Oral Activated Charcoal Adsorbent (AST-120) Ameliorates Chronic Kidney Disease-Induced Intestinal Epithelial Barrier Disruption

Abstract

Background: Chronic kidney disease (CKD) impairs intestinal barrier function which by allowing influx of noxious products causes systemic inflammation. We have recently shown that intestinal barrier dysfunction in CKD is due to degradation of epithelial tight junction (TJ) which is, in part, mediated by influx of urea and its conversion to ammonia by microbial urease. We hypothesized that by adsorbing urea and urea-derived ammonia, oral activated charcoal (AST-120) may ameliorate CKD-induced intestinal epithelial barrier disruption and systemic inflammation. Methods: Rats were randomized to the CKD or control groups. The CKD group was fed a chow containing 0.7% adenine for 2 weeks. They were then randomized to receive a chow with or without AST-120 (4 g/kg/day) for 2 weeks. Rats consuming regular diet served as controls. Animals were then euthanized, colons were removed and processed for Western blot and immunohistology, and plasma was used to measure endotoxin and oxidative and inflammatory markers. Results: Compared with the controls, the untreated CKD rats showed elevated plasma endotoxin, IL-6, TNF-α, MCP-1, CINC-3, L-selectin, ICAM-1, and malondialdehyde, and depletions of colonic epithelial TJ proteins, claudin-1, occludin, and ZO1.Administrationof AST-120 resulted in partial restoration of the epithelial TJ proteins and reduction in plasma endotoxin and markers of oxidative stress and inflammation. Conclusions: CKD animals exhibited depletion of the key protein constituents of the colonic epithelial TJ which was associated with systemic inflammation, oxidative stress and endotoxemia. Administration of AST-120 attenuated uremia-induced disruption of colonic epithelial TJ and the associated endotoxemia, oxidative stress and inflammation.

Role of Nrf2 Dysfunction in Uremia-Associated Intestinal Inflammation and Epithelial Barrier Disruption

“…Treatment with dh404 reduced NFkB activity and inflammatory mediators and ameliorated depletion of the tight junction proteins. Earlier studies conducted by our group demonstrated the role of urea-derived ammonia and ammonium hydroxide generated by microbial urease in the gut lumen as a major cause of the disruption of intestinal epithelial tight junction [9], and its partial restoration by oral adsorbent [7]. The other potential mechanism known to cause tight junction breakdown is intestinal inflammation which leads to endocytosis of claudins and occludin as seen in inflammatory bowel diseases [12,40].…”

“…Almost 30 years ago, Vaziri et al [4] showed the presence of inflammation throughout the gastrointestinal tract (including gastritis, enteritis, and colitis) in a postmortem analysis of 78 hemodialysis patients. Recent studies by our group have demonstrated disruption of the epithelial tight junction throughout the gastrointestinal tract and its association with endotoxemia, local and systemic inflammation, and oxidative stress in animal models of CKD [5][6][7]. Subsequent in vitro studies revealed the role of urea and its conversion to ammonia and ammonium hydroxide as a main cause of the breakdown of the gut epithelial tight junction [8,9].…”

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

“…Moreover, in vitro studies revealed significant depletion of the tight junction proteins and reduction of trans-epithelial electrical resistance in cultured human colonocytes incubated 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 [12,13].…”

The influence of mutant lactobacilli on serum creatinine and urea nitrogen concentrations and renal pathology in 5/6 nephrectomized rats

“…This, in turn, leads to system inflammation and progressive damage to the renal function by allowing absorption of plasma endotoxin, IL-6, TNF-a, MCP-1, CINC-3, L-selectin, ICAM-1, and malondialdehyde into the circulatory system. 18 Experiments in a rat model of chronic kidney failure showed that urea directly enhances oxidative stress and insulin resistance, which play a central role in the pathogenesis of accelerated cardiovascular disease and numerous other CKD-associated complications. It was also observed that proteinuria was reduced and the decline in renal function was delayed by lowering the levels of blood urea in patients with CKD.…”