Microbes Contribute to Chemopreventive Efficacy, Intestinal Tumorigenesis, and the Metabolome

Bacteria are believed to play an important role in intestinal tumorigenesis and contribute to both gut luminal and circulating metabolites. Celecoxib, a selective cyclooxygen-ase-2 inhibitor, alters gut bacteria and metabolites in asso-ciation 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/ thorn mice, we demonstrated that treatment with broad-spectrum antibiotics (ABx) reduced abundance of gut bacteria and attenuated the ability of celecoxib to sup-press 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/ thorn 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.

Automated summary

Bacteria and metabolites are important in intestinal tumorigenesis, and celecoxib can suppress intestinal tumor development by altering gut bacteria and metabolites. The use of broad-spectrum antibiotics reduced gut bacteria abundance and attenuated the inhibitory effects of celecoxib on intestinal tumorigenesis. Antibiotics also affected microbial populations and gut luminal and circulating metabolites. Patients with colon cancer treated with antibiotics also showed alterations in blood metabolites. These findings suggest the potential role of bacterial metabolites in mediating the chemopreventive effects of celecoxib and intestinal tumor growth.