The Accumulation of Gut Microbiome-derived Indoxyl Sulfate and P-Cresyl Sulfate in Patients With End-stage Renal Disease

Objectives: Indoxyl sulfate (IS) and p-cresyl sulfate (pCS) are two important gut microbiota-generated protein-bound uremic toxins. The present study aims to explore the alterations of serum IS and pCS concentrations, their production, and daily removal in end-stage renal disease (ESRD). Methods: A case-controlled study was conducted based on 11 patients with ESRD and 11 healthy volunteers. The metabolic processes for IS and pCS were compared in these two groups, including gut microbiome, fecal indole and p-cresol, indole-producing bacteria and p-cresol-producing bacteria, serum total IS and pCS concentrations, and their daily removal by urine and spent dialyzate. Results: Compared with healthy controls, patients with ESRD exhibited higher relative abundance of the indole-producing bacteria Escherichia coli (P < .001) and Bacteroides fragilis (P = .010) and p-cresol-producing bacteria Bacteroides fragilis (P = .010) and Bacteroides caccae (P = .047). The predicted functional profiles of gut microbiome based on 16S rRNA gene PhyloChip analysis showed that the microbial tryptophan metabolism pathway (map00380, P = .0006) was significantly enriched in patients with ESRD. However, the fecal precursors indole (P = .332) and p-cresol concentrations (P = .699) were comparable between the two groups. The serum IS (P < .001) and pCS (P < .001) concentrations were far higher in patients with ESRD than those in healthy controls, whereas the daily total removal by urine and dialyzate was much lower for the former than that for the latter (P = .019 for IS, P = .016 for pCS). Conclusions: The present study showed serious IS and pCS accumulation in patients with ESRD, with significant expansion of indoleproducing bacteria and p-cresol-producing bacteria, upregulation of the bacterial tryptophan metabolism pathway, and greatly increased serum IS and pCS concentrations, whereas significant decline of daily IS and pCS removal.