Microbiota-related metabolites fueling the understanding of ischemic heart disease

Abstract

Up-to-date knowledge of gut microbial taxa associated with ischemic heart disease (IHD). Microbial metabolites for mechanistic dissection of IHD pathology. Microbiome-based therapies in IHD prevention and treatment.

Figure 1

Phylogenetic tree of bacterial species associated with ischemic heart disease (IHD). This phylogenetic tree summarizes the numerous reported gut bacterial species associated with IHD. Background colors in the inner ring indicate all species that belong to the same phylum. The outer rings indicate the enrichment status of each listed bacterial species in IHD cases compared with healthy microbiota. Orange color denotes bacterial species increased in IHD cases, whereas green color denotes bacterial species decreased in IHD cases. This phylogenetic tree was created with iTOL (v6, https://itol.embl.de/).

Figure 2

Gut‐heart axis: the potential mechanisms. An overview of some of the microbially produced compounds affecting the well‐being of cardiometabolic homeostasis during the dysbiosis associated with ischemic heart disease (IHD). Dietary l‐carnitine is metabolized by gut microbiota producing trimethylamine (TMA), which is subsequently N‐oxidized by liver flavin‐containing monooxygenases (FMOs) and producing trimethylamine N‐oxide (TMAO). TMAO has been recognized as an important contributor to atherosclerotic consequences. Secondary bile acids (BAs), synthesized from primary BAs by the intestinal microbiota, act through farnesoid X receptor (FXR) and Takeda G‐protein‐coupled receptor‐5 (TGR5) (also known as G protein‐coupled BA receptor 1 [Gpbar1]) receptors to reduce inflammation, thereby counteracting atherosclerosis. Short‐chain fatty acids (SCFAs) produced by gut microbiota through G‐protein receptor (GPR) 41/43 regulating systematic inflammation. Lipopolysaccharides (LPS), a class of pro‐inflammatory compounds, act on Toll‐like receptors, thereby activating atherosclerogenesis. Adrenoceptors have been identified as binding receptors for microbiota‐synthesized phenylacetylglutamine (PAGln). The Aryl hydrocarbon receptors (AHRs) plays crucial roles in mediating impact of two uremic toxins, p‐cresol sulfate and indoxyl sulfate, on cardiovascular system. IL, interleukin; NLRP3, NLR family pyrin domain containing 3; TNF‐α, tumor necrosis factor‐α; TXNIP, thioredoxin interacting protein; VCAM‐1, vascular cell adhesion molecule 1.

Figure 3

Gut microbiome‐targeted interventions in humans with ischemic heart disease (IHD). For general restoration of microbial composition and functions, there are interests in testing the microbiome‐targeted interventions on the disrupted microbiome of IHD patients. Various approaches include fecal microbiota transplantation either in heterologous or autologous manner; antibiotics treatment aiming at restructuring the gut microbiome; individualized nutrition to change the gut microbiome and metabolism; use of probiotics and prebiotics or combination of various probiotics strains and prebiotics; and finally, an emerging potential frontier of using drugs targeting specific IHD‐related microbial metabolites or pathways. Illustration was created with biorender (https://biorender.com/).