Butyrate Mediates Tumor-Suppressive Effects of Dietary Fiber

Whether dietary fi ber intake reduces colorectal cancer risk remains controversial, possibly because epidemiologic studies have not controlled for gut microbiota composition. Bacteria in the colon convert fi ber into metabolites such as butyrate, which serves as the primary energy source for normal colonocytes but also inhibits histone deacetylases (HDAC) to epigenetically regulate gene expression. To address whether butyrate and the microbiota mediate protective effects of fi ber, Donohoe and colleagues fed gnotobiotic mice colonized with the butyrate-producing bacterium Butyrivibrio fi brisolvens a highfi ber diet prior to chemically inducing colorectal carcinogenesis. The combination of B. fi brisolvens and high fi ber conferred a greater protective effect than either alone, whereas a mutant B. fi brisolvens strain defi cient in butyrate production had a diminished protective effect that could be rescued by exogenous butyrate. Because butyrate is minimally metabolized in colorectal cancer cells due to the Warburg effect, which promotes a shift to glucose dependency through increased glycolysis and decreased mitochondrial oxidative phosphorylation, butyrate preferentially accumulates within colorectal tumors. Consistent with butyrate’s role as an HDAC inhibitor, histone H3 acetylation was signifi cantly increased in tumor cells compared with adjacent normal colonocytes and was associated with increased expression of genes that promote apoptosis and cell-cycle arrest. Collectively, these fi ndings provide mechanistic evidence for how dietary fi ber protects against colorectal cancer that can be evaluated in future epidemiologic and microbiome studies and raise the possibility that modulation of an endogenous HDAC inhibitor by diet or microbiotic supplementation could be a chemopreventative strategy. ■