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Gut Microbial Associations to Plasma Metabolites Linked to Cardiovascular Phenotypes and Risk: A Cross-Sectional Study
Open accessAbstract
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.
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“Menaquinol synthesis pathways are enriched in various chronic inflammatory and cardiovascular diseases28–31.”
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Metadata
- Authors
- Kurilshikov, A., van den Munckhof, I. C. L., Chen, L., Bonder, M. J., Schraa, K., Rutten, J. H. W., Riksen, N. P., de Graaf, J., Oosting, M., Sanna, S., Joosten, L. A. B., van der Graaf, M., Brand, T., Koonen, D. P. Y., van Faassen, M., LifeLines DEEP Cohort Study, B. M. C., Slagboom, P. E., Xavier, R. J., Kuipers, F., Hofker, M. H., Wijmenga, C., Netea, M. G., Zhernakova, A., & Fu, J.
- Affiliations
- University Medical Center Groningen (NL)
- 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
- Radboud University Nijmegen (NL)
- Department of Radiology and Nuclear Medicine (M.v.d.G.), Radboud University Medical Center, Nijmegen, the Netherlands
- Department of Laboratory Medicine (M.v.F., F.K.), University of Groningen, University Medical Center Groningen, the Netherlands
- Leiden University Medical Center (NL)
- Broad Institute (US)
- University of Bonn (DE)
- ORCID
- Venue
- Circulation Research
- Published
- 2019-06-07
- Volume
- 124
- Issue
- 12
- Pages
- 1808-1820
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2938364298
- Cited by
- 178
- References
- 70
- Citations by year
- 2026: 11 · 2025: 15 · 2024: 19 · 2023: 18 · 2022: 41 · 2021: 37 · 2020: 29 · 2019: 8
- FWCI
- 9.85
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- Locations
- Circulation Research (publishedVersion, other-oa)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (acceptedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- Funders
- European Commission (322698, FP7/2007–2013/ERC, 2007–2013, FP7 2007-2013, 310372, 715772, FP7/2007)
- Rijksuniversiteit Groningen (CVON2012-03)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (FP7 2007-2013, NWO-VIDI 864.13.013, 864.13.013, NWO-VIDI016, SPI 94- 212, 016.Vidi.178.056, 2012-322698, SPI 92-266)
- Universitair Medisch Centrum Groningen
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Keywords
- gut microbiota, plasma metabolites, cardiovascular risk, obesity, lipoprotein subclasses, Ruminococcus, atherosclerosis, liver fat, short-chain fatty acids, inflammation, cardiometabolic phenotypes
- MeSH terms
- Gastrointestinal Microbiome, Adult, Aged, Cardiovascular Diseases, Female, Humans, Male, Middle Aged, Netherlands, Obesity, Phenotype, Prospective Studies, Risk Factors, Cohort Studies, Metabolome
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