Celecoxib alters the intestinal microbiota and metabolome in association with reducing polyp burden

David C. Montrose, Xi Kathy Zhou, Erin M. McNally, Erika Sue, Rhonda K. Yantiss, Steven S. Gross, Nitai D. Leve, Edward D. Karoly, Chen S. Suen, Lilan Ling, Robert Benezra, Eric G. Pamer, Andrew J. Dannenberg

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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 APCMin/+ mice. Treatment with celecoxib also altered select luminal bacterial populations in both APCMin/? 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 APCMin/+ 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.

Original languageEnglish (US)
Pages (from-to)721-731
Number of pages11
JournalCancer Prevention Research
Volume9
Issue number9
DOIs
StatePublished - Sep 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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