Prebiotic, Probiotic, and Synbiotic Supplementation in Chronic Kidney Disease: A Systematic Review and Meta-analysis.

Gut dysbiosis has been implicated in the pathogenesis of chronic kidney disease (CKD). Restoring gut microbiota with prebiotic, probiotic, and synbiotic supplementation has emerged as a potential therapeutic intervention but has not been systematically evaluated in the CKD population. This is a systematic review. A structured search of MEDLINE, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials, and the International Clinical Trials Register Search Portal was conducted for articles published since inception until July 2017. Included studies were randomized controlled trials investigating the effects of prebiotic, probiotic, and/or synbiotic supplementation (>1 week) on uremic toxins, microbiota profile, and clinical and patient-centered outcomes in adults and children with CKD. Sixteen studies investigating 645 adults met the inclusion criteria; 5 investigated prebiotics, 6 probiotics, and 5 synbiotics. The quality of the studies (Grades of Recommendation, Assessment, Development and Evaluation) ranged from moderate to very low. Prebiotic, probiotic, and synbiotic supplementation may have led to little or no difference in serum urea (9 studies, 345 participants: mean difference [MD] -0.30 mmol/L, 95% confidence interval [CI] -2.20 to 1.61, P = .76, I2 = 53%), indoxyl sulfate (4 studies, 144 participants: MD -0.02 mg/dL, 95% CI -0.09 to 0.05, P = .61, I2 = 0%), and p-cresyl sulfate (4 studies, 144 participants: MD -0.13 mg/dL, 95% CI -0.41 to 0.15, P = .35, I2 = 0%). Prebiotic supplementation may have slightly reduced serum urea concentration (4 studies, 105 participants: MD -2.23 mmol/L, 95% CI -3.83 to -0.64, P = .006, I2 = 11). Of the 2 studies investigating microbiota changes, synbiotic interventions significantly increased Bifidobacterium. Supplement effects on clinical outcomes were uncertain. There is limited evidence to support the use of prebiotics, probiotics, and/or synbiotics in CKD management.

McFarlane C ，Ramos CI ，Johnson DW ，Campbell KL ... -  《-》

Synbiotics, prebiotics and probiotics for people with chronic kidney disease.

Chronic kidney disease (CKD) is a major public health problem affecting 13% of the global population. Prior research has indicated that CKD is associated with gut dysbiosis. Gut dysbiosis may lead to the development and/or progression of CKD, which in turn may in turn lead to gut dysbiosis as a result of uraemic toxins, intestinal wall oedema, metabolic acidosis, prolonged intestinal transit times, polypharmacy (frequent antibiotic exposures) and dietary restrictions used to treat CKD. Interventions such as synbiotics, prebiotics, and probiotics may improve the balance of the gut flora by altering intestinal pH, improving gut microbiota balance and enhancing gut barrier function (i.e. reducing gut permeability). This review aimed to evaluate the benefits and harms of synbiotics, prebiotics, and probiotics for people with CKD. We searched the Cochrane Kidney and Transplant Register of Studies up to 9 October 2023 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. We included randomised controlled trials (RCTs) measuring and reporting the effects of synbiotics, prebiotics, or probiotics in any combination and any formulation given to people with CKD (CKD stages 1 to 5, including dialysis and kidney transplant). Two authors independently assessed the retrieved titles and abstracts and, where necessary, the full text to determine which satisfied the inclusion criteria. Data extraction was independently carried out by two authors using a standard data extraction form. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) or standardised mean difference (SMD) and 95% CI for continuous outcomes. The methodological quality of the included studies was assessed using the Cochrane risk of bias tool. Data entry was carried out by one author and cross-checked by another. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Forty-five studies (2266 randomised participants) were included in this review. Study participants were adults (two studies in children) with CKD ranging from stages 1 to 5, with patients receiving and not receiving dialysis, of whom half also had diabetes and hypertension. No studies investigated the same synbiotic, prebiotic or probiotic of similar strains, doses, or frequencies. Most studies were judged to be low risk for selection bias, performance bias and reporting bias, unclear risk for detection bias and for control of confounding factors, and high risk for attrition and other biases. Compared to prebiotics, it is uncertain whether synbiotics improve estimated glomerular filtration rate (eGFR) at four weeks (1 study, 34 participants: MD -3.80 mL/min/1.73 m², 95% CI -17.98 to 10.38), indoxyl sulfate at four weeks (1 study, 42 participants: MD 128.30 ng/mL, 95% CI -242.77 to 499.37), change in gastrointestinal (GI) upset (borborymgi) at four weeks (1 study, 34 participants: RR 15.26, 95% CI 0.99 to 236.23), or change in GI upset (Gastrointestinal Symptom Rating Scale) at 12 months (1 study, 56 participants: MD 0.00, 95% CI -0.27 to 0.27), because the certainty of the evidence was very low. Compared to certain strains of prebiotics, it is uncertain whether a different strain of prebiotics improves eGFR at 12 weeks (1 study, 50 participants: MD 0.00 mL/min, 95% CI -1.73 to 1.73), indoxyl sulfate at six weeks (2 studies, 64 participants: MD -0.20 μg/mL, 95% CI -1.01 to 0.61; I² = 0%) or change in any GI upset, intolerance or microbiota composition, because the certainty of the evidence was very low. Compared to certain strains of probiotics, it is uncertain whether a different strain of probiotic improves eGFR at eight weeks (1 study, 30 participants: MD -0.64 mL/min, 95% CI -9.51 to 8.23; very low certainty evidence). Compared to placebo or no treatment, it is uncertain whether synbiotics improve eGFR at six or 12 weeks (2 studies, 98 participants: MD 1.42 mL/min, 95% CI 0.65 to 2.2) or change in any GI upset or intolerance at 12 weeks because the certainty of the evidence was very low. Compared to placebo or no treatment, it is uncertain whether prebiotics improves indoxyl sulfate at eight weeks (2 studies, 75 participants: SMD -0.14 mg/L, 95% CI -0.60 to 0.31; very low certainty evidence) or microbiota composition because the certainty of the evidence is very low. Compared to placebo or no treatment, it is uncertain whether probiotics improve eGFR at eight, 12 or 15 weeks (3 studies, 128 participants: MD 2.73 mL/min, 95% CI -2.28 to 7.75; I² = 78%), proteinuria at 12 or 24 weeks (1 study, 60 participants: MD -15.60 mg/dL, 95% CI -34.30 to 3.10), indoxyl sulfate at 12 or 24 weeks (2 studies, 83 participants: MD -4.42 mg/dL, 95% CI -9.83 to 1.35; I² = 0%), or any change in GI upset or intolerance because the certainty of the evidence was very low. Probiotics may have little or no effect on albuminuria at 12 or 24 weeks compared to placebo or no treatment (4 studies, 193 participants: MD 0.02 g/dL, 95% CI -0.08 to 0.13; I² = 0%; low certainty evidence). For all comparisons, adverse events were poorly reported and were minimal (flatulence, nausea, diarrhoea, abdominal pain) and non-serious, and withdrawals were not related to the study treatment. We found very few studies that adequately test biotic supplementation as alternative treatments for improving kidney function, GI symptoms, dialysis outcomes, allograft function, patient-reported outcomes, CVD, cancer, reducing uraemic toxins, and adverse effects. We are not certain whether synbiotics, prebiotics, or probiotics are more or less effective compared to one another, antibiotics, or standard care for improving patient outcomes in people with CKD. Adverse events were uncommon and mild.

