The Impact of Diet on the Human Gut Microbiota in the Context of Colorectal Cancer

Abstract

Though strong evidence suggests the gut microbiota contributes to colorectal cancer (CRC) onset and/or progression, there is no universal signature of a gut microbe or microbiota associated with the disease. The functional capability of gut communities could be more useful in predicting CRC risk and more valuable in understanding the role of the gut microbiota in CRC than gut microbiota composition. Additionally, diet is a key contributor to the function of the gut microbiota and certain diets (e.g., protein- and fibre-rich) have been associated with CRC risk. As such, this thesis was driven by a global purpose: to characterize potential microbe-microbe and diet-microbe interactions that may influence CRC. To fulfill this purpose, taxonomic composition, metabolic function, and carriage of CRC-linked virulence determinants were characterized for CRC biopsy-derived gut microbial communities and known CRC-linked virulence determinants were characterized in individual strains. The influence of protein- and fibre-rich diets on the taxonomic composition and metabolic output of three CRC biopsy- and three healthy fecal donor-derived communities was assessed with a focus on taxa and metabolites linked to CRC. Lastly, free amino acid pools representative of major dietary protein sources were applied to individual strains of CRC-linked bacteria Fusobacterium spp. to assess potential diet-influenced differences in growth among CRC-relevant fusobacterial strains. Although colonic isolates of Fusobacterium nucleatum subsp. animalis were found to co-aggregate with strains of several CRC-relevant species, no known strain-level CRC-relevant virulence determinants were found in the CRC biopsy-derived communities, and no CRC-linked metabolites could be consistently linked to taxa between the characterized gut microbial communities. Protein- and fibre-rich diets were found to enrich for CRC- and colonic health-associated bacterial taxa and metabolites within human colonic sample-derived bacterial communities, respectively. Dietary protein-representative free amino acid pools differentially influenced the growth of individual Fusobacterium strains, including CRC-relevant strains, although the amino acid preferences and growth strategies employed by fusobacterial strains were highly heterogeneous. Ultimately, this work underlines the complexity in host-microbiota interactions and serves as a preliminary step towards holistic characterization of interactions between the human host, the resident gut microbiota, and CRC.