Ferrara Carmen R, Bai Ji Dong K, McNally Erin M, Putzel Gregory G, Zhou Xi Kathy, Wang Hanhan, Lang Alan, Nagle Deborah, Denoya Paula, Krumsiek Jan, Dannenberg Andrew J, Montrose David C
Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York.
Departments of Medicine, Weill Cornell Medical College, New York, New York.
Cancer Prev Res (Phila). 2022 Dec 1;15(12):803-814. doi: 10.1158/1940-6207.CAPR-22-0244.
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.
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.
细菌被认为在肠道肿瘤发生中起重要作用，并对肠道腔内和循环代谢物都有影响。塞来昔布是一种选择性环氧化酶-2抑制剂，它在抑制小鼠肠道息肉发展的同时会改变肠道细菌和代谢物。本研究旨在评估塞来昔布是否部分通过肠道细菌和代谢组学改变发挥其化学预防作用。使用ApcMin/+小鼠，我们证明用广谱抗生素（ABx）治疗可降低肠道细菌丰度，并减弱塞来昔布抑制肠道肿瘤发生的能力。使用ABx还损害了塞来昔布改变微生物种群以及肠道腔内和循环代谢物的能力。单独用ABx治疗可显著减少ApcMin/+小鼠的肿瘤数量和大小，同时深刻改变肠腔和血液的代谢物谱。肠道和循环中的许多代谢物变化相互重叠，包括微生物衍生代谢物的变化。为补充在小鼠中的这些发现，我们评估了ABx对结肠癌患者循环代谢物的影响。这表明ABx治疗导致血液代谢物发生变化，包括几种源自细菌的代谢物。重要的是，接受ABx治疗的患者体内代谢物的变化与接受ABx治疗的小鼠中发现的变化相互重叠。综上所述，这些发现表明细菌代谢物在介导塞来昔布的化学预防作用和肠道肿瘤生长方面具有潜在作用。
本研究揭示了化学预防剂发挥作用以及肠道微生物群影响肠道肿瘤发展的新机制。这些发现有可能通过调节微生物及其代谢物来改进癌症预防策略。
