It is controversial whether dietary fiber protects against colorectal cancer because of conflicting results from human epidemiologic studies. However, these studies and mouse models of colorectal cancer have not controlled the composition of gut microbiota, which ferment fiber into short-chain fatty acids such as butyrate. Butyrate is noteworthy because it has energentic and epigenetic functions in colonocytes and tumor-suppressive properties in colorectal cancer cell lines. We colonized BALB/c mice with wild-type or mutant strains of a butyrate-producing bacterium in a gnotobiotic facility, provided them with high- or low-fiber diets that were otherwise identical and isocaloric, and used azoxymethane (AOM) to induce colorectal tumors. Analysis of these gnotobiotic mouse models demonstrated that fiber conferred a significant tumor-suppressive effect but in a microbiota- and butyrate-dependent manner. To confirm that butyrate is a causal factor, the anticancer chemoprotective effect was recapitulated in mice without any butyrate-producing bacteria when they were provided a tributyrin-fortified diet. Our data support a general mechanism that includes microbial fermentation of fiber rather than fiber exclusively speeding colonic transit to minimize the exposure of colonocytes to ingested carcinogens. Our data also support a molecular mechanism that is metaboloepigenetic. Normal colonocytes utilize butyrate as their primary energy source, whereas cancerous colonocytes rely on glucose because of the Warburg effect. Due to this metabolic difference, butyrate accumulated in tumors and functioned as an HDAC inhibitor to increase histone acetylation levels globally and at pro-apototic (Fas) and cell-cycle (p21 and p27) target genes, which culminated in increased apoptosis and decreased cell proliferation. To support the relevance of this mechanism in human cancer, we demonstrate that butyrate and histone acetylation levels are elevated in colorectal adenocarcinomas compared to normal colonic tissues. These results, which link diet and microbiota to a tumor-suppressive metabolite, provide insight into conflicting epidemiologic findings and suggest that probiotic/prebiotic strategies can modulate an endogenous HDAC inhibitor for anticancer chemoprevention without the adverse effects associated with synthetic HDAC inhibitors used in chemotherapy.
Citation Format: Dallas Donohoe, Darcy Holley, Leonard Collins, Stephanie Montgomery, Alan Whitmore, Kaitlin Curry, Sarah Renner, Alicia Greenwalt, Elizabeth Ryan, Virginia Godfrey, Deborah Threadgill, James Swenberg, David Threadgill, Scott Bultman. A gnotobiotic mouse model demonstrates that dietary fiber protects against colorectal tumorigenesis in a microbiota- and butyrate-dependent manner. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr PL03-01.