Gut Microbial Associations to Plasma Metabolites Linked to Cardiovascular Phenotypes and Risk

Alexander Kurilshikov¹, Inge C L van den Munckhof², Lianmin Chen^{1

3}, Marc J Bonder¹, Kiki Schraa², Joost H W Rutten², Niels P Riksen², Jacqueline de Graaf², Marije Oosting², Serena Sanna¹, Leo A B Joosten², Marinette van der Graaf⁴, Tessa Brand², Debby P Y Koonen³, Martijn van Faassen⁵; LifeLines DEEP Cohort Study, BBMRI Metabolomics Consortium; P Eline Slagboom⁶, Ramnik J Xavier^{7

8

9

10}, Folkert Kuipers^{3

5}, Marten H Hofker³, Cisca Wijmenga^{1

11}, Mihai G Netea^{2

12

13}, Alexandra Zhernakova¹, Jingyuan Fu^{1

3}

Affiliations

¹ From the Department of Genetics (A.K., L.C., M.J.B., S.S., C.W., A.Z., J.F.), University of Groningen, University Medical Center Groningen, the Netherlands.
² Department of Internal Medicine and Radboud Center for Infectious Diseases (I.C.L.v.d.M., K.S., J.H.W.R., N.P.R., J.d.G., M.O., L.A.B.J., T.B., M.G.N.), Radboud University Medical Center, Nijmegen, the Netherlands.
³ Department of Pediatrics (L.C., D.P.Y.K., F.K., M.H.H., J.F.), University of Groningen, University Medical Center Groningen, the Netherlands.
⁴ Department of Radiology and Nuclear Medicine (M.v.d.G.), Radboud University Medical Center, Nijmegen, the Netherlands.
⁵ Department of Laboratory Medicine (M.v.F., F.K.), University of Groningen, University Medical Center Groningen, the Netherlands.
⁶ Section of Molecular Epidemiology, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, the Netherlands (P.E.S.).
⁷ Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston (R.J.X.).
⁸ Broad Institute of MIT and Harvard, Cambridge, MA (R.J.X.).
⁹ Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston (R.J.X.).
¹⁰ Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge (R.J.X.).
¹¹ Department of Immunology, K.G. Jebsen Coeliac Disease Research Centre, University of Oslo, Norway (C.W.).
¹² Department for Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, Germany (M.G.N.).
¹³ Human Genomics Laboratory, Craiova University of Medicine and Pharmacy, Romania (M.G.N.).

PMID: 30971183
DOI: 10.1161/CIRCRESAHA.118.314642

Free article

Gut Microbial Associations to Plasma Metabolites Linked to Cardiovascular Phenotypes and Risk

Alexander Kurilshikov et al. Circ Res. 2019.

Free article

. 2019 Jun 7;124(12):1808-1820.

doi: 10.1161/CIRCRESAHA.118.314642. Epub 2019 Apr 11.

Authors

Affiliations

¹ From the Department of Genetics (A.K., L.C., M.J.B., S.S., C.W., A.Z., J.F.), University of Groningen, University Medical Center Groningen, the Netherlands.
² Department of Internal Medicine and Radboud Center for Infectious Diseases (I.C.L.v.d.M., K.S., J.H.W.R., N.P.R., J.d.G., M.O., L.A.B.J., T.B., M.G.N.), Radboud University Medical Center, Nijmegen, the Netherlands.
³ Department of Pediatrics (L.C., D.P.Y.K., F.K., M.H.H., J.F.), University of Groningen, University Medical Center Groningen, the Netherlands.
⁴ Department of Radiology and Nuclear Medicine (M.v.d.G.), Radboud University Medical Center, Nijmegen, the Netherlands.
⁵ Department of Laboratory Medicine (M.v.F., F.K.), University of Groningen, University Medical Center Groningen, the Netherlands.
⁶ Section of Molecular Epidemiology, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, the Netherlands (P.E.S.).
⁷ Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston (R.J.X.).
⁸ Broad Institute of MIT and Harvard, Cambridge, MA (R.J.X.).
⁹ Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston (R.J.X.).
¹⁰ Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge (R.J.X.).
¹¹ Department of Immunology, K.G. Jebsen Coeliac Disease Research Centre, University of Oslo, Norway (C.W.).
¹² Department for Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, Germany (M.G.N.).
¹³ Human Genomics Laboratory, Craiova University of Medicine and Pharmacy, Romania (M.G.N.).

PMID: 30971183
DOI: 10.1161/CIRCRESAHA.118.314642

Abstract

Rationale: Altered gut microbial composition has been linked to cardiovascular diseases (CVDs), but its functional links to host metabolism and immunity in relation to CVD development remain unclear.

Objectives: To systematically assess functional links between the microbiome and the plasma metabolome, cardiometabolic phenotypes, and CVD risk and to identify diet-microbe-metabolism-immune interactions in well-documented cohorts.

Methods and results: We assessed metagenomics-based microbial associations between 231 plasma metabolites and microbial species and pathways in the population-based LLD (Lifelines DEEP) cohort (n=978) and a clinical obesity cohort (n=297). After correcting for age, sex, and body mass index, the gut microbiome could explain ≤11.1% and 16.4% of the variation in plasma metabolites in the population-based and obesity cohorts, respectively. Obese-specific microbial associations were found for lipid compositions in the VLDL, IDL, and LDL lipoprotein subclasses. Bacterial L-methionine biosynthesis and a Ruminococcus species were associated to cardiovascular phenotypes in obese individuals, namely atherosclerosis and liver fat content, respectively. Integration of microbiome-diet-inflammation analysis in relation to metabolic risk score of CVD in the population cohort revealed 48 microbial pathways associated to CVD risk that were largely independent of diet and inflammation. Our data also showed that plasma levels rather than fecal levels of short-chain fatty acids were relevant to inflammation and CVD risk.

Conclusions: This study presents the largest metagenome-based association study on plasma metabolism and microbiome relevance to diet, inflammation, CVD risk, and cardiometabolic phenotypes in both population-based and clinical obesity cohorts. Our findings identified novel bacterial species and pathways that associated to specific lipoprotein subclasses and revealed functional links between the gut microbiome and host health that provide a basis for developing microbiome-targeted therapy for disease prevention and treatment.

Keywords: atherosclerosis; inflammation; metabolomics; metagenomics; microbiota.

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Comment in

The Microbiome, Plasma Metabolites, Dietary Habits, and Cardiovascular Risk Unravelling Their Interplay.
Mozaffarian D. Mozaffarian D. Circ Res. 2019 Jun 7;124(12):1695-1696. doi: 10.1161/CIRCRESAHA.119.315206. Epub 2019 Jun 6. Circ Res. 2019. PMID: 31170040 Free PMC article. No abstract available.

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Gut Microbial Associations to Plasma Metabolites Linked to Cardiovascular Phenotypes and Risk

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Gut Microbial Associations to Plasma Metabolites Linked to Cardiovascular Phenotypes and Risk

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