title: Black raspberries suppress colonic adenoma development in ApcMin/+ mice: relation to metabolite profiles.
abstract: Freeze-dried black raspberries (BRBs) have demonstrated chemopreventive effects in a dietary intervention trial with human colorectal cancer patients. The aim of this study was to investigate BRB-caused metabolite changes using the Apc(Min/+) mouse as a model of human colorectal cancer. Wild-type (WT) mice were fed control diet, and Apc(Min/+) mice were fed either control diet or control diet supplemented with 5% BRBs for 8 weeks. Colonic and intestinal polyp size and number were measured. A non-targeted metabolomic analysis was conducted on colonic mucosa, liver and fecal specimens. Eight weeks of BRB treatment significantly decreased intestinal and colonic polyp number and size in Apc(Min/+) mice. The apc gene mutation significantly changed 52 metabolites in colonic mucosa associated with increased amino acid and decreased lipid metabolites, as well as 39 liver and 8 fecal metabolites. BRBs significantly reversed 23 apc-regulated metabolites, including 13 colonic mucosa, 8 liver and 2 fecal metabolites that were involved in amino acid, glutathione, lipid and nucleotide metabolism. Of these, changes in eight metabolites were linearly correlated with decreased colonic polyp number and size in BRB-treated Apc(Min/+) mice. Elevated levels of putrescine and linolenate in Apc(Min/+) mice were significantly decreased by BRBs. Ornithine decarboxylase expression, the key enzyme in putrescine generation, was fully suppressed by BRBs. These results suggest that BRBs produced beneficial effects against colonic adenoma development in Apc(Min/+) mice and modulated multiple metabolic pathways. The metabolite changes produced by BRBs might potentially reflect the BRB-mediated chemopreventive effects in colorectal cancer patients.
authors.forename: Pan
authors.initials: P
authors.lastname: Pan
authors.forename: Chad W
authors.initials: CW
authors.lastname: Skaer
authors.forename: Hsin-Tzu
authors.initials: HT
authors.lastname: Wang
authors.affiliation: Clinical Research and Development, Metabolon, Inc., Durham, NC 27713, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Stirdivant
authors.affiliation: Division of Cancer Prevention, National Cancer Institute, Frederick, MD 20850, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Young
authors.affiliation: Department of Pathology and.
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Oshima
authors.forename: Gary D
authors.initials: GD
authors.lastname: Stoner
authors.forename: John F
authors.initials: JF
authors.lastname: Lechner
authors.affiliation: Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Huang
authors.forename: Li-Shu
authors.initials: LS
authors.lastname: Wang
mesh_terms: D000236:Adenoma / Q000178:diet therapy* / Q000378:metabolism / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000818:Animals; D015179:Colorectal Neoplasms / Q000178:diet therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005638:Fruit; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D011700:Putrescine / Q000096:biosynthesis; D065856:Rubus; D017962:alpha-Linolenic Acid / Q000096:biosynthesis
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D017962:alpha-Linolenic Acid; D011700:Putrescine