Aspirin Modulation of the Colorectal Cancer-Associated Microbe <named-content content-type='genus-species'>Fusobacterium nucleatum</named-content>

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—Fusobacterium nucleatum. We show that aspirin and its primary metabolite salicylic acid alter F. nucleatum 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 F. nucleatum may be relevant in vivo, we use the ApcMin/1 mouse intestinal tumor model in which Fn7-1 is orally inoculated daily to reveal that aspirin-supplemented chow is sufficient to inhibit F. nucleatum-potentiated colonic tumorigenesis. We expand our characterization of aspirin sensitivity across other F. nucleatum strains, including those isolated from human CRC tissues, as well as other CRC-associated microbes, enterotoxigenic Bacteroides fragilis, and colibactin-producing Escherichia coli. 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 F. nucleatum 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. IMPORTANCE 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 Fusobacterium nucleatum 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 Citation Brennan CA, Nakatsu G, Gallini Comeau CA, Drew DA, Glickman JN, Schoen RE, Chan AT, Garrett WS. 2021. Aspirin modulation of the colorectal cancer-associated microbe Fusobacterium nucleatum. mBio 12:e00547-21. https://doi.org/10.1128/mBio.00547-21. EditorMartin J. Blaser, Rutgers University Copyright © 2021 Brennan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. Address correspondence to Wendy S. Garrett, wgarrett@hsph.harvard. edu. * Present address: Carey Ann Gallini Comeau, Greentown Labs, Somerville, Massachusetts, USA. This article is a direct contribution from Wendy S. Garrett, a Fellow of the American Academy of Microbiology, who arranged for and secured reviews by Kim Lewis, Northeastern University, and Daniel Slade, Virginia Polytechnic Institute and State University. Received 26 February 2021 Accepted 4 March 2021 Published 6 April 2021 March/April 2021 Volume 12 Issue 2 e00547-21 ® mbio.asm. org 1 RESEARCH ARTICLE