title: Celecoxib Alters the Intestinal Microbiota and Metabolome in Association with Reducing Polyp Burden.
abstract: Treatment with celecoxib, a selective COX-2 inhibitor, reduces formation of premalignant adenomatous polyps in the gastrointestinal tracts of humans and mice. In addition to its chemopreventive activity, celecoxib can exhibit antimicrobial activity. Differing bacterial profiles have been found in feces from colon cancer patients compared with those of normal subjects. Moreover, preclinical studies suggest that bacteria can modulate intestinal tumorigenesis by secreting specific metabolites. In the current study, we determined whether celecoxib treatment altered the luminal microbiota and metabolome in association with reducing intestinal polyp burden in mice. Administration of celecoxib for 10 weeks markedly reduced intestinal polyp burden in APC(Min/+) mice. Treatment with celecoxib also altered select luminal bacterial populations in both APC(Min/+) and wild-type mice, including decreased Lactobacillaceae and Bifidobacteriaceae as well as increased Coriobacteriaceae Metabolomic analysis demonstrated that celecoxib caused a strong reduction in many fecal metabolites linked to carcinogenesis, including glucose, amino acids, nucleotides, and lipids. Ingenuity Pathway Analysis suggested that these changes in metabolites may contribute to reduced cell proliferation. To this end, we showed that celecoxib reduced cell proliferation in the base of normal appearing ileal and colonic crypts of APC(Min/+) mice. Consistent with this finding, lineage tracing indicated that celecoxib treatment reduced the rate at which Lgr5-positive stem cells gave rise to differentiated cell types in the crypts. Taken together, these results demonstrate that celecoxib alters the luminal microbiota and metabolome along with reducing epithelial cell proliferation in mice. We hypothesize that these actions contribute to its chemopreventive activity. Cancer Prev Res; 9(9); 721-31. ©2016 AACR.
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: David C
authors.initials: DC
authors.lastname: Montrose
authors.affiliation: Department of Healthcare Policy and Research, Weill Cornell Medical College, New York, New York.
authors.forename: Xi Kathy
authors.initials: XK
authors.lastname: Zhou
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Erin M
authors.initials: EM
authors.lastname: McNally
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Erika
authors.initials: E
authors.lastname: Sue
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Rhonda K
authors.initials: RK
authors.lastname: Yantiss
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, New York.
authors.forename: Steven S
authors.initials: SS
authors.lastname: Gross
authors.affiliation: Department of Healthcare Policy and Research, Weill Cornell Medical College, New York, New York.
authors.forename: Nitai D
authors.initials: ND
authors.lastname: Leve
authors.affiliation: Metabolon, Inc., Durham, North Carolina.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Karoly
authors.affiliation: Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland.
authors.forename: Chen S
authors.initials: CS
authors.lastname: Suen
authors.affiliation: Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Lilan
authors.initials: L
authors.lastname: Ling
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Robert
authors.initials: R
authors.lastname: Benezra
authors.affiliation: Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York. Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York. Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Eric G
authors.initials: EG
authors.lastname: Pamer
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York. ajdannen@med.cornell.edu.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Dannenberg
mesh_terms: D000818:Animals; D000068579:Celecoxib / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D005243:Feces / Q000737:chemistry / Q000382:microbiology; D000069196:Gastrointestinal Microbiome / Q000187:drug effects*; D007417:Intestinal Polyps / Q000473:pathology*; D008297:Male; D055442:Metabolome / Q000187:drug effects*; D051379:Mice
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D000068579:Celecoxib