Abstract
Although substantial evidence supports aspirin's efficacy in colorectal cancer chemoprevention, key molecular mechanisms are uncertain. An untargeted metabolomics approach with high-resolution mass spectrometry was used to elucidate metabolic effects of aspirin treatment in human colon tissue. We measured 10,269 metabolic features in normal mucosal biopsies collected at colonoscopy after approximately 3 years of randomized treatment with placebo, 81 or 325 mg/day aspirin from 325 participants in the Aspirin/Folate Polyp Prevention Study. Linear regression was used to identify aspirin-associated metabolic features and network analysis was used to identify pathways and predict metabolite identities. Poisson regression was used to examine metabolic features associations with colorectal adenoma risk. We detected 471 aspirin-associated metabolic features. Aside from the carnitine shuttle, aspirin-associated metabolic pathways were largely distinct for 81 mg aspirin (e.g., pyrimidine metabolism) and 325 mg (e.g., arachidonic acid metabolism). Among aspirin-associated metabolic features, we discovered three that were associated with adenoma risk and could contribute to the chemopreventive effect of aspirin treatment, and which have also previously been associated with colorectal cancer: creatinine, glycerol 3-phosphate, and linoleate. The last two of these are in the glycerophospholipid metabolism pathway, which was associated with 81 mg aspirin treatment and provides precursors for the synthesis of eicosanoids from arachidonic acid upstream of cyclooxygenase inhibition by aspirin. Conversely, carnitine shuttle metabolites were increased with aspirin treatment and associated with increased adenoma risk. Thus, our untargeted metabolomics approach has identified novel metabolites and pathways that may underlie the effects of aspirin during early colorectal carcinogenesis.
