Synbiotics Easing Renal Failure by Improving Gut Microbiology (SYNERGY): A Randomized Trial.
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.
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.
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.
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.
Rossi M
，Johnson DW
，Morrison M
，Pascoe EM
，Coombes JS
，Forbes JM
，Szeto CC
，McWhinney BC
，Ungerer JP
，Campbell KL
... -
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The Impact of Synbiotic Treatment on the Levels of Gut-Derived Uremic Toxins, Inflammation, and Gut Microbiome of Chronic Kidney Disease Patients-A Randomized Trial.
Altering dysbiotic gut flora through synbiotic supplementation has recently been recognized as a potential treatment strategy to reduce the levels of gut-derived uremic toxins and decrease inflammation. Assessing its efficacy and safety has been the main goal of our randomized, double-blind, placebo-controlled study.
A total of 34 nondialyzed chronic kidney disease patients, aged ≥18 years, with an estimated glomerular filtration rate between 15 and 45 mL/minute, were randomized either to an intervention group (n = 17), receiving synbiotic (Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium lactis, 32 billion colony forming units per day plus 3.2 g of inulin), or control group (n = 17), receiving placebo during 12 weeks. The impact of treatment on the dynamic of serum levels of gut-derived uremic toxins, total serum indoxyl sulfate, p-cresyl sulfate, and trimethylamine N-oxide, was defined as the primary outcome of the study. Secondary outcomes included changes in the stool microbiome, serum interleukin-6 levels, high-sensitivity C-reactive protein, estimated glomerular filtration rate, albuminuria, diet, gastrointestinal symptom dynamics, and safety. Serum levels of uremic toxins were determined using ultraperformance liquid chromatography. The stool microbiome analysis was performed using the 16S ribosomal ribonucleic acid gene sequencing approach.
Synbiotic treatment significantly modified gut microbiome with Bifidobacteria, Lactobacillus, and Subdoligranulum genera enrichment and consequently reduced serum level of indoxyl sulfate (ΔIS -21.5% vs. 5.3%, P < .001), improved estimated glomerular filtration rate (ΔeGFR 12% vs. 8%, P = .029), and decreased level of high-sensitivity C-reactive protein (-39.5 vs. -8.5%, P < .001) in treated patients. Two patients of the intervention arm complained of increased flatulence. No other safety issues were noted.
Synbiotics could be available, safe, and an effective therapeutic strategy we could use in daily practice in order to decrease levels of uremic toxins and microinflammation in chronic kidney disease patients.
Mitrović M
，Stanković-Popović V
，Tolinački M
，Golić N
，Soković Bajić S
，Veljović K
，Nastasijević B
，Soldatović I
，Svorcan P
，Dimković N
... -
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