Profiling of faecal water and urine metabolites among Papua New Guinea highlanders believed to be adapted to low protein intake
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Role of urea in intestinal barrier dysfunction and disruption of epithelial tight junction in CKD
"The rise in urea concentration in the intra-cellular and extra-cellular fluid compartments results in its heavy influx into the gastro-intestinal tract (7). Within the intestinal lumen urea is hydrolyzed by microbial urease forming large quantities of ammonia [CO(NH2)2 +H2O → CO2+2NH3] which is readily converted to ammonium hydroxide [NH3 + H2O → NH4OH] (8,9). Ammonium hydroxide, in turn, leads to a modest rise in the luminal fluid's pH, causes mucosal irritation and promotes enterocolitis [10,11]. Based on these observations we hypothesize that ammonium hydroxide generated from hydrolysis of urea by microbial urease in the intestinal lumen of uremic patients may contribute to the epithelial barrier dysfunction and erosion of the TJ protein constituents."
"The present study revealed that at clinically-relevant concentrations, urea significantly lowered the TER [Transepithelial Electrical Resistance] in the tight junction-forming polarized human colonic epithelial cell monolayer in vitro. The effect of urea was dramatically amplified by urease which was used to simulate the effect of urease-possessing microbial species in the colon. These observations illustrate the potential contribution of influx of urea into the intestinal tract in the pathogenesis of the uremia-induced intestinal barrier dysfunction in the uremic patients. The observed fall in the TER was accompanied by and was largely due to the urea-concentration-dependent depletion of occludin, claudin 1, and ZO1 which are the key protein constituents of the epithelial TJ. The erosive effect of urea on the measured TJ proteins was greatly intensified in the presence of urease leading to near complete depletion of ZO1 and occludin and severe reduction in claudin 1 abundance."
"As noted above, accumulation of urea in the intra- and extra-cellular fluid compartments in patients and animals with advanced CKD results in its heavy influx into the gastro-intestinal tract via passive diffusion and incorporation in the glandular secretions (7–9). As noted earlier within the intestinal lumen urea is hydrolyzed spontaneously and by microbial urease forming large quantities of ammonia [8,9]. Ammonia is, in turn, converted to ammonium hydroxide which is a caustic base capable of causing cytotoxicity and tissue damage. Recent studies conducted by our group have shown marked changes in the composition of microbial flora in humans and animals with advanced CKD [21]. Five of the 10 microbial families which were most abundant in the CKD patients possessed functional urease [2,21]. Thus massive influx of urea into the gastrointestinal tract together with the dominance of urease-possessing bacteria in the uremic individuals, work in concert to promote formation of ammonia and ammonium hydroxide in the intestinal tract [8,9]. This can account for the dramatic impairment of the barrier function and destruction of TJ apparatus observed in the present in vitro experiments designed to simulate the effect of uremia in vivo."