Cooper TE ，Khalid R ，Chan S ，Craig JC ，Hawley CM ，Howell M ，Johnson DW ，Jaure A ，Teixeira-Pinto A ，Wong G ... -  《Cochrane Database of Systematic Reviews》

The effect of probiotics, prebiotics or synbiotics on metabolic outcomes in individuals with diabetes: a systematic review and meta-analysis.

Bock PM ，Telo GH ，Ramalho R ，Sbaraini M ，Leivas G ，Martins AF ，Schaan BD ... -  《-》

Effect of Probiotic, Prebiotic, and Synbiotic Supplementation on Cardiometabolic and Oxidative Stress Parameters in Patients With Chronic Kidney Disease: A Systematic Review and Meta-analysis.

Chronic kidney disease (CKD) is a major health problem worldwide. Evidence supporting the use of probiotic, prebiotic, and synbiotic supplementation in the management of CKD is mixed, although some studies suggest they may be useful. A systematic review and meta-analysis was performed to evaluate the effectiveness of probiotic, prebiotic, and synbiotic supplementation for improving cardiometabolic and oxidative stress parameters in patients with CKD. A comprehensive key word search was performed in EMBASE, Medline, Scopus, Cochrane Central, and Web of Science until April 2020. Randomized controlled trials investigating the effectiveness of probiotic, synbiotic, and prebiotic supplementation for the management of adults with CKD were included. Primary outcomes were measures of cardiometabolic parameters such as cholesterol and fasting blood glucose. Secondary outcomes were measures of oxidative stress (eg, malondialdehyde levels) and body mass index. Random effects meta-analyses were used to estimate mean treatment effects. Results are reported as standardized mean differences (SMDs) and 95% CIs. Fourteen articles were included. In patients with CKD, probiotic, prebiotic, and synbiotic supplementation significantly reduced total cholesterol (SMD, -0.25; 95% CI, -0.46 to -0.04; I2 = 00.0%), fasting blood glucose (SMD, -0.41; 95% CI, -0.65 to -0.17; I2 = 00.0%), homeostatic model assessment of insulin resistance (SMD, -0.63; 95% CI, -0.95 to -0.30; I2 = 43.3%), insulin levels (SMD, -0.49; 95% CI, -0.90 to -0.08; I2 = 65.2%), high-sensitivity C-reactive protein levels (SMD, -0.52; 95% CI, -0.81 to -0.22; I2 = 52.7%), and malondialdehyde levels (SMD, -0.79; 95% CI, -1.22 to -0.37; I2 = 69.8%) compared with control interventions. Supplementation significantly increased the quantitative insulin sensitivity check index (SMD, 0.78; 95% CI, 0.51 to 1.05; I2 = 00.0%), total antioxidant capacity (SMD, 0.42; 95% CI, 0.18 to 0.66; I2 = 00.0%), and glutathione levels (SMD, 0.52; 95% CI, 0.19 to 0.86; I2 = 37.0%). Probiotic, prebiotic, and synbiotic supplementation seems to be a promising intervention for improving cardiometabolic and oxidative stress parameters in patients with CKD.

Bakhtiary M ，Morvaridzadeh M ，Agah S ，Rahimlou M ，Christopher E ，Zadro JR ，Heshmati J ... -  《-》

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 ... -  《-》