An Innovative Synbiotic Formulation Decreases Free Serum Indoxyl Sulfate, Small Intestine Permeability and Ameliorates Gastrointestinal Symptoms in a Randomized Pilot Trial in Stage IIIb-IV CKD Patients

Abstract

Proteolytic dysbiosis of the gut microbiota has been recognized as both a typical feature of chronic kidney disease (CKD) and a risk factor for its progression. Blood accumulation of gut-derived uremic toxins (UTs) like indoxyl sulfate (IS) and p-cresyl sulfate (PCS), intestinal permeability and constipation are typical features accompanying CKD progression and triggering chronic inflammation. In order to verify the efficacy of the innovative synbiotic formulation NATUREN G^® in modulating the levels of circulating UTs, intestinal permeability and gastrointestinal symptoms, we set up a randomized, single-blind, placebo-controlled, pilot trial in stage IIIb-IV CKD patients and in healthy controls. Two-month administration of the synbiotic resulted in a decrease of free IS, as compared with the placebo-treated arm, only in the CKD group. The other UTs did not significantly change, although different trends in time (increase in the placebo arm and decrease in the synbiotic arm) were observed. Moreover, after supplementation, reduction of small intestinal permeability and amelioration of abdominal pain and constipation syndromes were observed only in the CKD group. The obtained results suggest the specificity of action of NATUREN G^® in CKD and justify further validation in a wider study population.

Keywords: chronic kidney disease; gut microbiota; indoxyl sulfate; intestinal permeability; randomized pilot trial; synbiotic; uremic toxins.

Figure 1

CONSORT study design. Eligibility was assessed in 441 CKD patients, and 41 healthy volunteers with 23 CKD patients and 27 healthy volunteers enrolled and randomized in the Synbiotic (S) (n = 13 CKD, n = 12 healthy) and Placebo (P) arm (n = 10 CKD, n = 15 healthy). No CKD patient dropped out, while in the healthy volunteer group, three subjects dropped out, two allocated in the S-arm and one in the P-arm.

Figure 2

NATUREN G^® reduces serum concentration of free IS only in the CKD group. The figure shows the serum levels of total PCS (A) and IS (B) and free PCS (C) and IS (D) in the CKD group (13 S and 10 P). (E–H) show the serum levels of total PCS, total IS, free PCS and free IS in the healthy volunteer group (10 S and 14 P). Only in the CKD group, at T2, free IS levels were significantly lower in the S-arm as compared with the P-arm (D). * p < 0.05 vs. placebo. Data are expressed with medians, interquartile ranges and minimum to maximum values, differences tested by Kruskal–Wallis multiple-comparison z-value test.

Figure 3

Baseline colon permeability, as measured by % of sucralose recovery, in healthy subjects and in CKD patients in stage IIIB and IV. * p < 0.05 vs. healthy subjects (one-way ANOVA followed by Fisher’s LSD Multiple comparison test).

Figure 4

Linear regression analysis between mannitol recovery (%) and eGFR (mL/min) in CKD patients. Measurements were taken at entry (baseline). R = 0.60. p = 0.0034.

Figure 5

Linear regression analysis between sucralose recovery (%), an expression of colon permeability and eGFR (mL/min) in CKD patients. Measurements were taken at entry (baseline). R = 0.54. p = 0.01.

Figure 6

Spearman correlations between azotemia and total IS (A) or free IS (B); correlation of Ca × P product with total IS (C).