Gut Microbiota and Cardiovascular Uremic Toxicities

Abstract

Cardiovascular disease (CVD) remains a major cause of high morbidity and mortality in patients with chronic kidney disease (CKD). Numerous CVD risk factors in CKD patients have been described, but these do not fully explain the high pervasiveness of CVD or increased mortality rates in CKD patients. In CKD the loss of urinary excretory function results in the retention of various substances referred to as “uremic retention solutes”. Many of these molecules have been found to exert toxicity on virtually all organ systems of the human body, leading to the clinical syndrome of uremia. In recent years, an increasing body of evidence has been accumulated that suggests that uremic toxins may contribute to an increased cardiovascular disease (CVD) burden associated with CKD. This review examined the evidence from several clinical and experimental studies showing an association between uremic toxins and CVD. Special emphasis is addressed on emerging data linking gut microbiota with the production of uremic toxins and the development of CKD and CVD. The biological toxicity of some uremic toxins on the myocardium and the vasculature and their possible contribution to cardiovascular injury in uremia are also discussed. Finally, various therapeutic interventions that have been applied to effectively reduce uremic toxins in patients with CKD, including dietary modifications, use of prebiotics and/or probiotics, an oral intestinal sorbent that adsorbs uremic toxins and precursors, and innovative dialysis therapies targeting the protein-bound uremic toxins are also highlighted. Future studies are needed to determine whether these novel therapies to reduce or remove uremic toxins will reduce CVD and related cardiovascular events in the long-term in patients with chronic renal failure.

Maternal Adenine-Induced Chronic Kidney Disease Programs Hypertension in Adult Male Rat Offspring: Implications of Nitric Oxide and Gut Microbiome Derived Metabolites

“…In support of the notion that uremic toxins contribute to hypertension in CKD [ 12 , 20 ], our results demonstrated that maternal adenine-induced CKD mother rats exhibited hypertension related to elevated plasma levels of ADMA, SDMA, and TMAO. ADMA and SDMA are both uremic toxins, and their most well-known effect is the suppression of NO production [ 12 ].…”

Direct Impairment of the Endothelial Function by Acute Indoxyl Sulfate through Declined Nitric Oxide and Not Endothelium-Derived Hyperpolarizing Factor or Vasodilator Prostaglandins in the Rat Superior Mesenteric Artery

“…1,2,10,68,69) Although the molecular basis for the correlation among indoxyl sulfate, eNOS, NO-related signaling, and ROS remains undefined in this study, future research should focus on the mechanisms underlying specifically impaired NO component in the rat superior mesenteric arteries by indoxyl sulfate. Several reports have suggested that the indoxyl sulfate levels in the circulatory system may increase under various conditions, including in CKD and diabetic nephropathy, 37,38,70) and impaired NO-mediated vasorelaxation was observed in both these diseases. 7,8,36) Thus, our findings indicate that indoxyl sulfate may be a causative factor for specifically impaired NO-mediated relaxation in such diseases; however, additional studies on the relationship among time course exposure of indoxyl sulfate, vascular function, and the development of complications in such pathophysiological states are required.…”

“…Reportedly, uremic toxins are accrued in chronic kidney disease (CKD) and display toxic effects on the blood and vessel wall. 7,[36][37][38] Various uremic toxins, mostly protein-bound, exert specific endothelial toxicity and cause endothelial dysfunction, including homocysteine, asymmetric dimethylarginine (ADMA), advanced glycation end products (AGEs), p-cresyl sulfate, and indoxyl sulfate. 7) Several studies have suggested a correlation between uremic toxins and endothelial function.…”

Exploration of the microbiota and metabolites within body fluids could pinpoint novel disease mechanisms

“…Phenolic and indolic compounds are products of catabolism of aromatic amino acids: phenylalanine, tyrosine and tryptophan are converted by the colonic bacteria to phenylacetate, p ‐cresol and indole, which are further conjugated with glutamine or sulfate in the gut mucosa and the liver to form phenylacetylglutamine, p ‐cresyl sulfate and indoxyl sulfate, respectively, and excreted in the urine. All these molecules are well‐known uraemic toxins which have been associated with CVD , particularly with chronic kidney disease , although their metabolic effects are largely unexplored. Phenylalanine and tyrosine microbial metabolism can also produce other phenolic metabolites such as phenylpropionic acids, phenyllactic acids or hippuric acid .…”