Bacteria are believed to play an important role in intestinal
tumorigenesis and contribute to both gut
luminal and circulating metabolites.
Celecoxib, a selective
cyclooxygenase-2 inhibitor, alters gut bacteria and metabolites in association with suppressing the development of
intestinal polyps in mice. The current study sought to evaluate whether
celecoxib exerts its chemopreventive effects, in part, through intestinal bacteria and metabolomic alterations. Using ApcMin/+ mice, we demonstrated that treatment with broad-spectrum
antibiotics (ABx) reduced abundance of gut bacteria and attenuated the ability of
celecoxib to suppress intestinal
tumorigenesis. Use of ABx also impaired
celecoxib's ability to shift microbial populations and gut
luminal and circulating metabolites. Treatment with ABx alone markedly reduced
tumor number and size in ApcMin/+ mice, in conjunction with profoundly altering the metabolite profiles of the intestinal lumen and blood. Many of the metabolite changes in the gut and circulation overlapped and included shifts in microbially derived metabolites. To
complement these findings in mice, we evaluated the effects of ABx on circulating metabolites in patients with
colon cancer. This showed that ABx treatment led to a shift in blood metabolites, including several that were of bacterial origin. Importantly, changes in metabolites in patients given ABx overlapped with alterations found in mice that also received ABx. Taken together, these findings suggest a potential role for bacterial metabolites in mediating both the chemopreventive effects of
celecoxib and intestinal
tumor growth.
PREVENTION RELEVANCE: This study demonstrates novel mechanisms by which chemopreventive agents exert their effects and gut microbiota impact intestinal
tumor development. These findings have the potential to lead to improved
cancer prevention strategies by modulating microbes and their metabolites.