Intestinal Microbiota in Cardiovascular Health and Disease: JACC State-of-the-Art Review

Abstract

Despite major strides in reducing cardiovascular disease (CVD) burden with modification of classic CVD risk factors, significant residual risks remain. Recent discoveries that linked intestinal microbiota and CVD have broadened our understanding of how dietary nutrients may affect cardiovascular health and disease. Although next-generation sequencing techniques can identify gut microbial community participants and provide insights into microbial composition shifts in response to physiological responses and dietary exposures, provisions of prebiotics or probiotics have yet to show therapeutic benefit for CVD. Our evolving understanding of intestinal microbiota-derived physiological modulators (e.g., short-chain fatty acids) and pathogenic mediators (e.g., trimethylamine N-oxide) of host disease susceptibility have created novel potential therapeutic opportunities for improved cardiovascular health. This review discusses the roles of human intestinal microbiota in normal physiology, their associations with CVD susceptibilities, and the potential of modulating intestinal microbiota composition and metabolism as a novel therapeutic target for CVD.

Keywords: dysbiosis; intestinal microbiota; secondary bile acids; short-chain fatty acid; trimethylamine N-oxide.

Central Illustration.. Intestinal microbiota and its metabolic contributions to cardiovascular health and disease.

Dietary nutrients are filtered by intestinal microbiota by both metabolism-dependent effects (generation of microbial metabolites such as short-chain fatty acids and trimethylamine from dietary carbohydrates and choline/carnitine, respectively) and metabolism-independent effects (lipopolysaccharides and peptidoglycans) leading to downstream metabolic alterations affect cardiovascular and end-organ functions. (145)

Figure 1:. Phytogenetic Tree Representing Human Gut Microbiota.

Taxonomic cladogram reporting all clades present in one or both cohorts of gut microbiota in asymptomatic Western populations as inferred by MetaPhlAn on 224 samples combining Human Microbiome Project (n=139) and MetaHIT (n=85) cohorts. Circle size is proportional to the log of average abundance, color represents relative enrichment of the most abundant taxa (≥1% average in ≥1 cohort). Nodes’ size reflect their relative abundance.(143).

Figure 2:. Contemporary Techniques for Metagenomic Sequencing.

Bioinformatic methods for functional metagenomics to define the composition and function of uncultured microbial communities using sequencing-based assays. Community DNA Is extracted from a sample and the bacterial taxa present are most frequently defined by amplifying the 16S rRNA gene and sequencing it with highly similar sequences grouped into Operational Taxonomic Units (OTUs). Direct metagenomic sequencing using a “shotgun” approach to directly compare with reference genomes or gene catalogues improves taxonomic resolution and allow observation of single nucleotide polymorphisms and other variant sequences with functional capabilities determined by comparing the sequences to functional databases (144).

Figure 3:. Relationship between plasma levels of TMAO and all-cause mortality in stable cardiac patients.

Increase in proportional hazards with fasting TMAO levels in a cohort of 2,235 patients undergoing elective coronary angiography. The fasting TMAO 4^th quartile cut-off of 6.2 μM represented heightened 5-year all-cause mortality risk.