Contribution of Gut Microbiota-Derived Uremic Toxins to the Cardiovascular System Mineralization

Abstract

Chronic kidney disease (CKD) affects more than 10% of the world population and leads to excess morbidity and mortality (with cardiovascular disease as a leading cause of death). Vascular calcification (VC) is a phenomenon of disseminated deposition of mineral content within the media layer of arteries preceded by phenotypic changes in vascular smooth muscle cells (VSMC) and/or accumulation of mineral content within the atherosclerotic lesions. Medial VC results in vascular stiffness and significantly contributes to increased cardio-vascular (CV) morbidity, whereas VC of plaques may rather increase their stability. Mineral and bone disorders of CKD (CKD-MBD) contribute to VC, which is further aggravated by accumulation of uremic toxins. Both CKD-MBD and uremic toxin accumulation affect not only patients with advanced CKD (glomerular filtration rate (GFR) less than 15 mL/min./1.72 m2, end-stage kidney disease) but also those on earlier stages of a disease. The key uremic toxins that contribute to VC, i.e., p-cresyl sulphate (PCS), indoxyl sulphate (IS) and trimethylamine-N-oxide (TMAO) originate from bacterial metabolism of gut microbiota. All mentioned toxins promote VC by several mechanisms, including: Transdifferentiation and apoptosis of VSMC, dysfunction of endothelial cells, oxidative stress, interaction with local renin–angiotensin–aldosterone system or miRNA profile modification. Several attractive methods of gut microbiota manipulations have been proposed in order to modify their metabolism and to limit vascular damage (and VC) triggered by uremic toxins. Unfortunately, to date no such method was demonstrated to be effective at the level of “hard” patient-oriented or even clinically relevant surrogate endpoints.

The potential impact of a probiotic: Akkermansia muciniphila in the regulation of blood pressure—the current facts and evidence

“…The general effects of these uremic toxins are vascular dysfunction, such as increased vasoconstriction and decreased vasorelaxation, decrease in NO production, induction of oxidative stress, promotion of vascular cell apoptosis, and vascular remodeling [ 113 ]. Also, IS and PCS have been reported to promote vascular calcification [ 114 ]. Collectively all these detrimental effects are significantly associated with the pathogenesis of HTN.…”

Hypomagnesemia as a Risk Factor and Accelerator for Vascular Aging in Diabetes Mellitus and Chronic Kidney Disease

“…Those toxins promote vascular calcification by several mechanisms. The most important of these are trans-differentiation and apoptosis of vascular smooth muscle cells (VSMC), dysfunction of endothelial cells, oxidative stress, and interaction with the local renin-angiotensin-aldosterone system or microRNA (micro ribonucleotide acid) profile modification [ 39 ]. The therapeutic “gastrointestinal decontamination” is a potential anti-vascular calcification strategy, with the removal of toxins in situ or impediment of absorption within the gastrointestinal tract [ 40 ].…”

The Contribution of Extracellular Vesicles From Senescent Endothelial and Vascular Smooth Muscle Cells to Vascular Calcification

“…Thus, vascular damage leads to VC, which is triggered by uremic toxins resulting from CKD. The imbalance of the bacterial metabolism in the gut microbiota promotes the production of uremic toxins and increases the possibility of VC development (54). Therefore, the generation of uremic toxins caused by microbiota imbalance that ultimately produces vascular senescence and VC in CKD was a novel way to develop VC.…”