Diet and Gut Microbes Act Coordinately to Enhance Programmed Cell Death and Reduce Colorectal Cancer Risk

Diet is an important risk factor for colorectal cancer (CRC), and several dietary constituents implicated in CRC are modified by gut microbial metabolism. Microbial fermentation of dietary fiber produces short-chain fatty acids, e.g., acetate, propionate, and butyrate. Dietary fiber has been shown to reduce colon tumors in animal models, and, in vitro, butyrate influences cellular pathways important to cancer risk. Furthermore, work from our group suggests that the combined effects of butyrate and omega-3 polyunsaturated fatty acids (n-3 PUFA) may enhance the chemopreventive potential of these dietary constituents. We postulate that the relatively low intakes of n-3 PUFA and fiber in Western populations and the failure to address interactions between these dietary components may explain why chemoprotective effects of n-3 PUFA and fermentable fibers have not been detected consistently in prospective cohort studies. In this review, we summarize the evidence outlining the effects of n-3 long-chain PUFA and highly fermentable fiber with respect to alterations in critical pathways important to CRC prevention, particularly intrinsic mitochondrial-mediated programmed cell death resulting from the accumulation of lipid reactive oxygen species (ferroptosis), and epigenetic programming related to lipid catabolism and beta-oxidation-associated genes.