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. 2023 Aug 22;44(32):3085-3096.
doi: 10.1093/eurheartj/ehad333.

Atlas of gut microbe-derived products from aromatic amino acids and risk of cardiovascular morbidity and mortality

Ina Nemet  1   2 , Xinmin S Li  1   2 , Arash Haghikia  3   4   5 , Lin Li  1   2 , Jennifer Wilcox  1   2 , Kymberleigh A Romano  1   2 , Jennifer A Buffa  1   2 , Marco Witkowski  1   2 , Ilja Demuth  6   7 , Maximilian König  6 , Elisabeth Steinhagen-Thiessen  6 , Fredrik Bäckhed  8 , Michael A Fischbach  9   10   11   12 , W H Wilson Tang  1   2   13 , Ulf Landmesser  3   4   5 , Stanley L Hazen  1   2   13
Affiliations

Atlas of gut microbe-derived products from aromatic amino acids and risk of cardiovascular morbidity and mortality

Ina Nemet et al. Eur Heart J. .

Abstract

Aims: Precision microbiome modulation as a novel treatment strategy is a rapidly evolving and sought goal. The aim of this study is to determine relationships among systemic gut microbial metabolite levels and incident cardiovascular disease risks to identify gut microbial pathways as possible targets for personalized therapeutic interventions.

Methods and results: Stable isotope dilution mass spectrometry methods to quantitatively measure aromatic amino acids and their metabolites were used to examine sequential subjects undergoing elective diagnostic cardiac evaluation in two independent cohorts with longitudinal outcome data [US (n = 4000) and EU (n = 833) cohorts]. It was also used in plasma from humans and mice before vs. after a cocktail of poorly absorbed antibiotics to suppress gut microbiota. Multiple aromatic amino acid-derived metabolites that originate, at least in part, from gut bacteria are associated with incident (3-year) major adverse cardiovascular event (MACE) risks (myocardial infarction, stroke, or death) and all-cause mortality independent of traditional risk factors. Key gut microbiota-derived metabolites associated with incident MACE and poorer survival risks include: (i) phenylacetyl glutamine and phenylacetyl glycine (from phenylalanine); (ii) p-cresol (from tyrosine) yielding p-cresol sulfate and p-cresol glucuronide; (iii) 4-OH-phenyllactic acid (from tyrosine) yielding 4-OH-benzoic acid and 4-OH-hippuric acid; (iv) indole (from tryptophan) yielding indole glucuronide and indoxyl sulfate; (v) indole-3-pyruvic acid (from tryptophan) yielding indole-3-lactic acid and indole-3-acetyl-glutamine, and (vi) 5-OH-indole-3-acetic acid (from tryptophan).

Conclusion: Key gut microbiota-generated metabolites derived from aromatic amino acids independently associated with incident adverse cardiovascular outcomes are identified, and thus will help focus future studies on gut-microbial metabolic outputs relevant to host cardiovascular health.

Keywords: Aromatic amino acids; Cardiovascular disease; Gut microbiome; Metabolism; Phenylacetylglutamine.

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Conflict of interest statement

Conflict of interest: Dr. Hazen reports being named as co-inventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics, being a paid consultant formerly for Procter & Gamble in the past, and currently with Zehna Therapeutics. He also reports having received research funds from Procter & Gamble, Zehna Therapeutics and Roche Diagnostics, and being eligible to receive royalty payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Procter & Gamble, Zehna Therapeutics, and Cleveland HeartLab, a wholly owned subsidiary of Quest Diagnostics. Jennifer Buffa reports having received royalty payments from Proctor & Gamble. Dr. Fischbach is a co-founder and director of Federation Bio and Viralogic, a co-founder of Revolution Medicines, a member of the scientific advisory. M. Fischbach also reports Consultancy: NGM Bio; Ownership Interest: Kelonia, NGM Bio; Patents or Royalties: Federation Bio; and Advisory or Leadership Role: Federation Bio, Kelonia, Board of NGM Biopharmaceuticals, and an innovation partner at The Column Group. Dr. Tang reports being a consultant for Sequana Medical A.G., Owkin Inc, Relypsa Inc, and PreCardiac Inc, having received honorarium from Springer Nature for authorship/editorship and American Board of Internal Medicine for exam writing committee participation—all unrelated to the subject and contents of this paper. The other authors report they have no relationships relevant to the contents of this paper to disclose.

