Dietary Fiber Modulates Macrophage Activity in a Microfluidic Model of Colonocyte-Microbiota Interactions in Colorectal Cancer

Abstract

Dietary fiber has been consistently associated with a decreased risk of colorectal cancer (CRC) development. While the apoptotic effect of dietary fiber microbial fermentation products 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 the colon; however, the effect of dietary fiber fermentation by microbiota on macrophage-colonocyte interaction in colorectal cancer has been difficult to dissect due to a lack of complex in vitro models of CRC containing both immune cells and microbiota. Recently, we developed a microfluidic model that facilitates the coculture of CRC 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. Combinatorial coculture of colonocytes with microbiota and macrophages revealed that alterations in microbial production of SCFA derived from dietary fiber fermentation correlated with enhanced colonocyte death, possibly mediated by an increase in transcription of tumor pro-apoptotic signals by macrophages. Our work highlights the capacity of complex in vitro systems to study the role of microbial metabolism of dietary molecules on CRC colonocyte viability and macrophage activity.