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

Abstract

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 colon cancer patients. 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.

Altered lipid metabolism in APC-driven colorectal cancer: the potential for therapeutic intervention

“…found a significant reduction in adenoma recurrence in NSAID users, particularly in advanced polyps ( 28 , 30 ). Interestingly, multiple studies report differences in the gut microbiome and metabolome in patients using NSAIDs as compared to those not using NSAIDs, suggesting that protective anti-inflammatory effects of NSAIDs on polyp formation are potentially mediated by intestinal flora and microbe-derived metabolites ( 27 , 29 ).…”

“…An increase in production of 4-hydroxy-2-nonenal (4-HNE), a DNA mutagen and an autochthonous mitotic spindle poison, produced by peroxidation of w6 polyunsaturated fatty acids, and upregulation of COX-2 in primary colon cells by commensal infected microphages have been reported as CRC initiation contributing factors (23)(24)(25). Inactivation of COX-1 and COX-2 have been shown to significantly reduce polyp numbers in multiple animal models (26). Furthermore, knockout mutation for prostaglandin E2 receptor EP2 introduced into Apc D716 mice results in a reduced number and size of intestinal polyps (98).…”

The role of gut microbiota and drug interactions in the development of colorectal cancer

“…Celecoxib reduced the luminal microbiome and metabolome associated with intestinal stem cell proliferation, inhibited c-Met, and exerted anti-CRC effects ( Jendrossek, 2013 ; Lin et al, 2019 ). The ability of celecoxib to chemoprevent CRC is mediated by the gut microbiota and microbe-derived metabolites ( Ferrara et al, 2022 ). In hepatocellular carcinoma, celecoxib enhances the anti-tumor function of immune cells by up-regulating the abundance of Bacteroides Acidifaciens , Odoribacter Laneus, and Odoribacter splanchnicus ( Pan et al, 2023 ).…”