Colorectal cancer (CRC) is the third most diagnosed and deadly cancer in the United States. Numerous epidemiological studies have shown that a high-fiber diet is correlated with decreased incidence of CRC. Although the underlying mechanism is unknown, we hypothesize that dietary fiber has a protective effect because it is metabolized by anaerobic bacteria in the colon and fermented into butyrate. Butyrate is a potent histone deacetylase (HDAC) inhibitor that alters epigenetic events and gene expression and might maintain cell proliferation and cell death homeostasis to prevent CRC. The objective of this application is to investigate the mechanistic link between dietary fiber, gut microflora, butyrate, and epigenetic modifications which result in gene expression changes that alter cancer susceptibility. To tightly control experimental variables, the proposed experimental plan utilizes several mouse models of CRC. ApcMin/+, azoxymethane (AOM) treated, and AOM plus dextran sodium sulfate (DSS) treated mice will be maintained with defined gut microflora or germfree and be fed high- or low-fiber diets to determine whether gut microflora is required for a high-fiber diet to protect against CRC. To determine whether bacterial fermentation of fiber into butyrate is the mechanism of the fiber effect, germfree mice will be recolonized with bacteria that produce high or low levels of butyrate. CpG methylation and gene expression will be analyzed in a genome-wide manner using methylated DNA immunoprecipitation (MeDIP) combined with BAG and CpG island microarrays and transcript profiling. CpG methylation and gene expression profiles from mice fed a high- or low-fiber diet in the presence or absence of gut microflora will be compared. Superimposing these data sets will identify CpGs with altered methylation that are also associated with changes in gene expression and cancer susceptibility. These sites will be considered candidates for contributing to altered risk for CRC. To understand the role of dietary fiber and gut microflora at a molecular level, epigenetic events will be analyzed at several candidate genes before and after the onset of tumor formation using chromatin immunoprecipitation (ChIP) assays, sodium bisulfite mutagenesis followed by sequencing, and DNase I hypersensitivity assays. This work should elucidate the mechanisim of the fiber effect on CRC susceptibility and may lead to new preventative strategies for CRC. ? ? ?

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Ross, Sharon A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
Zip Code
Bhatt, Aadra P; Redinbo, Matthew R; Bultman, Scott J (2017) The role of the microbiome in cancer development and therapy. CA Cancer J Clin 67:326-344
Willis, Monte S; Holley, Darcy Wood; Wang, Zhongjing et al. (2017) BRG1 and BRM function antagonistically with c-MYC in adult cardiomyocytes to regulate conduction and contractility. J Mol Cell Cardiol 105:99-109
Bultman, Scott J (2017) Interplay between diet, gut microbiota, epigenetic events, and colorectal cancer. Mol Nutr Food Res 61:
Bultman, Scott J; Holley, Darcy Wood; G de Ridder, Gustaaf et al. (2016) BRG1 and BRM SWI/SNF ATPases redundantly maintain cardiomyocyte homeostasis by regulating cardiomyocyte mitophagy and mitochondrial dynamics in vivo. Cardiovasc Pathol 25:258-269
Bultman, Scott J (2016) The microbiome and its potential as a cancer preventive intervention. Semin Oncol 43:97-106
Albini, Sonia; Coutinho Toto, Paula; Dall'Agnese, Alessandra et al. (2015) Brahma is required for cell cycle arrest and late muscle gene expression during skeletal myogenesis. EMBO Rep 16:1037-50
Banerjee, Ranjan; Bultman, Scott J; Holley, Darcy et al. (2015) Non-targeted metabolomics of Brg1/Brm double-mutant cardiomyocytes reveals a novel role for SWI/SNF complexes in metabolic homeostasis. Metabolomics 11:1287-1301
Smith-Roe, Stephanie L; Nakamura, Jun; Holley, Darcy et al. (2015) SWI/SNF complexes are required for full activation of the DNA-damage response. Oncotarget 6:732-45
Holley, Darcy W; Groh, Beezly S; Wozniak, Glenn et al. (2014) The BRG1 chromatin remodeler regulates widespread changes in gene expression and cell proliferation during B cell activation. J Cell Physiol 229:44-52
Bultman, Scott J (2014) Emerging roles of the microbiome in cancer. Carcinogenesis 35:249-55

Showing the most recent 10 out of 24 publications