title: Synbiotics Easing Renal Failure by Improving Gut Microbiology (SYNERGY): A Randomized Trial.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: School of Medicine, Translational Research Institute, Brisbane, Queensland, Australia; Nephrology Department, Princess Alexandra Hospital, Brisbane, Queensland, Australia; megan.rossi@uq.net.au.
authors.forename: Megan
authors.initials: M
authors.lastname: Rossi
authors.affiliation: School of Medicine, Translational Research Institute, Brisbane, Queensland, Australia; Nephrology Department, Princess Alexandra Hospital, Brisbane, Queensland, Australia;
authors.forename: David W
authors.initials: DW
authors.lastname: Johnson
authors.affiliation: Translational Research Institute, Brisbane, Queensland, Australia; Diamantina Institute.
authors.forename: Mark
authors.initials: M
authors.lastname: Morrison
authors.affiliation: School of Medicine.
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Pascoe
authors.affiliation: Human Movement and Nutrition Sciences, and.
authors.forename: Jeff S
authors.initials: JS
authors.lastname: Coombes
authors.affiliation: School of Medicine, Translational Research Institute, Brisbane, Queensland, Australia; Mater Research Institute, The University of Queensland, Brisbane, Queensland, Australia;
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Forbes
authors.affiliation: Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China; and.
authors.forename: Cheuk-Chun
authors.initials: CC
authors.lastname: Szeto
authors.affiliation: Department of Chemical Pathology, Pathology Queensland, Brisbane, Queensland, Australia.
authors.forename: Brett C
authors.initials: BC
authors.lastname: McWhinney
authors.affiliation: Department of Chemical Pathology, Pathology Queensland, Brisbane, Queensland, Australia.
authors.forename: Jacobus P J
authors.initials: JP
authors.lastname: Ungerer
authors.affiliation: School of Medicine, Translational Research Institute, Brisbane, Queensland, Australia; Nephrology Department, Princess Alexandra Hospital, Brisbane, Queensland, Australia;
authors.forename: Katrina L
authors.initials: KL
authors.lastname: Campbell
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D001419:Bacteria / Q000187:drug effects / Q000378:metabolism*; D003408:Cresols / Q000097:blood; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005243:Feces / Q000382:microbiology; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000187:drug effects; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000382:microbiology*; D005919:Glomerular Filtration Rate; D006801:Humans; D007200:Indican / Q000097:blood; D007668:Kidney / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D056692:Prebiotics / Q000009:adverse effects; D019936:Probiotics / Q000009:adverse effects / Q000627:therapeutic use*; D011793:Queensland; D051437:Renal Insufficiency / Q000097:blood / Q000175:diagnosis / Q000382:microbiology / Q000628:therapy*; D012720:Severity of Illness Index; D013463:Sulfuric Acid Esters / Q000097:blood; D058616:Synbiotics / Q000009:adverse effects; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D003408:Cresols; D056692:Prebiotics; D013463:Sulfuric Acid Esters; C408690:4-cresol sulfate; D007200:Indican
keywords: chronic kidney disease; glomerular filtration rate; humans; indoxyl sulphate; microbiota; p-cresyl sulphate; probiotics; renal insufficiency, chronic; synbiotics; uremic toxins