Gut Microbial Translocation in the Pathogenesis of Systemic Inflammation in Patients with End-Stage Renal Disease

Dig Dis Sci DOI 10.1007/s10620-014-3287-z EDITORIAL Gut Microbial Translocation in the Pathogenesis of Systemic Inflammation in Patients with End-Stage Renal Disease Nosratola D. Vaziri O Springer Science+Business Media New York 2014 Background Chronic kidney disease (CKD) accelerates cardiovascular disease, increases the incidence and severity of microbial infections, anemia, cachexia and numerous other morbidi- ties that shorten the life span and greatly impair the quality of patients’ lives. These abnormalities are associated with and are largely mediated by systemic inflammation and oxidative stress, common features of CKD [1], which have been attributed to numerous factors [2]. The severity of CKD-associated systemic inflammation correlates directly with the magnitude of endotoxemia in the absence of clinically detectable infection [3]. Although presence of endotoxin in the blood of ESRD patients was attributed to dialysate contamination, its presence in patients who do not receive dialysis treatment and in animals with experimental renal failure supports its endogenous origin, the most likely source being the gastrointestinal tract, home to a huge microbial community. This assumption is supported by several studies which have reported the presence of gut bacterial DNA fragments in the blood of CKD patients maintained on hemodialysis [4] and in CKD patients who did not receive dialysis treatment [5]. Moreover, colonic bacterial DNA has been detected in the mesenteric lymph nodes, blood, liver and spleen of animals with experimental CKD [6]. CKD-Induced Disruption of Intestinal Epithelial Barrier Since in healthy humans and animals, the epithelial barrier prevents translocation of bacteria and their harmful by-products and components, the presence of endotoxemia and the detection of the gut microbial DNA in the blood of ESRD patients and in the blood and multiple tissues of CKD animals point to impairment of intestinal barrier structure and function. This barrier consists of the apical membrane of the epithelial cells and the junctional adhesion complex that seals the gap between adjacent cells and includes the tight junction (TJ) and the subjacent adherens junction. There is mounting evidence that advanced CKD impairs intestinal epithelial barrier structure and function, thereby enabling the entry of endotoxin and other bacterial components in the intestinal wall and systemic circulation [7, 8]. In fact, massive depletion of the gastrointestinal epithelial tight junction proteins was reported in CKD animals [9, 10]. Moreover, in vitro studies revealed significant depletion of the tight junction proteins and reduction of trans-epithelial electrical resistance in cultured human colonocytes incu- bated in media containing human uremic plasma [11]. Subsequent experiments have lead to the identification of ammonia, a product of microbial urease, as the principal mediator of uremia-induced intestinal barrier disruption Effect of CKD on Intestinal Microbiome N. D. Vaziri (&) Division of Nephrology and Hypertension, Schools of Medicine, University of California Irvine, Irvine, CA, USA e-mail: ndvaziri@uci.edu In addition to disrupting the epithelial barrier, advanced CKD alters the composition [4–6, 14] and function [15] of the intestinal microbiome. This phenomenon is driven by the luminal influx of urea, dietary restrictions and