Sequence meets function-microbiota and cardiovascular disease

Abstract

The discovery that gut-microbiota plays a profound role in human health has opened a new avenue of basic and clinical research. Application of ecological approaches where the bacterial 16S rRNA gene is queried has provided a number of candidate bacteria associated with coronary artery disease and hypertension. We examine the associations between gut microbiota and a variety of cardiovascular disease (CVD) including atherosclerosis, coronary artery disease, and blood pressure. These approaches are associative in nature and there is now increasing interest in identifying the mechanisms underlying these associations. We discuss three potential mechanisms including: gut permeability and endotoxemia, increased immune system activation, and microbial derived metabolites. In addition to discussing these potential mechanisms we highlight current studies manipulating the gut microbiota or microbial metabolites to move beyond sequence-based association studies. The goal of these mechanistic studies is to determine the mode of action by which the gut microbiota may affect disease susceptibility and severity. Importantly, the gut microbiota appears to have a significant effect on host metabolism and CVD by producing metabolites entering the host circulatory system such as short-chain fatty acids and trimethylamine N-Oxide. Therefore, the intersection of metabolomics and microbiota research may yield novel targets to reduce disease susceptibility. Finally, we discuss approaches to demonstrate causality such as specific diet changes, inhibition of microbial pathways, and fecal microbiota transplant.

Keywords: Atherosclerosis; Cardiovascular diseases; Hypertension; Microbiota.

Figure 1

Towards Function and Mechanistic Understanding of the Microbiota in CVD. Examples of ways to move from association to causation. (A) Examples of microbiome approaches include where conventional mice are provided an agent to perturb the microbiota (either expand specific taxa or inhibit a pathway). (B) Examples of forward microbiome approaches include a comparison of the gut microbiome between controls and CVD subjects from human cohorts. These fecal microbiota samples are then transplanted into germ-free or antibiotic-treated animals to determine the gut microbiota community effect on BP. (C) Diet, specific bacterial enzyme inhibitor, or engineered microbiota can be introduced to animal model to establish a causal relation.

Figure 2

Overview of potential mechanisms of microbiota–host interactions and CVD. 1- Pathogenic bacteria or bacterial components (LPS) can enter the host circulation resulting in endotoxemia and an inflammatory response. 2- local and systemic inflammatory processes can affect CVD development 3- Metabolites such as SCFAs and TMA can either bind host receptors or be further metabolized to pro- or anti- CVD molecules. SCFAs, short-chain fatty acids; GPR, G protein-coupled receptor; TLR, toll-like receptor; TMA, trimethylamine; TMAO, trimethylamine N-oxide; FMOs, flavin-containing monooxygenases; IL, interleukin; IFN, interferon; TGF-B, transforming growth factor beta.

Figure 3

Therapeutic interventions for improving CVD. Current strategies for improving cardiovascular disease by manipulating intestinal microbiota, including bacterial TMA lyase enzyme inhibitors, fecal microbial transplantation, prebiotics, probiotics, and dietary interventions.