Synbiotics easing renal failure by improving gut microbiology (SYNERGY): A randomized trial

Abstract

Background and objectives: The generation of key uremic nephrovascular toxins, indoxyl sulfate (IS), and p-cresyl sulfate (PCS), is attributed to the dysbiotic gut microbiota in CKD. The aim of our study was to evaluate whether synbiotic (pre- and probiotic) therapy alters the gut microbiota and reduces serum concentrations of microbiome–generated uremic toxins, IS and PCS, in patients with CKD. Design, setting, participants, & measurements: Predialysis adult participants with CKD (eGFR=10–30 ml/min per 1.73 m2) were recruited between January 5, 2013 and November 12, 2013 to a randomized, double–blind, placebo–controlled, crossover trial of synbiotic therapy over 6 weeks (4-week washout). The primary outcome was serum IS. Secondary outcomes included serum PCS, stool microbiota profile, eGFR, proteinuria-albuminuria, urinary kidney injury molecule-1, serum inflammatory biomarkers (IL-1β, IL-6, IL-10, and TNF-α), serum oxidative stress biomarkers (F2-isoprostanes and glutathione peroxidase), serum LPS, patient-reported health, Gastrointestinal Symptom Score, and dietary intake. A prespecified subgroup analysis explored the effect of antibiotic use on treatment effect. Results: Of 37 individuals randomized (age =69±10 years old; 57% men; eGFR=24±8 ml/min per 1.73 m2), 31 completed the study. Synbiotic therapy did not significantly reduce serum IS (−2 μmol/L; 95% confidence interval [95% CI], −5 to 1 μmol/L) but did significantly reduce serum PCS (−14 μmol/L; 95% CI, −27 to −2 μmol/L). Decreases in both PCS and IS concentrations were more pronounced in patients who did not receive antibiotics during the study (n=21; serum PCS, −25 μmol/L; 95% CI, −38 to −12 μmol/L; serum IS, −5 μmol/L; 95% CI, −8 to −1 μmol/L). Synbiotics also altered the stool microbiome, particularly with enrichment of Bifidobacterium and depletion of Ruminococcaceae. Except for an increase in albuminuria of 38 mg/24 h (P=0.03) in the synbiotic arm, no changes were observed in the other secondary outcomes. Conclusion: In patients with CKD, synbiotics did not significantly reduce serum IS but did decrease serum PCS and favorably modified the stool microbiome. Large–scale clinical trials are justified.