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

Autor:	Ferrara CR; Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York., Bai JDK; Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York., McNally EM; Departments of Medicine, Weill Cornell Medical College, New York, New York., Putzel GG; Departments of Medicine, Weill Cornell Medical College, New York, New York., Zhou XK; Healthcare Policy and Research, Weill Cornell Medical College, New York, New York., Wang H; Healthcare Policy and Research, Weill Cornell Medical College, New York, New York., Lang A; Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York., Nagle D; Department of Surgery, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York., Denoya P; Department of Surgery, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York., Krumsiek J; Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York.; Sandra and Edward Meyer Cancer Center, New York, New York.; Caryl and Israel Englander Institute for Precision Medicine, New York, New York., Dannenberg AJ; Department of Medicine (retired), Weill Cornell Medical College, New York, New York., Montrose DC; Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York.; Stony Brook Cancer Center, Stony Brook, New York.
Jazyk:	angličtina
Zdroj:	Cancer prevention research (Philadelphia, Pa.) [Cancer Prev Res (Phila)] 2022 Dec 01; Vol. 15 (12), pp. 803-814.
DOI:	10.1158/1940-6207.CAPR-22-0244
Abstrakt:	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. (©2022 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu