Plasma Gut Microbe-Derived Metabolites Associated with Peripheral Artery Disease and Major Adverse Cardiac Events

Karen J. Ho; Joel L. Ramirez; Rohan Kulkarni; Katharine G. Harris; Irene Helenowski; Liqun Xiong; C. Keith Ozaki; S. Marlene Grenon

doi:10.3390/microorganisms10102065

Plasma Gut Microbe-Derived Metabolites Associated with Peripheral Artery Disease and Major Adverse Cardiac Events

Karen J. Ho^*, Joel L. Ramirez, Rohan Kulkarni, Katharine G. Harris, Irene Helenowski, Liqun Xiong, C. Keith Ozaki, S. Marlene Grenon

^*Corresponding author for this work

Surgery, Vascular Surgery Division

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

14 Scopus citations

Abstract

Cardiovascular diseases are associated with gut dysbiosis, but the role of microbe-derived metabolites as biomarkers or modulators of cardiovascular disease are not well understood. This is a targeted metabolomics study to investigate the association of nine microbe-derived metabolites with lower extremity peripheral artery disease (PAD), a form of atherosclerosis, and major adverse cardiac events (MACE). The study cohort consists of individuals with intermittent claudication and ankle-brachial index (ABI) < 0.9 (N = 119) and controls without clinically-apparent atherosclerosis (N = 37). The primary endpoint was MACE, a composite endpoint of myocardial infarction, coronary revascularization, stroke, transient ischemic attack, or cardiac-related death. Plasma metabolite concentrations differed significantly between the PAD and control groups. After adjustment for traditional atherosclerosis risk factors, kynurenine, hippuric acid, indole-3-propionic acid (IPA), and indole-3-aldehyde (I3A) concentrations were negatively associated with PAD, whereas indoxyl sulfate and 3-hydroxyanthranilic acid were positively associated. Hippuric acid, IPA, and I3A correlated with ABI, a surrogate for atherosclerotic disease burden. Those in the highest I3A concentration quartile had significantly improved freedom from MACE during follow-up compared to those in the lowest quartile. This study identifies specific indole- and phenyl-derived species impacted by gut microbial metabolic pathways that could represent novel microbiome-related biomarkers of PAD.

Original language	English (US)
Article number	2065
Journal	Microorganisms
Volume	10
Issue number	10
DOIs	https://doi.org/10.3390/microorganisms10102065
State	Published - Oct 2022

Funding

This work was supported by the National Heart, Lung and Blood Institute (K08HL130601 and R03HL146880 to K.J.H., K23HL122446 to S.M.G., and R01HL133500 to C.K.O.), the National Center for Advancing Translational Sciences (TL1TR001871 to J.R.); National Center for Research Resources (KL2RR024130 to S.M.G.); the American College of Surgeons (Career Development Awards to K.J.H. and S.M.G.); the Society for Vascular Surgery (Career Development Awards to K.J.H. and S.M.G., Clinical Research Seed Grant to S.M.G., Student Research Fellowship Award to J.R.); the American Heart Association (Student Scholarships to J.R. and R.K.); the Northern California Institute for Research and Education (to S.M.G.); Vascular Cures (to K.J.H.); the Northwestern Memorial Foundation, Eleanor Wood-Prince Grants Initiative (to K.J.H.); and the Northwestern University Feinberg School of Medicine, Division of Vascular Surgery (the Vascular Surgery Student Research Award from the Joseph B. & Marjorie M. Lanterman Endowed Research and Education fund to R.K.).

Keywords

ankle-brachial index
microbiome
peripheral artery disease

ASJC Scopus subject areas

Microbiology (medical)
Virology
Microbiology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/microorganisms10102065

Cite this

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title = "Plasma Gut Microbe-Derived Metabolites Associated with Peripheral Artery Disease and Major Adverse Cardiac Events",

abstract = "Cardiovascular diseases are associated with gut dysbiosis, but the role of microbe-derived metabolites as biomarkers or modulators of cardiovascular disease are not well understood. This is a targeted metabolomics study to investigate the association of nine microbe-derived metabolites with lower extremity peripheral artery disease (PAD), a form of atherosclerosis, and major adverse cardiac events (MACE). The study cohort consists of individuals with intermittent claudication and ankle-brachial index (ABI) < 0.9 (N = 119) and controls without clinically-apparent atherosclerosis (N = 37). The primary endpoint was MACE, a composite endpoint of myocardial infarction, coronary revascularization, stroke, transient ischemic attack, or cardiac-related death. Plasma metabolite concentrations differed significantly between the PAD and control groups. After adjustment for traditional atherosclerosis risk factors, kynurenine, hippuric acid, indole-3-propionic acid (IPA), and indole-3-aldehyde (I3A) concentrations were negatively associated with PAD, whereas indoxyl sulfate and 3-hydroxyanthranilic acid were positively associated. Hippuric acid, IPA, and I3A correlated with ABI, a surrogate for atherosclerotic disease burden. Those in the highest I3A concentration quartile had significantly improved freedom from MACE during follow-up compared to those in the lowest quartile. This study identifies specific indole- and phenyl-derived species impacted by gut microbial metabolic pathways that could represent novel microbiome-related biomarkers of PAD.",

keywords = "ankle-brachial index, microbiome, peripheral artery disease",

author = "Ho, {Karen J.} and Ramirez, {Joel L.} and Rohan Kulkarni and Harris, {Katharine G.} and Irene Helenowski and Liqun Xiong and Ozaki, {C. Keith} and Grenon, {S. Marlene}",

