Microbial modulation of cardiovascular disease

Abstract

Although diet has long been known to contribute to the pathogenesis of cardiovascular disease (CVD), research over the past decade has revealed an unexpected interplay between nutrient intake, gut microbial metabolism and the host to modify the risk of developing CVD. Microbial-associated molecular patterns are sensed by host pattern recognition receptors and have been suggested to drive CVD pathogenesis. In addition, the host microbiota produces various metabolites, such as trimethylamine-N-oxide, short-chain fatty acids and secondary bile acids, that affect CVD pathogenesis. These recent advances support the notion that targeting the interactions between the host and microorganisms may hold promise for the prevention or treatment of CVD. In this Review, we summarize our current knowledge of the gut microbial mechanisms that drive CVD, with special emphasis on therapeutic interventions, and we highlight the need to establish causal links between microbial pathways and CVD pathogenesis.

Figure 1. Direct engagement of pattern recognition receptors by microbial-associated molecular patterns driving CVD

Microbial-associated molecular patterns (MAMPs) can promote CVD via the direct engagement of host pattern recognition receptors (PRRs), promoting chronic inflammatory processes in the host. In the context of cardiovascular disease, dysbiosis in both the oral and gut microbiome can elicit local MAMP-PRR signaling within those microenvironments (not shown). In addition, systemic bacterial translocation can promote CVD by MAMP-PRR signaling in distant sites, including the liver and artery wall. Abbreviations: CD14, cluster of differentiation 14; CpG ODNs, CpG oligodeoxynucleotides; LPS, lipopolysaccharide; MI, myocardial infarction; NOD1, nucleotide oligomerization domain-containing 1; TLR, toll-like receptor.

Figure 2. The metaorganismal TMAO pathway as a driver of CVD

Postprandial delivery of choline, phosphatidylcholine (PC), carnitine, γ-butyrobetaine, and likely other methylamine-containing source nutrient gut microbes provides substrate for the gut-microbial-mediated production of trimethylamine (TMA). Microbial TMA lyase enzymes (CutC/D, CntA/B, and YeaW/X) can then generate TMA, which enters the portal circulation and is ultimately delivered to the host liver. The host flavin-containing monooxygenase (FMO) family of enzymes, especially FMO3, can then convert TMA to TMAO. TMAO can then promote atherosclerosis, thrombosis, heart failure, insulin resistance, and kidney disease via tissue or cell type-specific reprogramming. Through an unknown receptor-mediated sensing mechanism (indicated as TMAO sensor), TMAO drives cell-specific signaling events that promote CVD pathogenesis. In platelets, TMAO rapidly enhances stimulus-induced calcium (Ca2+) release, which signals to drive pro-thrombotic programmes. In endothelial and smooth muscle cells TMAO rapidly activates mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-kB) to promote the expression of adhesion molecules such as ICAM and E-selectin. In addition, TMAO can signal through currently unidentified pathways to regulate increased macrophage foam cell formation. TMAO can also initiate profibrotic programmes in the heart and kidney via a transforming growth factor β (TGFβ) – phospho-SMAD3 signaling axis. Collectively, these cellular events converge to promote atherosclerosis, thrombotic vascular disease, and associated renal impairment.

Figure 3. Microbial production of secondary bile acids in CVD

Initially, primary bile acids are synthesized in the host liver from cholesterol. De novo synthesized primary bile acids such as cholic acid, chenodeoxycholic acid (CDCA) and muricholic acid (MCA; only produced in rodents) are then conjugated with either glycine (humans) or taurine (humans and mice) at the C-24 carboxyl position. Following conjugation, resulting bile salts are secreted into bile along with cholesterol and phospholipids to form mixed micelles, which are transiently stored in the gall bladder. When a meal is ingested, the gall bladder contracts to release mixed micelles into the proximal intestine where they function as essential emulsifiers to enable proper absorption of hydrophobic molecules such as fatty acids and fat-soluble vitamins (such as vitamin A, vitamin D, vitamin E and vitamin K) (not shown). Importantly, bile salts are left behind in the intestinal lumen where they ultimately traverse to the colon. Once in the colonic microenvironment, they participate in a bi-directional interplay regulating microbial community structure, and they are subsequent microorganism-driven metabolism of primary bile salts into secondary bile acids (deoxycholic acid and lithocholic acid), which can have an impact on host physiology and disease susceptibility. Importantly, after aiding in intestinal lipid absorption both primary bile salts and secondary bacterial metabolites are almost quantitatively re-absorbed (>95% recovered) in the ileum via dedicated host transporters in ileal enterocytes (not shown). This reabsorptive process provides newly diversified bile acid species, which can then signal to the host through dedicated receptor systems, including farnesoid X receptor (FXR), protein-coupled bile acid receptor 1 (TGR5), pregnane X receptor (PXR), vitamin D receptor (VDR), muscarinic receptors 2 and 3 (M2/M3), and sphingosine-1-phosphate receptor 2 (S1PR2).