title: A gnotobiotic mouse model demonstrates that dietary fiber protects against colorectal tumorigenesis in a microbiota- and butyrate-dependent manner.
abstract: Whether dietary fiber protects against colorectal cancer is controversial 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 energetic and epigenetic functions in colonocytes and tumor-suppressive properties in colorectal cancer cell lines. We used gnotobiotic mouse models colonized with wild-type or mutant strains of a butyrate-producing bacterium to demonstrate that fiber does have a potent tumor-suppressive effect but in a microbiota- and butyrate-dependent manner. Furthermore, due to the Warburg effect, butyrate was metabolized less in tumors where it accumulated and functioned as a histone deacetylase (HDAC) inhibitor to stimulate histone acetylation and affect apoptosis and 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 with normal colonic tissues.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Dallas R
authors.initials: DR
authors.lastname: Donohoe
authors.affiliation: Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Darcy
authors.initials: D
authors.lastname: Holley
authors.affiliation: Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Leonard B
authors.initials: LB
authors.lastname: Collins
authors.affiliation: College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Montgomery
authors.affiliation: Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina. Carolina Vaccine Institute, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Alan C
authors.initials: AC
authors.lastname: Whitmore
authors.affiliation: Department of Molecular and Cellular Medicine, Texas A&M University, College Station, Texas.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hillhouse
authors.affiliation: Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Kaitlin P
authors.initials: KP
authors.lastname: Curry
authors.affiliation: Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Sarah W
authors.initials: SW
authors.lastname: Renner
authors.affiliation: Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Alicia
authors.initials: A
authors.lastname: Greenwalt
authors.affiliation: Department of Environmental and Radiological Health, Colorado State University, Fort Collins, Colorado.
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Ryan
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Virginia
authors.initials: V
authors.lastname: Godfrey
authors.affiliation: Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina. Carolina Vaccine Institute, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Heise
authors.affiliation: Department of Veterinary Pathobiology, Texas A&M University, College Station, Texas.
authors.forename: Deborah S
authors.initials: DS
authors.lastname: Threadgill
authors.affiliation: Department of Nutrition, University of Tennessee, Knoxville, Tennessee.
authors.forename: Anna
authors.initials: A
authors.lastname: Han
authors.affiliation: Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: James A
authors.initials: JA
authors.lastname: Swenberg
authors.affiliation: Department of Molecular and Cellular Medicine, Texas A&M University, College Station, Texas. Department of Veterinary Pathobiology, Texas A&M University, College Station, Texas.
authors.forename: David W
authors.initials: DW
authors.lastname: Threadgill
authors.affiliation: Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina. Scott_Bultman@med.unc.edu.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Bultman
mesh_terms: D000818:Animals; D002087:Butyrates / Q000378:metabolism*; D002273:Carcinogens / Q000008:administration & dosage; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000209:etiology* / Q000473:pathology; D004043:Dietary Fiber; D004195:Disease Models, Animal; D005856:Germ-Free Life; D006801:Humans; D007413:Intestinal Mucosa / Q000473:pathology; D051379:Mice; D064307:Microbiota; D060787:Neoplasm Grading
chemical_list: D002087:Butyrates; D002273:Carcinogens; D004043:Dietary Fiber