Abstract
Numerous studies have indicated that the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD) is strictly associated with the accumulation of toxic metabolites in blood and other metabolic compartments. This accumulation was suggested to be related to enhanced generation of toxins from the dysbiotic microbiome accompanied by their reduced elimination by impaired kidneys. Intestinal microbiota play a key role in the accumulation of uremic toxins due to the fact that numerous uremic solutes are generated in the process of protein fermentation by colonic microbiota. Some disease states, including CKD, are associated with the presence of dysbiosis, which can be defined as an “imbalanced intestinal microbial community with quantitative and qualitative changes in the composition and metabolic activities of the gut microbiota”. The results of studies have confirmed the altered composition and functions of gut microbial community in chronic kidney disease. In the course of CKD protein-bound uremic toxins, including indoxyl sulfate, p-cresyl glucuronide, p-cresyl sulfate and indole-3-acetic acid are progressively accumulated. The presence of chronic kidney disease may be accompanied by the development of intestinal inflammation and epithelial barrier impairment leading to hastened systemic translocation of bacterial-derived uremic toxins and consequent oxidative stress injury to the kidney, cardiovascular and endocrine systems. These findings offer new therapeutic possibilities for the management of uremia, inflammation and kidney disease progression and the prevention of adverse outcomes in CKD patients. It seems that dietary interventions comprising prebiotics, probiotics, and synbiotics could pose a promising strategy in the management of uremic toxins in CKD.
Highlights
indoxyl sulfate (IS) stimulates macrophage function and enhances inflammatory response associated with LPS, contributing to altered immune response dysfunctions observed in chronic kidney disease (CKD)
Overload of IS on remnant nephrons is involved in the increased bioactivity of transforming growth factor (TGF)-beta 1 in uremic kidneys, which enhances the renal expression of TIMP-1 and type 1 collagen, leading to the progression of CRF
It has already been demonstrated that the presence of chronic kidney disease may be accompanied by the development of intestinal inflammation and epithelial barrier impairment leading to hastened systemic translocation of the bacterial-derived uremic toxins (e.g., p-cresyl sulphate, indoxyl sulphate, trimethylamine N-oxide (TMAO), etc.) and consequent oxidative stress injury to the kidney as well as to cardiovascular and endocrine systems
Summary
The results of studies confirm that the composition and functions of gut microbial community are altered in chronic kidney disease [5,6,7]. Impairment of colonic epithelial tight junction may enable the aforementioned translocation of bacteria and endotoxin through the intestinal wall into the underlying tissue compartments, which could activate innate immunity and trigger a local inflammatory process contributing to perpetuating gut barrier damage [23,24]. The question of the exact mechanisms related to gut microbiota-mediated changes in ESRD metabolome remains unanswered [10] The unravelling of these mechanisms may have therapeutic significance since according to some researchers the change of specific gut microbes may translate into the regulation of circulating uremic toxin concentrations [28]
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