Dietary metabolism, the gut microbiome, and heart failure

Abstract

Advances in our understanding of how the gut microbiota contributes to human health and diseases have expanded our insight into how microbial composition and function affect the human host. Heart failure is associated with splanchnic circulation congestion, leading to bowel wall oedema and impaired intestinal barrier function. This situation is thought to heighten the overall inflammatory state via increased bacterial translocation and the presence of bacterial products in the systemic blood circulation. Several metabolites produced by gut microorganisms from dietary metabolism have been linked to pathologies such as atherosclerosis, hypertension, heart failure, chronic kidney disease, obesity, and type 2 diabetes mellitus. These findings suggest that the gut microbiome functions like an endocrine organ by generating bioactive metabolites that can directly or indirectly affect host physiology. In this Review, we discuss several newly discovered gut microbial metabolic pathways, including the production of trimethylamine and trimethylamine N-oxide, short-chain fatty acids, and secondary bile acids, that seem to participate in the development and progression of cardiovascular diseases, including heart failure. We also discuss the gut microbiome as a novel therapeutic target for the treatment of cardiovascular disease, and potential strategies for targeting intestinal microbial processes.

Figure 1.. Microbial-host meta-organismal pathway linking dietary metabolism, gut microbiota, and cardio-renal disease progression.

Legend: Poor cardiac output in heart failure results in intestinal ischemia, edema, and inflammation which leads to a “leaky” intestinal barrier. This allows for increased passage of inflammatory bacterial products to enter the bloodstream causing chronic low-grade inflammation. Furthermore, this alters the intestinal environment and impacts both the normal microbial community which resides in the gut and subsequently, the metabolic products from these bacteria. The metabolic pathways include fermentation of indigestible fiber to short chain fatty acids which have protective properties reducing inflammation and improving vascular tone. Dietary sources including choline, phosphatidylcholine, l-carnitine and other methylamine-containing nutrients provide substrates for microbiota mediated production of trimethylamine (TMA). TMA then enters the portal circulation and is converted by the hepatic host flavin-containing monooxygenase (FMO) family of enzymes to trimethylamine n-oxide (TMAO). TMAO can promote the development of atherogenesis, thrombosis, kidney disease, and heart failure. Additionally, the bacterial transformation of bile acids can result in altered bile acid profiles which then can affect systemic inflammatory and fibrotic processes. Collectively, these processes can influence the individual susceptibility, severity of heart failure.

Figure 2.. Downstream Effects of Gut Microbiota-generated Short-chain Fatty Acid (SCFA) in Cardiovascular System

Legend: SCFAs produced by gut microbiota exert their cardiovascular effects by 1) indirectly improving intestinal barrier function by promoting mucous production; 2) activate Olfr78 in mouse (or hOR51E2 in humans) in the renal juxtaglomerular apparatus (JGA) and peripheral vasculature, that leads to increased renin release, and raised blood pressure thereby counteracting hypotensive responses mediated by GPR41; and 3) activate histone acetyltransferases (HAT) and inhibit histone deacetylases (HDACs) thereby inhibiting inflammation, balancing gene regulation (epigenome) and modulates immune cell activation.

Figure 3:. Microbial Generation of Dietary-Induced Trimethylamine (TMA) and Trimethylamine N-oxide (TMAO)

Legend: Diets rich in choline/phosphatidylcholine and carnitine can be metabolized by certain species of gut microbiota to TMA that is then converted to TMAO by hepatic flavin mono-oxygenase (FMO, especially FMO3) and excreted via the kidneys from the circulation. Accumulation of TMAO levels has been associated with atherogenesis, platelet hyperactivation, and future development of adverse cardiac events such as myocardial infarction, stroke, and death. Adverse cardiac remodeling is also associated with elevated TMAO levels. Gamma butyrobetaine, a precursor for endogenous synthesis of carnitine, can also be converted to TMA (Modified from Wang et al, Nature 2011; Koeth et al, Nat Med 2013; Koeth et al, Nat Med 2014)^,,

Figure 4.. The relationship between plasma levels of TMAO and 5yr mortality risk in Patients with Chronic Heart Failure.

Legend: Patients with a history of heart failure stratified according to quartiles of fasting TMAO levels and circulating B-type natriuretic peptide (BNP) levels showing an increased incidence of 5-year mortality with rising TMAO levels, independent of BNP levels (from Tang WH et al., J Am Coll Cardiol 2014)

Figure 5.. Microbial Metabolic Pathways as Potential Druggable Targets.

Caption: Carnitine (and gamma butyrobetaine) can be converted by gut microbiota to trimethylamine (TMA) via carnitine TMA lyases such as CntA/B or YeaW/X, whereas choline can be converted to TMA via choline TMA lyases such as CutC/D or YeaW/X. Betaine conversion to TMA is in much lower quantities. Many of these enzymes are unique in some microbial species, making them attractive druggable targets for inhibition to reduce TMA production (such as 3,3-dimethyl-1-butanol [DMB] as choline TMA lyase inhibitors (Wang et al., Cell 2015).