Celecoxib Alters The Intestinal Microbiota And Metabolome In Association With Reducing Polyp Burden

Introduction: Celecoxib is a chemopreventive agent that reduces adenomatous polyp number in the gastrointestinal tract of humans and mice and is thought to exert its effects exclusively through inhibition of COX-2. Bacteria have been shown to impact upon intestinal tumorigenesis in part by secretion of key metabolites. However, it is unknown whether celecoxib may be reducing polyp burden at least in part, through effects on the luminal microbiota or metabolome. This study tested whether celecoxib can alter the luminal microbiota and metabolome in association with reducing intestinal polyps in APCMin/+ mice, potentially providing a novel mechanism by which it exerts its chemopreventive effects. Methods: APCMin/+ and wild-type (WT) mice were co-housed for 2 weeks to normalize their microbiota, then individually housed and administered control or celecoxib-containing diet from 6 to 16 weeks of age. Feces were collected at 6, 11 and 16 weeks of age and ileal content and intestinal tissue (to quantify polyp burden) were collected at 16 weeks. Bacterial composition analysis on ileal content and feces was carried out using 16S rDNA sequencing and relative fecal metabolite levels were measured using UPLC/MS/MS and GC/MS. Results: As expected, administration of celecoxib for 10 weeks markedly reduced intestinal polyp burden in APCMin/+ mice. Concomitant with this effect, drug administration altered the luminal bacterial populations, a shift that also occurred in WT mice. These changes included increased Coriobacteriaceae and decreased Lactobacillaceae and Bifidobacteriaceae. Subsequent metabolomic analysis demonstrated that celecoxib caused a strong reduction in many fecal metabolites including glucose, amino acids, nucleotides and lipids. Ingenuity Pathway Analysis revealed that this change in metabolomic profile was associated with pathway perturbations that could contribute to reduced cell proliferation. Lastly, we showed that the observed changes were associated with a reduction in stem cell proliferation in normal intestinal crypts of APCMin/+ mice. Conclusions: These results demonstrate that celecoxib treatment profoundly altered the luminal microbiota and metabolome of mice and we hypothesize that these actions contribute to its chemopreventive activity. Further studies are warranted to confirm this hypothesis and assess whether our findings extend to humans and to other nonsteroidal anti-inflammatory drugs. Citation Format: David C. Montrose, Xi K. Zhou, Erin M. McNally, Erika Sue, Steven S. Gross, Nitai D. Leve, Edward D. Karoly, Lilan Ling, Eric G. Pamer, Andrew J. Dannenberg. Celecoxib alters the intestinal microbiota and metabolome in association with reducing polyp burden. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-302.