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

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.

The gut microbiota and its interactions with cardiovascular disease

“…In recent decades, the term ‘cardiometabolic syndrome’ has been mentioned in the context of various conditions (Yang et al , ,). A study of a population cohort identified metabolic risks related to microbiome functional parameters, such as lipoprotein particle composition, fatty acid saturation, and carbohydrate and sugar derivative metabolism that could predict the probability of CVD consequences (Kurilshikov, et al , ). A growing body of studies suggests that the gut microbiota can mechanistically impact host lipid levels.…”

Cervicovaginal Microbiome and Urine Metabolome Paired Analysis Reveals Niche Partitioning of the Microbiota in Patients with Human Papilloma Virus Infections

“…Microorganisms colonizing the cervicovaginal microenvironment produce a broad range of metabolites that are important for genital health. However, the relationship between taxonomic and functional shifts of the host's microbiome and peripheral site metabolomes remains largely unexplored, and only a few studies so far have characterized the associations of individual taxa with circulation metabolome using plasma [27] and serum [25,26]. Nevertheless, a recent study aimed to identify taxonomic and metabolic alterations in the cervicovaginal microbiome and urine metabolome in women at risk of preterm premature rupture of the membranes found functional associations between microbiome and metabolome, which could facilitate an appropriate response to a given treatment regime [31].…”

“…Most of the studies associating the microbiome and systemic health were conducted via assessment of interactions between the gut microbiome and gut metabolome [23]. A popular strategy now is to explore associations between the gut microbiome and serum metabolome due to the ability of circulating metabolites to translocate through the host's barriers, and therefore, giving the potential for the identification of systemic health effects [24][25][26][27]. Since metabolites from the gut are absorbed into the circulation and finally excreted through urine [28], recent studies suggest that exploration of the association between urine metabolome and host-microbiome may complement sequencing-based approaches with a functional readout of the gut microbiome [29].…”

Exploration of the microbiota and metabolites within body fluids could pinpoint novel disease mechanisms

“…Therefore, the combination of metagenomics and metabolomics will provide a more comprehensive and insightful understanding of the complex microbiome–host interactions and can unravel potential mechanism linking microbiome with host health and disease. Despite a decade ago the marriage between metagenomics and metabolomics was proposed , only few human studies have combined metagenomics and urine , plasma or faecal metabolomics () to dissect metabolic disease. In addition, although all these biofluids contain host and gut microbiota cometabolites, microbial‐derived metabolites may account for up to 90% of the faecal metabolome , whereas they only represent about 10% and 3% of the plasma and urinary metabolome , respectively.…”