Uremic toxins originating from colonic microbial metabolism

Abstract

Numerous molecules, which are either excreted or metabolized by the kidney, accumulate in patients with chronic kidney disease (CKD). These uremic retention molecules (URMs), contributing to the syndrome of uremia, may be classified according to their site of origin, that is, endogenous metabolism, microbial metabolism, or exogenous intake. It is increasingly recognized that bacterial metabolites, such as phenols, indoles, and amines, may contribute to uremic toxicity. In vitro studies have implicated bacterial URMs in CKD progression, cardiovascular disease, and bone and mineral disorders. Furthermore, several observational studies have demonstrated a link between serum levels of bacterial URMs and clinical outcomes. Bacterial metabolism may therefore be an important therapeutic target in CKD. There is evidence that besides reduced renal clearance, increased colonic generation and absorption explain the high levels of bacterial URMs in CKD. Factors promoting URM generation and absorption include an increased ratio of dietary protein to carbohydrate due to insufficient intake of fiber and/or reduced intestinal protein assimilation, as well as prolonged colonic transit time. Two main strategies exist to reduce bacterial URM levels: interventions that modulate intestinal bacterial growth (e.g., probiotics, prebiotics, dietary modification) and adsorbent therapies that bind bacterial URMs in the intestines to reduce their absorption (e.g., AST-120, sevelamer). The efficacy and clinical benefit of these strategies are currently an active area of interest.

Metabolism, Protein Binding, and Renal Clearance of Microbiota–Derived p-Cresol in Patients with CKD

“…PCS originates from colonic microbial fermentation of tyrosine to p-cresol with subsequent endogenous sulfate conjugation (2,22). PCG is another p-cresol derivative, albeit with substantially lower total serum levels compared with PCS (11,12).…”

Alzheimer’s disease and gut microbiota

“…These changes are not the production of new metabolites, but the alterations of concentration of the existing metabolites in urine, and these changes often occur before the pathological changes in brain. A large part of the ingredients in urine are originated from the metabolism of gut microbiota, and the changes of urine components also indicate the changes of gut microbiota (Evenepoel et al, 2009). The alterations of the urine metabolome in AD mice may be associated with the differences of gut microbiota.…”

Grape seed proanthocyanidin extract protects human umbilical vein endothelial cells from indoxyl sulfate-induced injury via ameliorating mitochondrial dysfunction

“…[4][5][6] Dialysis is usually not powerful to remove protein-bound uremic toxins alone. 7,8 AST-120 (Kremezin), however, in a recent large randomized controlled trial in the United States and Europe, the positive effect of removing indoxyl sulfate could not be confirmed.…”