A gnotobiotic mouse model demonstrates that dietary fiber protects against colorectal tumorigenesis in a microbiota- and butyrate-dependent manner.

Autor:	Donohoe DR; Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina., Holley D; Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina., Collins LB; Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina., Montgomery SA; College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina., Whitmore AC; 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., Hillhouse A; Department of Molecular and Cellular Medicine, Texas A&M University, College Station, Texas., Curry KP; Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina., Renner SW; Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina., Greenwalt A; Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina., Ryan EP; Department of Environmental and Radiological Health, Colorado State University, Fort Collins, Colorado., Godfrey V; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina., Heise MT; 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., Threadgill DS; Department of Veterinary Pathobiology, Texas A&M University, College Station, Texas., Han A; Department of Nutrition, University of Tennessee, Knoxville, Tennessee., Swenberg JA; Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina., Threadgill DW; Department of Molecular and Cellular Medicine, Texas A&M University, College Station, Texas. Department of Veterinary Pathobiology, Texas A&M University, College Station, Texas., Bultman SJ; Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina. Scott_Bultman@med.unc.edu.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2014 Dec; Vol. 4 (12), pp. 1387-97. Date of Electronic Publication: 2014 Sep 29.
DOI:	10.1158/2159-8290.CD-14-0501
Abstrakt:	Unlabelled: 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. Significance: 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. (©2014 American Association for Cancer Research.)
Databáze:	MEDLINE
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