Gut microbiota generation of protein-bound uremic toxins and related metabolites is not altered at different stages of chronic kidney disease.

Chronic kidney disease (CKD) is characterized by accumulation of protein-bound uremic toxins such as p-cresyl sulfate, p-cresyl glucuronide, indoxyl sulfate and indole-3-acetic acid, which originate in the gut. Intestinal bacteria metabolize aromatic amino acids into p-cresol and indole, (further conjugated in the colon mucosa and liver) and indole-3-acetic acid. Here we measured fecal, plasma and urine metabolite concentrations; the contribution of gut bacterial generation to plasma protein-bound uremic toxins accumulation; and influx into the gut of circulating protein-bound uremic toxins at different stages of CKD. Feces, blood and urine were collected from 14 control individuals and 141 patients with CKD. Solutes were quantified by ultra-high performance liquid chromatography. To assess the rate of bacterial generation of p-cresol, indole and indole-3-acetic acid, fecal samples were cultured ex vivo. With CKD progression, an increase in protein-bound uremic toxins levels was observed in plasma, whereas the levels of these toxins and their precursors remained the same in feces and urine. Anaerobic culture of fecal samples showed no difference in ex vivo p-cresol, indole and indole-3-acetic acid generation. Therefore, differences in plasma protein-bound uremic toxins levels between different CKD stages cannot be explained by differences in bacterial generation rates in the gut, suggesting retention due to impaired kidney function as the main contributor to their increased plasma levels. Thus, as fractional clearance decreased with the progression of CKD, tubular clearance appeared to be more affected than the glomerular filtration rate, and there was no net increase in protein-bound uremic toxins influx into the gut lumen with increased plasma levels.

Gryp T ，De Paepe K ，Vanholder R ，Kerckhof FM ，Van Biesen W ，Van de Wiele T ，Verbeke F ，Speeckaert M ，Joossens M ，Couttenye MM ，Vaneechoutte M ，Glorieux G ... -  《-》

Isolation and Quantification of Uremic Toxin Precursor-Generating Gut Bacteria in Chronic Kidney Disease Patients.

Gryp T ，Huys GRB ，Joossens M ，Van Biesen W ，Glorieux G ，Vaneechoutte M ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

The Impact of CKD on Uremic Toxins and Gut Microbiota.

Rysz J ，Franczyk B ，Ławiński J ，Olszewski R ，Ciałkowska-Rysz A ，Gluba-Brzózka A ... -  《Toxins》

Gut Microbiota and Their Derived Metabolites, a Search for Potential Targets to Limit Accumulation of Protein-Bound Uremic Toxins in Chronic Kidney Disease.

Steenbeke M ，Valkenburg S ，Gryp T ，Van Biesen W ，Delanghe JR ，Speeckaert MM ，Glorieux G ... -  《-》

The Effect of Sevelamer on Serum Levels of Gut-Derived Uremic Toxins: Results from In Vitro Experiments and A Multicenter, Double-Blind, Placebo-Controlled, Randomized Clinical Trial.

Bennis Y ，Cluet Y ，Titeca-Beauport D ，El Esper N ，Ureña P ，Bodeau S ，Combe C ，Dussol B ，Fouque D ，Choukroun G ，Liabeuf S ... -  《Toxins》