Effects of Microbiota-Driven Therapy on Circulating Indoxyl Sulfate and P-Cresyl Sulfate in Patients with Chronic Kidney Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Abstract

Indoxyl sulfate (IS) and p-cresyl sulfate (PCS), protein-bound uremic toxins, exacerbate the deterioration of renal function and increase the risk of cardiovascular events in chronic kidney disease (CKD) patients. The effects of microbiota-driven therapy (probiotics, prebiotics, or synbiotics) on decreasing circulating IS and PCS concentrations are controversial; thus, we performed the present systematic review and meta-analysis to assess the effects of microbiota-driven therapy on circulating IS and PCS concentrations in CKD patients. PubMed, EMBASE, and Cochrane Library databases were systematically searched from inception to 22 July, 2021, and randomized controlled trials (RCTs) investigating the effects of microbiota-driven therapy on circulating IS and PCS concentrations in CKD patients were included. In all, 14 RCTs with 513 participants were eligible for the meta-analysis. The effects of microbiota-driven therapy on the circulating IS and PCS concentrations were evaluated with weighted mean differences (WMDs) measured by a fixed-effects model or a random-effects model. Compared with placebo, microbiota-driven therapy had no statistically significant effect on the circulating IS concentration (WMD: -1.64 mg/L; 95% CI: -3.46, 0.18 mg/L; P = 0.077) but it decreased the circulating PCS concentration (WMD: -2.42 mg/L; 95% CI: -3.81, -1.04 mg/L; P = 0.001). In the subgroup analyses, prebiotic (n = 6) and synbiotic (n = 3) supplementation significantly decreased the circulating PCS concentration, whereas probiotic (n = 3) supplementation did not. Meta-regression showed that the effects of microbiota-driven therapy were not associated with the supplementation time or the year of publication. Moreover, there was no significant evidence of publication bias. This review found that microbiota-driven therapy decreased the circulating PCS concentration in CKD patients. Additional large, well-designed RCTs with improved methodology and reporting are necessary to assess the effects of microbiota-driven therapy on circulating IS and PCS concentrations in the long term. This systematic review was registered at www.crd.york.ac.uk/prospero/ as CRD42021269146.

Keywords: chronic kidney disease; indoxyl sulfate; meta-analysis; microbiota-driven therapy; p-cresyl sulfate.

FIGURE 1

Flow diagram for the study selection process. RCT, randomized controlled trial.

FIGURE 2

Risk of bias graph. Values are percentages.

FIGURE 3

Risk of bias summary.

FIGURE 4

Forest plot for circulating p-cresyl sulfate concentration: microbiota-driven therapy compared with placebo (fixed-effect model). WMD, weighted mean difference.

FIGURE 5

Meta-regression plot. (A, B) Change in PCS concentration according to (A) supplementation time of microbiota-driven therapy and (B) year of publication. (C, D) Change in IS concentration according to (C) supplementation time of microbiota-driven therapy and (D) year of publication. IS, indoxyl sulfate; PCS, p-cresyl sulfate.

FIGURE 6

Forest plot for circulating indoxyl sulfate concentration: microbiota-driven therapy compared with placebo (random-effect model). WMD, weighted mean difference.

FIGURE 7

Publication bias. (A) Funnel plot, (B) Begg test, and (C) Egger test for circulating IS concentration. (D) Funnel plot, (E) Begg test, and (F) Egger test for circulating PCS concentration. IS, indoxyl sulfate; PCS, p-cresyl sulfate; WMD, weighted mean difference.