed an in vitro model to study host-microbiota interactions in the colorectal cancer tumor microenvironment. By leveraging engineering tools and experimental optimization, we designed a microfluidic device that allows the coculture of colonocytes and a diverse fecal microbiota in a microenvironment more relevant to the colorectal tumor than conventional cell cultures. We employed this device to explore the interactions between pathogens, microbiota, immune cells, dietary molecules, and host genotype. First, we demonstrated that a commensal microbiota attenuates the effect of the suspected carcinogenic bacteria Fusobacterium nucleatum on host gene expression, while F. nucleatum simultaneously impacts microbiota composition in a manner consistent with clinical observations. Then, we identified a potential role of dietary fiber-induced changes in microbiota metabolism as enhancers of the cytotoxic activity of macrophages against colonocytes. Lastly, we explored the capacity of host molecular alterations to influence microbiota composition in vitro. In this way, we demonstrate the capacity of our model to recapitulate key features of host-microbiota interaction and its usefulness to dissect complex biological interactions to increase our understanding of the role of microbiota in colorectal cancer.