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

Iwona Filipska,Monika Knysak,Agata Winiarska,Tomasz Stompór

doi:10.3390/toxins13040274

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.

Highlights

Pathologic Calcification in Cardiovascular SystemVascular calcification (VC) is defined as a process of organized hydroxyapatite crystal deposition within blood vessel walls
Endothelial progenitor cells cultured with extracelluar matrix vesicles (EMV) derived from indoxyl sulphate (IS)-treated endothelial cells human umbilical vein endothelial cells (HUVEC)
Almost all known pathways contributing to VC in chronic kidney disease (CKD) can be linked at some way with the molecular effects of gut microbiota-derived uremic toxins

Summary

Introduction

Vascular calcification (VC) is defined as a process of organized hydroxyapatite crystal deposition within blood vessel walls To some extent it can be considered physiologic (as an element of physiologic aging, when calcification is limited to the atherosclerotic plaques), but in certain chronic diseases, such as: Type 1 or type 2 diabetes, metabolic syndrome, chronic kidney disease (CKD) or postmenopausal osteoporosis, it may be excessive and may contribute to the cardiovascular disease and, in consequence, to increased cardiovascular (CV) mortality. Calcification of media ( known as Mönckeberg sclerosis) is more generalized and disseminated (seen as “linear” upon imaging) It leads to arterial stiffness, contributes to systolic hypertension with increased pulse pressure, promotes the development of heart failure with preserved ejection fraction and increases the risk of stroke and myocardial infarction (but in the mechanism distinct from plaque instability and rupture) [3]. Adeney et al demonstrated that even in patients with moderately advanced CKD

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