Despite substantial observational and experimental evidence that
aspirin use can provide protection against the development of colorectal
neoplasia, our understanding of the molecular mechanisms involved is inadequate and limits our ability to use this drug effectively and safely for
chemoprevention. We employed an untargeted plasma metabolomics approach using liquid chromatography with high-resolution mass spectroscopy to explore novel metabolites that may contribute to the chemopreventive effects of
aspirin. Associations between levels of metabolic features in plasma and
aspirin treatment were investigated among 523 participants in a randomized placebo-controlled clinical trial of two doses of
aspirin (81 or 325 mg/day) and were linked to risk of colorectal
adenoma occurrence over 3 years of follow-up. Metabolic pathways that were altered with
aspirin treatment included
linoleate and
glycerophospholipid metabolism for the 81-mg dose and
carnitine shuttle for both doses. Metabolites whose levels increased with 81 mg/day
aspirin treatment and were also associated with decreased risk of
adenomas during follow-up included certain forms of
lysophosphatidylcholine and
lysophosphatidylethanolamine as well as trihydroxyoctadecenoic
acid, which is a derivative of
linoleic acid and is upstream of
cyclooxygenase inhibition by
aspirin in the
linoleate and
arachidonic acid metabolism pathways. In conclusion, our findings regarding
lysophospholipids and metabolites in the
linoleate metabolism pathway may provide novel insights into the chemopreventive effects of
aspirin in the colorectum, although they should be considered hypothesis-generating at this time.
PREVENTION RELEVANCE: This research used metabolomics, an innovative discovery-based approach, to identify molecular changes in human blood that may help to explain how
aspirin use reduces the risk of colorectal
neoplasia in some individuals. Ultimately, this work could have important implications for optimizing
aspirin use in the prevention of
colorectal cancer.