Interplay Between Dietary Fiber, Macrophages and Colonocytes in a Microfluidic Model of Host-Microbiota Interactions in Colorectal Cancer

Abstract

Dietary fiber has been consistently associated with a decreased risk of colorectal cancer development. While the apoptotic effect of dietary fiber microbial fermentation products such as short chain fatty acids on tumor colonocytes is well established, the role of these products on other components of the tumor microenvironment remains unexplored. Tumor associated macrophages play a critical role in tumor development in colorectal cancer; however, the effect of dietary fiber fermentation by microbiota on the interaction between macrophages and colonocytes in the colorectal cancer microenvironment has been difficult to dissect due to a lack of in vitro models of colorectal cancer containing immune cells, colonocytes, and microbiota. Recently, we developed a microfluidic model that facilitates the coculture of colorectal cancer spheroids with complex microbial communities. Here, we expand our model to include macrophages and employ it to study the impact of dietary fiber on macrophage-colonocyte interaction. We optimized monocyte differentiation parameters in vitro and demonstrated the capacity of our model to recapitulate changes in microbiota composition and metabolic output associated with dietary fiber administration in vivo. Coculture of colonocytes with microbiota and macrophages revealed that alterations in microbial production of short chain fatty acids derived from dietary fiber fermentation correlated with decreased colonocyte viability, possibly mediated by an increase in production of tumor pro-apoptotic cytokines by macrophages. Our work highlights the capacity of microfluidic in vitro models to study the role of microbial metabolism of dietary molecules on colorectal cancer colonocyte viability in the presence of macrophages.