Gut Microbial Associations to Plasma Metabolites Linked to Cardiovascular Phenotypes and Risk: A Cross-Sectional Study

Alexander Kurilshikov, Inge Cl van den Munckhof, Lianmin Chen, Marc Jan Bonder, Kiki Schraa, Joost Rutten, Niels P Riksen, Jacqueline de Graaf, Marije Oosting, Serena Sanna, Leo Ab Joosten, Marinette van der Graaf, Tessa Brand, Debby Py Koonen, Martijn Jr van Faassen, P Eline Slagboom, Ramnik J Xavier, Folkert Kuipers, Marten Hofker, Cisca WijmengaMihai G Netea, Alexandra Zhernakova, Jingyuan Fu

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

OBJECTIVE: 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 Lifelines-DEEP cohort (n=978) and a clinical obesity cohort (n=297). After correcting for age, gender and BMI, the gut microbiome could explain up to 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.

Original languageEnglish
Pages (from-to)1808-1820
Number of pages13
JournalCirculation research
Issue number12
Publication statusPublished - 7-Jun-2019

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