Trillions of microbes inhabit the human gut, not only providing nutrients and energy to the host from the ingested food, but also producing metabolic bioactive signaling molecules to maintain health and elicit disease, such as cardiovascular disease (CVD). CVD is the leading cause of mortality worldwide. In this review, we presented gut microbiota derived metabolites involved in cardiovascular health and disease, including trimethylamine-N-oxide (TMAO), uremic toxins, short chain fatty acids (SCFAs), phytoestrogens, anthocyanins, bile acids and lipopolysaccharide. These gut microbiota derived metabolites play critical roles in maintaining a healthy cardiovascular function, and if dysregulated, potentially causally linked to CVD. A better understanding of the function and dynamics of gut microbiota derived metabolites holds great promise toward mechanistic predicative CVD biomarker discoveries and precise interventions.

The gut microbiome is a complex and metabolically active community that directly influences host phenotypes. In this study, we profile gut microbiota using 16S rRNA gene sequencing in 531 well-phenotyped Finnish men from the Metabolic Syndrome In Men (METSIM) study. We investigate gut microbiota relationships with a variety of factors that have an impact on the development of metabolic and cardiovascular traits. We identify novel associations between gut microbiota and fasting serum levels of a number of metabolites, including fatty acids, amino acids, lipids, and glucose. In particular, we detect associations with fasting plasma trimethylamine N-oxide (TMAO) levels, a gut microbiota-dependent metabolite associated with coronary artery disease and stroke. We further investigate the gut microbiota composition and microbiota–metabolite relationships in subjects with different body mass index and individuals with normal or altered oral glucose tolerance. Finally, we perform microbiota co-occurrence network analysis, which shows that certain metabolites strongly correlate with microbial community structure and that some of these correlations are specific for the pre-diabetic state. Our study identifies novel relationships between the composition of the gut microbiota and circulating metabolites and provides a resource for future studies to understand host–gut microbiota relationships.

Sniffing out atherosclerosis: Olfactory receptors are best known for their presence in the nose and their role in detecting smells, but they are also present in other tissues and perform additional biological functions. For example, vascular macrophages involved in the pathogenesis of atherosclerosis express multiple subtypes of olfactory receptors. Orecchioni et al . focused on olfactory receptor 2, a receptor for the compound octanal, and identified its contribution to atherosclerosis pathogenesis and the formation of atherosclerotic plaques (see the Perspective by Rayner and Rasheed). The authors show that most of the octanal was not directly derived from the diet, but rather was generated as a by-product of lipid peroxidation, suggesting a potential pathway for intervention. —YN

Background: Large-scale human and mechanistic mouse studies indicate a strong relationship between the microbiome-dependent metabolite trimethylamine N-oxide (TMAO) and several cardiometabolic diseases. This study aims to investigate the role of TMAO in the pathogenesis of abdominal aortic aneurysm (AAA) and target its parent microbes as a potential pharmacological intervention. Methods: TMAO and choline metabolites were examined in plasma samples, with associated clinical data, from 2 independent patient cohorts (N=2129 total). Mice were fed a high-choline diet and underwent 2 murine AAA models, angiotensin II infusion in low-density lipoprotein receptor–deficient ( Ldlr ^−/− ) mice or topical porcine pancreatic elastase in C57BL/6J mice. Gut microbial production of TMAO was inhibited through broad-spectrum antibiotics, targeted inhibition of the gut microbial choline TMA lyase (CutC/D) with fluoromethylcholine, or the use of mice genetically deficient in flavin monooxygenase 3 ( Fmo3 ^−/− ). Finally, RNA sequencing of in vitro human vascular smooth muscle cells and in vivo mouse aortas was used to investigate how TMAO affects AAA. Results: Elevated TMAO was associated with increased AAA incidence and growth in both patient cohorts studied. Dietary choline supplementation augmented plasma TMAO and aortic diameter in both mouse models of AAA, which was suppressed with poorly absorbed oral broad-spectrum antibiotics. Treatment with fluoromethylcholine ablated TMAO production, attenuated choline-augmented aneurysm initiation, and halted progression of an established aneurysm model. In addition, Fmo3 ^−/− mice had reduced plasma TMAO and aortic diameters and were protected from AAA rupture compared with wild-type mice. RNA sequencing and functional analyses revealed choline supplementation in mice or TMAO treatment of human vascular smooth muscle cells–augmented gene pathways associated with the endoplasmic reticulum stress response, specifically the endoplasmic reticulum stress kinase PERK. Conclusions: These results define a role for gut microbiota–generated TMAO in AAA formation through upregulation of endoplasmic reticulum stress–related pathways in the aortic wall. In addition, inhibition of microbiome-derived TMAO may serve as a novel therapeutic approach for AAA treatment where none currently exist.