The Microbiome and p-Inulin in Hemodialysis: A Feasibility Study

Abstract

Background: The intestinal microbiome is an appealing target for interventions in ESKD because of its likely contribution to uremic toxicity. Before conducting clinical trials of microbiome-altering treatments, it is necessary to understand the within-person and between-person variability in the composition and function of the gut microbiome in patients with ESKD.

Methods: We conducted a multicenter, nonrandomized, crossover feasibility study of patients on maintenance hemodialysis consisting of three phases: pretreatment (8 weeks); treatment, during which the prebiotic, p-inulin, was administered at a dosage of 8 g twice daily (12 weeks); and post-treatment (8 weeks). Stool samples were collected 1-2 times per week and blood was collected weekly for 28 weeks. The gut microbiome was characterized using 16S ribosomal-RNA sequencing and metabolomic profiling.

Results: A total of 11 of the 13 participants completed the 28-week study. Interparticipant variability was greater than intraparticipant variability for microbiome composition (P<0.001 by UniFrac distances) and metabolomic composition (P<0.001 by Euclidean distances). p-Inulin was well tolerated by 12 of 13 participants. Adherence to the frequent sample collection and self-aliquoting of stool samples were both 96%. A change in the microbiome composition from pretreatment to post-treatment was evident by the overall shifts in weighted UniFrac distances (P=0.004) and a progressive decrease in prevalence of high intraclass correlations, indicating an increase in intraparticipant microbiome diversity during and after p-inulin treatment. An effect of p-inulin on the metabolomic profile was not evident.

Conclusions: The intraparticipant stability of the gut microbiome under no-treatment conditions, the tolerability of p-inulin, the signals of increased diversity of the microbiome with p-inulin treatment, and the willingness of participants to provide stool samples all support the feasibility of a larger trial to investigate interventions targeting the gut microbiome in patients with ESKD. Whether or not p-inulin has sufficient efficacy as an intervention requires evaluation in larger studies.

Clinical trial registry name and registration number: Gut Microbiome and p-Inulin in Hemodialysis, NCT02572882.

Keywords: crossover trial; dialysis; feasibility studies; hemodialysis; microbiome; p-inulin; prebiotic.

Graphical abstract

Figure 1.

Study design. Biosample and data-collection schedule during the pretreatment, treatment, and post-treatment phases.

Figure 2.

Intra- and interparticipant variability using weighted UniFrac distance for the microbiome samples and Euclidean distance for the metabolome samples. (A) Microbiome, (B) stool metabolome, and (C) plasma metabolome. ***P<0.001.

Figure 3.

UniFrac distances from the initial measurement (week-2 samples) stratified by treatment phase. (A) For the microbiome samples, the weighted UniFrac distance was used to compute the distances for each sample. (B and C) For the metabolome samples, the Euclidean distance was used. Numeric values within the plots are P values. Differences between samples were determined on the basis of distances from the initial measurements to account for participant-level differences in initial abundance of microorganisms or concentration of metabolites. Measurements in each treatment phase were treated as repeated measurements because of time variability in treatment effects. Differences across the treatment phases were tested using a linear mixed-effects model.

Figure 4.

Density of intraclass correlation coefficients (ICC) for the microbiota.