Differences in gut microbiota composition are an important reason for lower serum p-cresol sulfate levels in anuric peritoneal dialysis patients compared to hemodialysis patients

• Distinct microbial communities are found in peritoneal dialysis (PD) and paired hemodialysis (HD) patients, despite similar microbiome diversity. • Serum p-cresyl sulfate (PCS) levels are significantly lower in PD patients compared to paired HD patients. • Altered microbial composition in PD patients, featuring more opportunistic pathogens and fewer beneficial bacteria, is linked to differences in metabolite profiles. • Fecal transplant experiments confirm that the HD-associated gut microbiota directly leads to higher PCS production. • Targeting the gut microbiota presents a potential therapeutic strategy to reduce uremic toxins in dialysis patients. Patients with end-stage kidney disease (ESKD) accumulate toxic metabolites that contribute to severe clinical complications. Peritoneal dialysis (PD) and hemodialysis (HD) exhibit distinct capacites for toxin clearance. Furthermore, the gut microbiota plays a significant role in toxin generation and is modulated by dialysis modality. This study aimed to compare gut microbiota composition and serum metabolite profiles between PD and HD patients, and to investigate their association with uremic toxin production. This single-center, cross-sectional study included 100 anuric ESKD patients (50 PD and 50 HD) matched for age, gender, and dialysis duration. Fecal and serum samples were collected and analyzed using 16S rRNA gene sequencing and non-targeted metabolomics. To validate the gut microbiota-serum metabolite relationship, fecal microbiota transplantation (FMT) was performed in germ-free CKD mice. No significant differences in alpha diversity were observed between PD and HD groups (all indices P>0.05), but beta diversity analysis revealed distinct gut microbial compositions (ANOSIM R=0.093, P=0.001), with PD patients showing higher abundance of opportunistic pathogens and lower abundance of beneficial bacteria. Non-targeted metabolomics identified 314 significantly different metabolites between the two groups, including significantly lower levels of p-cresyl sulfate (PCS) in PD patients (PD:19.16(7.24,53.83), HD:70.21(26.75,96.79), P