The Role of Macronutrient Distribution and Diet-Microbiome Interactions in the Development of Colorectal Cancer

Abstract

Colorectal cancer (CRC) is the third most common malignancy and is strongly associated with Western-style diets high in saturated fat, red meat, and low fibre. Diet is a modifiable determinant of CRC risk, shaping the gut microbiome, with complex diet–microbiome interactions influencing disease susceptibility. The Geometric Framework for Nutrition provides a systematic approach to evaluate macronutrient effects on disease. We applied this framework to examine complex diets in CRC using a dietary matrix varying in protein/fat ratios and sources with differing health implications (e.g., soy-based proteins, unsaturated fat, red meat, and saturated fat) in female C57BL/6 and BALB/c mice. Twelve diets from this matrix were administered short- or long-term to assess microbiome effects. Diets high in red meat and saturated fat reduced microbial diversity and enriched taxa linked to inflammatory bowel disease and CRC, whereas soy- or unsaturated fat-based diets did not. Responses were strain-specific: red meat predominantly influenced BALB/c communities, while macronutrient ratio accounted for most microbial variance in C57BL/6. Sulfate-reducing bacteria increased in both strains, exhibiting diet- and strain-dependent patterns. A refined subset of these diets was then applied in an azoxymethane/dextran sulfate sodium model of CRC. High-protein diets, irrespective of source, most strongly affected tumourigenesis, colitis, and survival. BALB/c mice showed higher tumour susceptibility and reduced microbial diversity, particularly on red meat diets, whereas C57BL/6 displayed stronger cytotoxic responses and fewer tumours, highlighting strain-specific differences. These findings demonstrate that macronutrient composition, protein source, and host genotype interact to shape the microbiome and CRC risk, providing a framework to guide dietary strategies and develop effective interventions for CRC prevention.