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.