Megan Rossi, David W Johnson, Mark Morrison, Elaine M Pascoe, Jeff S Coombes, Josephine M Forbes, Cheuk-Chun Szeto, Brett C McWhinney, Jacobus P J Ungerer, Katrina L Campbell
Journal: Clinical journal of the American Society of Nephrology : CJASN 2017;11(2):223-31
PMID: 26772193
Chronic kidney disease (CKD) patients have altered gut microbiota that produces uremic toxins p-cresyl sulphate (PCS) and indoxyl sulfate (IS). PCS and IS have been shown to promote kidney disease progression and cardiovascular disease in the CKD population. A recent systematic review has shown that the administration of pre- and/or probiotics has been promising for modifying the bacterial production of IS and PCS, however the available studies are very limited. The aim of this crossover study was to evaluate whether synbiotic therapy reduces the microbial production of PCS and IS, and assess alterations in the gut microbiota in patients with CKD. Thirty-seven participants were randomised to receive either synbiotic supplements or placebo for 6 weeks followed by a 4-week washout period. Serum and stool samples were collected and analysed after each 6-week intervention period. In this study, synbiotic therapy effectively lowered serum concentration of PCS and to a lesser extent IS, as well as improved stool microbiome, in patients with moderate to severe CKD. This result was more significant when participants did not receive antibiotics during the study period. The authors conclude larger randomised, controlled trials evaluating the effect synbiotic therapy in the CKD population is warranted
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 m(2)) 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 m(2)), 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.
Copyright © 2016 by the American Society of Nephrology.
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