Metabolomics analysis of aspirin’s effects in human colon tissue and associations with adenoma risk

Elizabeth L. Barry; Veronika Fedirko; Karan Uppal; Chunyu Ma; Ken Liu; Leila A. Mott; Janet L. Peacock; Michael N. Passarelli; John A. Baron; Dean P. Jones

doi:10.1158/1940-6207.CAPR-20-0014

Metabolomics analysis of aspirin’s effects in human colon tissue and associations with adenoma risk

Elizabeth L. Barry^*, Veronika Fedirko, Karan Uppal, Chunyu Ma, Ken Liu, Leila A. Mott, Janet L. Peacock, Michael N. Passarelli, John A. Baron, Dean P. Jones

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Pages (from-to)	863-875
Number of pages	13
Journal	Cancer Prevention Research
Volume	13
Issue number	10
DOIs	https://doi.org/10.1158/1940-6207.CAPR-20-0014
Publication status	Published - 1 Oct 2020

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10.1158/1940-6207.CAPR-20-0014

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@article{435b57fe06e7462da2572d6382df376e,

title = "Metabolomics analysis of aspirin{\textquoteright}s effects in human colon tissue and associations with adenoma risk",

abstract = "Although substantial evidence supports aspirin{\textquoteright}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.",

author = "Barry, {Elizabeth L.} and Veronika Fedirko and Karan Uppal and Chunyu Ma and Ken Liu and Mott, {Leila A.} and Peacock, {Janet L.} and Passarelli, {Michael N.} and Baron, {John A.} and Jones, {Dean P.}",

note = "Funding Information: E.L. Barry reports grants from NIH/NCI during the conduct of the study. J.A. Baron reports grants from NCI during the conduct of the study, as well as has a patent for chemopreventive use of aspirin issued (held with Dartmouth College). D.P. Jones reports grants from Emory University (received NIH grant support) during the conduct of the study. No potential conflicts of interest were disclosed by the other authors. Funding Information: These data are available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR000730. The data can be accessed directly via its Project DOI: 10.21228/M89X1C. This work was supported by NIH grant, U2C-DK119886. Funding Information: We would like to thank the participants and staff of the Aspirin/Folate Polyp Prevention Study for their valuable contributions. This work was supported by NCI/NIH R01CA188038 to E. Barry and R01CA059005 to J. Baron. The study biorepository was supported by NIGMS/NIH P20GM104416. Aspirin and placebo tablets used in the Aspirin/Folate Polyp Prevention Study were provided by the Bayer Corporation. Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2020",

month = oct,

day = "1",

doi = "10.1158/1940-6207.CAPR-20-0014",

language = "English",

volume = "13",

pages = "863--875",

journal = "Cancer Prevention Research",

issn = "1940-6207",

publisher = "American Association for Cancer Research",

number = "10",

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T1 - Metabolomics analysis of aspirin’s effects in human colon tissue and associations with adenoma risk

AU - Barry, Elizabeth L.

AU - Fedirko, Veronika

AU - Uppal, Karan

AU - Ma, Chunyu

AU - Liu, Ken

AU - Mott, Leila A.

AU - Peacock, Janet L.

AU - Passarelli, Michael N.

AU - Baron, John A.

AU - Jones, Dean P.

N1 - Funding Information: E.L. Barry reports grants from NIH/NCI during the conduct of the study. J.A. Baron reports grants from NCI during the conduct of the study, as well as has a patent for chemopreventive use of aspirin issued (held with Dartmouth College). D.P. Jones reports grants from Emory University (received NIH grant support) during the conduct of the study. No potential conflicts of interest were disclosed by the other authors. Funding Information: These data are available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR000730. The data can be accessed directly via its Project DOI: 10.21228/M89X1C. This work was supported by NIH grant, U2C-DK119886. Funding Information: We would like to thank the participants and staff of the Aspirin/Folate Polyp Prevention Study for their valuable contributions. This work was supported by NCI/NIH R01CA188038 to E. Barry and R01CA059005 to J. Baron. The study biorepository was supported by NIGMS/NIH P20GM104416. Aspirin and placebo tablets used in the Aspirin/Folate Polyp Prevention Study were provided by the Bayer Corporation. Publisher Copyright: © 2020 American Association for Cancer Research. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2020/10/1

Y1 - 2020/10/1

N2 - 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.

AB - 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.

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U2 - 10.1158/1940-6207.CAPR-20-0014

DO - 10.1158/1940-6207.CAPR-20-0014

M3 - Article

C2 - 32655007

AN - SCOPUS:85090257854

SN - 1940-6207

VL - 13

SP - 863

EP - 875

JO - Cancer Prevention Research

JF - Cancer Prevention Research

IS - 10

ER -

Metabolomics analysis of aspirin’s effects in human colon tissue and associations with adenoma risk

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