In a recent review published in International Journal of Molecular Sciencesresearchers in Canada are investigating the impact of gut microbiota dysbiosis on the incidence of atherosclerotic cardiovascular disease (ASCVD).
To study: Role of the gut microbiome in the development of atherosclerotic cardiovascular disease. Image credit: ART-ur / Shutterstock.com
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ASCVD is one of the leading causes of mortality worldwide. A detailed understanding of the association between the gut microbiome and the development of atherosclerosis is needed to develop preventive and therapeutic strategies, as well as to manage key factors that increase the risk of CVD, such as diabetes, hypertension, smoking , sedentary lifestyle and dyslipidemia.
Previous studies have reported that the gut microbiota is critically involved in the development of atherosclerosis. Essential intestinal metabolites such as trimethylamine N-oxide (TMAO), lipopolysaccharide (LPS), short-chain fatty acids (SCFA) and secondary bile acids are related to the severity of ischemic heart disease.
Metabolic pathways of intestinal dysbiosis leading to atherosclerosis
Increased dietary intake of phenylalanine, betaine, L-carnitine, and choline results in increased secretion of trimethylamine (TMA) from the gut and TMAO from the liver. This reduces reverse cholesterol transport (RCT) and increases foam cell formation in cholesterol plaques, platelet reactivity and endothelial dysfunction.
Reduced endothelial progenitor cell (EPC) production is associated with activation of the pyrin domain-containing nucleotide-binding oligomerization domain inflammasome 3 (NLRP3), which increases levels of reactive oxygen species (ROS) in mitochondrial pathways.
The increased secretion of secondary bile acids occurs in the intestine by the deconjugation of chenodeoxycholic acid and cholic acid. Secondary bile acid molecules allow absorption of fat-soluble vitamins and lipids, as well as activate Takeda G protein-coupled receptor 5 (TGR-5) and farnesoid X receptor (FXR). These receptors modulate cholesterol and glucose metabolism, as well as activate the nuclear factor kappa B (NF-κB) pathway, thereby increasing tumor necrosis factor-alpha (TNF-α), interleukin 1 (IL-1 ), IL-6 and IL-8 levels.
TGR-5 levels increase glucagon-like peptide 1 (GLP-1) expression, thereby improving glucose tolerance. NF-κB pathway activity is enhanced by LPS, which are bacterial endotoxins that are recognized by innate immune pathways through toll-like receptor-4 (TLR-4), which is a pattern recognition receptor (PRR).
Comparatively, SCFAs such as acetate, propionate and butyrate prevent atherosclerosis and are generated from the digestion of complex carbohydrates by intestinal bacteria such as Faecalibacterium prausnitzii, Roseburia intestinalis and Anaerostipes butyraticus. SCFAs inhibit the NF-κB pathway through enhanced production of regulatory T lymphocytes (Treg) and suppression of histone deacetylase (HDAC) and increased intestinal barrier stability.
Lipopolysaccharides are also recognized by receptor proteins, such as lipopolysaccharide-binding protein (LBP), cluster of differentiation-14 (CD-14), and myeloid differentiation protein-2 (MD-2).
The receptors, which are highly expressed on macrophage cells, activate and subsequently increase the expression of protein kinase molecules, including myeloid differentiation factor-88 (MyD88) and receptor-associated kinase IL-1 (IRAK-1).
Phenylacetic acid released from the gut leads to increased expression of phenylacetylglutamine (PAGln) from glutamine and platelet activation. PAGln enhances the platelet response, with a resulting increase in the potential for ASCVD-causing thrombosis.
In addition, PAGln transduces cellular events through G protein-coupled receptors such as α-2A, 2B, and beta-2 (β2) adrenergic receptors. PAGln also accelerates thrombus production and vessel occlusion rates.
Diet and atherosclerosis
A low-fiber diet is related to a lower concentration of SCFA in the blood, especially that of butyrate. This can exacerbate dysbiosis and inflammation through the leakage of toxins of bacterial origin such as LPS. This inflammation can lead to hypertension, diabetes, atherosclerosis, acute coronary syndrome or myocardial infarction.
LPS induces ROS generation by activating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, thereby increasing the expression of IL-6, IL-8, and TNF-α. Butyrate increases plaque stability by reducing the release of nitric oxide (NO) and ROS from macrophages and reduces the production of inflammatory molecules, such as matrix metalloproteinase-2 (MMP-2), the adhesion molecule of vascular cells-1 (VCAM-1) and chemotaxis. protein-1.
A modern Westernized diet rich in red meat, fish and eggs releases choline and L-carnitine, which increases bacterial generation of TMA. TMA undergoes oxidation to form TMAO in liver tissues through the activity of flavin-containing monooxygenase 3 (FMO3).
Hypertensive patients have less microbial diversity and richness, with reduced Lactobacillus counts and elevated Klebsiella and Prevotella counts compared to healthy individuals. This dysbiosis causes inflammation.
SCFAs can lower blood pressure due to their anti-inflammatory and vasorelaxant effects, while TMAO causes hypertension due to their prothrombotic, proatherogenic, and angiotensin-II-prolonging effects.
TMAO also hardens the carotid arteries and aorta, lowers high-density lipoprotein cholesterol (HDL-C) levels, increases cholesterol accumulation in cells, and increases the risks of obesity, dyslipidemia, and complications of type 2 diabetes. In addition, TMAO increases the expression of macrophage receptors, CD-36 and scavenger receptor-A (SR-A), all of which are linked to atherosclerosis. TMAO induces vascular inflammation by increasing leukocyte recruitment to endothelial cells through G protein-coupled receptor (GPCR) activity and enhanced mitogen-activated protein kinase (MAPK) activity.
Conclusions
The current study elucidates the impact of intestinal microbial dysbiosis on the development of atherosclerosis. These findings indicate that secondary bile acids and SCFAs protect against dyslipidemia, while other metabolites, such as TMAO and LPS, increase cholesterol levels.
Journal reference:
Al Samarraie, A., Pichette, M. and Rousseau, G. (2023). Role of the gut microbiome in the development of atherosclerotic cardiovascular disease. International Journal of Molecular Science 24. doi:10.3390/ijms24065420
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