Co-toxicity of Endotoxin and Indoxyl Sulfate, Gut-Derived Bacterial Metabolites, to Vascular Endothelial Cells in Coronary Arterial Disease Accompanied by Gut Dysbiosis

Abstract

Gut dysbiosis, alongside a high-fat diet and cigarette smoking, is considered one of the factors promoting coronary arterial disease (CAD) development. The present study aimed to research whether gut dysbiosis can increase bacterial metabolites concentration in the blood of CAD patients and what impact these metabolites can exert on endothelial cells. The gut microbiomes of 15 age-matched CAD patients and healthy controls were analyzed by 16S rRNA sequencing analysis. The in vitro impact of LPS and indoxyl sulfate at concentrations present in patients’ sera on endothelial cells was investigated. 16S rRNA sequencing analysis revealed gut dysbiosis in CAD patients, further confirmed by elevated LPS and indoxyl sulfate levels in patients’ sera. CAD was associated with depletion of Bacteroidetes and Alistipes. LPS and indoxyl sulfate demonstrated co-toxicity to endothelial cells inducing reactive oxygen species, E-selectin, and monocyte chemoattractant protein-1 (MCP-1) production. Moreover, both of these metabolites promoted thrombogenicity of endothelial cells confirmed by monocyte adherence. The co-toxicity of LPS and indoxyl sulfate was associated with harmful effects on endothelial cells, strongly suggesting that gut dysbiosis-associated increased intestinal permeability can initiate or promote endothelial inflammation and atherosclerosis progression.

Single‐anastomosis duodeno‐ileal bypass with sleeve gastrectomy improves lipid and glucose homeostasis in ob/ob mice

“…After SADI-S, the decrease in fecal excretion of secondary BAs and coprostanol, which results from the conversion of cholesterol by various bacteria (Eubacterium, Bifidobacterium, Lactobacillus, Peptostreptococcus, and Bacteroides), in a stronger way than after RYGB suggests a specific impact of SADI-S on microbiota. These changes were associated after SADI-S with a decrease in indoxyl-3-sulfate, produced from indole oxidization resulting from the metabolism of tryptophan by gut bacteria, a parameter that has been associated with cardiovascular mortality [38].…”

The Variability of Tryptophan Metabolism in Patients with Mixed Type of Irritable Bowel Syndrome

“…This metabolite is considered a quantitative biomarker of the state of intestinal microbiome [ 46 , 47 ]. Indican exerts anti-inflammatory activities, but its toxic influences cannot be excluded [ 48 , 49 ]. In our material, the urinary excretion of indican increased during diarrhea, as did the concentration of hydrogen ions in the exhaled air.…”

Meta-analysis of the effect of probiotics or synbiotics on the risk factors in patients with coronary artery disease

“…The mechanism behind this phenomenon may originate from the following sources: (1) The intestinal flora reduces the permeability of intestinal epithelial cells through LRP6 and Wnt/ β-catenin pathway activation (31). This reversal of intestinal barrier damage further decreases the entry of harmful substances such as LPS and TMAO into the bloodstream (32). ( 2) LPS can activate NF-κB through MyD88 and TRIF pathways, leading to the production of inflammatory factors and an increase in reactive oxygen species (33).…”