note = "Funding Information: This work was supported by the National Heart, Lung and Blood Institute (K08HL130601 and R03HL146880 to K.J.H., K23HL122446 to S.M.G., and R01HL133500 to C.K.O.), the National Center for Advancing Translational Sciences (TL1TR001871 to J.R.); National Center for Research Resources (KL2RR024130 to S.M.G.); the American College of Surgeons (Career Development Awards to K.J.H. and S.M.G.); the Society for Vascular Surgery (Career Development Awards to K.J.H. and S.M.G., Clinical Research Seed Grant to S.M.G., Student Research Fellowship Award to J.R.); the American Heart Association (Student Scholarships to J.R. and R.K.); the Northern California Institute for Research and Education (to S.M.G.); Vascular Cures (to K.J.H.); the Northwestern Memorial Foundation, Eleanor Wood-Prince Grants Initiative (to K.J.H.); and the Northwestern University Feinberg School of Medicine, Division of Vascular Surgery (the Vascular Surgery Student Research Award from the Joseph B. & Marjorie M. Lanterman Endowed Research and Education fund to R.K.). Publisher Copyright: {\textcopyright} 2022 by the authors.",

year = "2022",

month = oct,

doi = "10.3390/microorganisms10102065",

language = "English (US)",

volume = "10",

journal = "Microorganisms",

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T1 - Plasma Gut Microbe-Derived Metabolites Associated with Peripheral Artery Disease and Major Adverse Cardiac Events

AU - Ho, Karen J.

AU - Ramirez, Joel L.

AU - Kulkarni, Rohan

AU - Harris, Katharine G.

AU - Helenowski, Irene

AU - Xiong, Liqun

AU - Ozaki, C. Keith

AU - Grenon, S. Marlene

N1 - Funding Information: This work was supported by the National Heart, Lung and Blood Institute (K08HL130601 and R03HL146880 to K.J.H., K23HL122446 to S.M.G., and R01HL133500 to C.K.O.), the National Center for Advancing Translational Sciences (TL1TR001871 to J.R.); National Center for Research Resources (KL2RR024130 to S.M.G.); the American College of Surgeons (Career Development Awards to K.J.H. and S.M.G.); the Society for Vascular Surgery (Career Development Awards to K.J.H. and S.M.G., Clinical Research Seed Grant to S.M.G., Student Research Fellowship Award to J.R.); the American Heart Association (Student Scholarships to J.R. and R.K.); the Northern California Institute for Research and Education (to S.M.G.); Vascular Cures (to K.J.H.); the Northwestern Memorial Foundation, Eleanor Wood-Prince Grants Initiative (to K.J.H.); and the Northwestern University Feinberg School of Medicine, Division of Vascular Surgery (the Vascular Surgery Student Research Award from the Joseph B. & Marjorie M. Lanterman Endowed Research and Education fund to R.K.). Publisher Copyright: © 2022 by the authors.

PY - 2022/10

Y1 - 2022/10

N2 - Cardiovascular diseases are associated with gut dysbiosis, but the role of microbe-derived metabolites as biomarkers or modulators of cardiovascular disease are not well understood. This is a targeted metabolomics study to investigate the association of nine microbe-derived metabolites with lower extremity peripheral artery disease (PAD), a form of atherosclerosis, and major adverse cardiac events (MACE). The study cohort consists of individuals with intermittent claudication and ankle-brachial index (ABI) < 0.9 (N = 119) and controls without clinically-apparent atherosclerosis (N = 37). The primary endpoint was MACE, a composite endpoint of myocardial infarction, coronary revascularization, stroke, transient ischemic attack, or cardiac-related death. Plasma metabolite concentrations differed significantly between the PAD and control groups. After adjustment for traditional atherosclerosis risk factors, kynurenine, hippuric acid, indole-3-propionic acid (IPA), and indole-3-aldehyde (I3A) concentrations were negatively associated with PAD, whereas indoxyl sulfate and 3-hydroxyanthranilic acid were positively associated. Hippuric acid, IPA, and I3A correlated with ABI, a surrogate for atherosclerotic disease burden. Those in the highest I3A concentration quartile had significantly improved freedom from MACE during follow-up compared to those in the lowest quartile. This study identifies specific indole- and phenyl-derived species impacted by gut microbial metabolic pathways that could represent novel microbiome-related biomarkers of PAD.

AB - Cardiovascular diseases are associated with gut dysbiosis, but the role of microbe-derived metabolites as biomarkers or modulators of cardiovascular disease are not well understood. This is a targeted metabolomics study to investigate the association of nine microbe-derived metabolites with lower extremity peripheral artery disease (PAD), a form of atherosclerosis, and major adverse cardiac events (MACE). The study cohort consists of individuals with intermittent claudication and ankle-brachial index (ABI) < 0.9 (N = 119) and controls without clinically-apparent atherosclerosis (N = 37). The primary endpoint was MACE, a composite endpoint of myocardial infarction, coronary revascularization, stroke, transient ischemic attack, or cardiac-related death. Plasma metabolite concentrations differed significantly between the PAD and control groups. After adjustment for traditional atherosclerosis risk factors, kynurenine, hippuric acid, indole-3-propionic acid (IPA), and indole-3-aldehyde (I3A) concentrations were negatively associated with PAD, whereas indoxyl sulfate and 3-hydroxyanthranilic acid were positively associated. Hippuric acid, IPA, and I3A correlated with ABI, a surrogate for atherosclerotic disease burden. Those in the highest I3A concentration quartile had significantly improved freedom from MACE during follow-up compared to those in the lowest quartile. This study identifies specific indole- and phenyl-derived species impacted by gut microbial metabolic pathways that could represent novel microbiome-related biomarkers of PAD.

KW - ankle-brachial index

KW - microbiome

KW - peripheral artery disease

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Plasma Gut Microbe-Derived Metabolites Associated with Peripheral Artery Disease and Major Adverse Cardiac Events

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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