Altered microbiome in chronic kidney disease: systemic effects of gut-derived uremic toxins

Abstract

In chronic kidney disease (CKD), influx of urea and other retained toxins exerts a change in the gut microbiome. There is decreased number of beneficial bacteria that produce short-chain fatty acids, an essential nutrient for the colonic epithelium, concurrent with an increase in bacteria that produce uremic toxins such as indoxyl sulphate, p-cresyl sulphate, and trimethylamine-N-oxide (TMAO). Due to intestinal wall inflammation and degradation of intercellular tight junctions, gut-derived uremic toxins translocate into the bloodstream and exert systemic effects. In this review, we discuss the evidence supporting a role for gut-derived uremic toxins in promoting multiorgan dysfunction via inflammatory, oxidative stress, and apoptosis pathways. End-organ effects include vascular calcification, kidney fibrosis, anemia, impaired immune system, adipocyte dysfunction with insulin resistance, and low turnover bone disease. Higher blood levels of gut-derived uremic toxins are associated with increased cardiovascular events and mortality in the CKD population. Clinical trials that have examined interventions to trap toxic products or reverse gut microbial dysbiosis via oral activated charcoal AST-120, prebiotics and probiotics have not shown impact on cardiovascular or survival outcomes but were limited by sample size and short trials. In summary, the gut microbiome is a major contributor to adverse cardiovascular outcomes and progression of CKD.

Systems biology in inflammatory bowel diseases: on the way to precision medicine

“…When homeostasis becomes unbalanced and microbial populations and functions are altered, the phenomenon is called dysbiosis. It has been directly associated [149][150][151] with the onset, progression and therapeutic response of multiple health conditions, including lung-associated disorders [152,153], obesity [154,155], diabetes [156,157], cardiovascular disease and atherosclerosis [158][159][160][161], chronic kidney disease [162][163][164], cancer [165][166][167], neurological and neuropsychiatric disorders [168][169][170][171], and, in the spirit of this review, IBD [172][173][174].…”

The Regulation of Host Intestinal Microbiota by Polyphenols in the Development and Prevention of Chronic Kidney Disease

“…There is now extensive evidence that the intestinal barrier is damaged in CKD, leading to the translocation of uremic toxins originating from bacteria and other noxious luminal products into the bloodstream, resulting in inflammation, and the activation of leukocytes. Gas chromatography studies in CKD rats and end-stage kidney disease (ESKD) patients showed significant changes in exhaled breath gases compared with those of healthy controls, further evidencing the altered gut microbe composition in these patients (89).…”

Exploring the Benefit of 2-Methylbutyric Acid in Patients Undergoing Hemodialysis Using a Cardiovascular Proteomics Approach

“…In humans, the SCFA content in the colon region represents at least 100 mM, while its concentration ranges from 0.1 to 10 mM in the bloodstream [26]. Although decreased numbers of SCFA-producing gut microbiota in CKD or HD patients were investigated [17,18], the concentration or uptake of SCFA in this population has not extensively measured. This study also provided fundamental information about the 2-methylbutyric acid level in HD patients.…”