Figures

Structured Graphical Abstract
Structured Graphical Abstract
Gut microbiota-generated metabolites and pathways derived from aromatic amino acids that independently associate with incident major adverse cardiovascular event (MACE) and death risk are identified using a combination of large-scale clinical association studies (US and European cohorts with longitudinal outcome data), and both human and animal studies involving gut microbial suppression with oral ingestion of a cocktail of poorly absorbed antibiotics.
Figure 1
Figure 1
Association between MACE and plasma metabolites derived from phenylalanine, tyrosine and tryptophan via gut microbes. Hazard ratio (95% CI) for incident (3-year) risks for major adverse cardiovascular events (MACE) to gut microbial-derived metabolites from aromatic amino acids in a cohort of stable cardiac patients from combined two independent cohorts [US cohort (n = 4000) and European cohort (n = 833)] undergoing elective diagnostic coronary evaluation. Hazard ratio (unadjusted, filled circles) and multivariable Cox model adjusted (open circles; adjusted for age, sex, smoking, HDL, LDL, TG, hypertension, diabetes mellitus, and hsCRP). Red, green, and black color is for compounds positively, negatively, and not associated with MACE, respectively. The 5%–95% confidence interval is indicated by line length.
Figure 2
Figure 2
An atlas of microbial phenylalanine and tyrosine pathways associated with MACE. Metabolic pathways for aromatic acid fermentation together with their association with MACE (red chemical structures for compounds positively associated with MACE while green structures for compounds negatively associated with MACE after adjusting for traditional risk factors and hsCRP) and effect of gut microbe depletion on their circulation levels both in humans (blue (left) arrow) and mice (red (right) arrow); (−) no effect. Abx = antibiotics.
Figure 3
Figure 3
An atlas of microbial tryptophan pathways associated with MACE. Metabolic pathways for aromatic acid fermentation together with their association with MACE (red chemical structures for compounds positively associated with MACE while green structures for compounds negatively associated with MACE after adjusting for traditional risk factors and hsCRP) and effect of gut microbe depletion on their circulation levels both in humans (blue (left) arrow) and mice (red (right) arrow); (−) no effect. Abx = antibiotics.
Figure 4
Figure 4
Association between all-cause mortality and plasma metabolites derived from phenylalanine, tyrosine and tryptophan via gut microbes. Hazard ratio (95% CI) for incident (3-year) risks for all-cause-mortality) to gut microbial-derived metabolites from aromatic amino acids in a cohort of stable cardiac patients from combined two independent cohorts [US cohort (n = 4000) and European cohort (n = 833)] undergoing elective diagnostic coronary evaluation. Hazard ratio (unadjusted, filled circles) and multivariable Cox model adjusted (open circles; adjusted for age, sex, smoking, HDL, LDL, TG, hypertension, diabetes mellitus, and hsCRP). Red, green, and black color is for compounds positively, negatively and not associated with MACE, respectively. The 5%–95% confidence interval is indicated by line length.
Figure 5
Figure 5
An atlas of microbial phenylalanine and tyrosine pathways associated with 3-year all-cause mortality. Metabolic pathways for aromatic acid fermentation together with their association with all-cause mortality (death) (red chemical structures for compounds positively associated with death while green structures for compounds negatively associated with death after adjusting for traditional risk factors and hsCRP) and effect of gut microbe depletion on their circulation levels both in humans (blue (left) arrow) and mice (red (right) arrow); (−) no effect. Abx = antibiotics.
Figure 6
Figure 6
An atlas of microbial tryptophan pathways associated with 3-year all-cause mortality. Metabolic pathways for aromatic acid fermentation together with their association with all-cause mortality (death) (red chemical structures for compounds positively associated with death while green structures for compounds negatively associated with death after adjusting for traditional risk factors and hsCRP) and effect of gut microbe depletion on their circulation levels both in humans (blue (left) arrow) and mice (red (right) arrow); (−) no effect. Abx = antibiotics.
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