Aspirin Modulation of the Colorectal Cancer-Associated Microbe Fusobacterium nucleatum.

Aspirin is a chemopreventive agent for colorectal adenoma and cancer (CRC) that, like many drugs inclusive of chemotherapeutics, has been investigated for its effects on bacterial growth and virulence gene expression. Given the evolving recognition of the roles for bacteria in CRC, in this work, we investigate the effects of aspirin with a focus on one oncomicrobe-<i>Fusobacterium nucleatum</i> We show that aspirin and its primary metabolite salicylic acid alter <i>F. nucleatum</i> strain Fn7-1 growth in culture and that aspirin can effectively kill both actively growing and stationary Fn7-1. We also demonstrate that, at levels that do not inhibit growth, aspirin influences Fn7-1 gene expression. To assess whether aspirin modulation of <i>F. nucleatum</i> may be relevant <i>in vivo</i>, we use the <i>Apc<sup>Min/+</sup></i> mouse intestinal tumor model in which Fn7-1 is orally inoculated daily to reveal that aspirin-supplemented chow is sufficient to inhibit <i>F. nucleatum</i>-potentiated colonic tumorigenesis. We expand our characterization of aspirin sensitivity across other <i>F. nucleatum</i> strains, including those isolated from human CRC tissues, as well as other CRC-associated microbes, enterotoxigenic <i>Bacteroides fragilis</i>, and colibactin-producing <i>Escherichia coli</i> Finally, we determine that individuals who use aspirin daily have lower fusobacterial abundance in colon adenoma tissues, as determined by quantitative PCR performed on adenoma DNA. Together, our data support that aspirin has direct antibiotic activity against <i>F. nucleatum</i> strains and suggest that consideration of the potential effects of aspirin on the microbiome holds promise in optimizing risk-benefit assessments for use of aspirin in CRC prevention and management.<b>IMPORTANCE</b> There is an increasing understanding of the clinical correlations and potential mechanistic roles of specific members of the gut and tumoral microbiota in colorectal cancer (CRC) initiation, progression, and survival. However, we have yet to parlay this knowledge into better CRC outcomes through microbially informed diagnostic, preventive, or therapeutic approaches. Here, we demonstrate that aspirin, an established CRC chemopreventive, exhibits specific effects on the CRC-associated <i>Fusobacterium nucleatum</i> in culture, an animal model of intestinal tumorigenesis, and in human colonic adenoma tissues. Our work proposes a potential role for aspirin in influencing CRC-associated bacteria to prevent colorectal adenomas and cancer, beyond aspirin's canonical anti-inflammatory role targeting host tissues. Future research, such as studies investigating the effects of aspirin on fusobacterial load in patients, will help further elucidate the prospect of using aspirin to modulate <i>F. nucleatum</i> <i>in vivo</i> for improving CRC outcomes.

Brennan CA, Chan AT, Drew DA, Gallini Comeau CA, Garrett WS, Glickman JN, Nakatsu G, Schoen RE

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mBio, 2021, 12 (2)

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