Randomized, Placebo-Controlled Trial of Rifaximin Therapy for Lowering Gut-Derived Cardiovascular Toxins and Inflammation in CKD

Abstract

Background: Recent evidence suggests the systemic accumulation of by-products of gut microbes contributes to cardiovascular morbidity in patients with CKD. Limiting the generation of toxic bacterial by-products by manipulating the intestinal microbiota may be a novel strategy for reducing cardiovascular disease in CKD. Rifaximin is a minimally absorbed, oral antibiotic that targets intestinal pathogens and is commonly used as chronic therapy for the prevention of encephalopathy in patients with cirrhosis.

Methods: We conducted a randomized, double-blinded, placebo-controlled trial to determine the effect of a 10-day course of oral rifaximin 550 mg BID versus placebo on circulating concentrations of gut-derived cardiovascular toxins and proinflammatory cytokines in patients with stage 3-5 CKD (n=38). The primary clinical outcome was change in serum trimethylamine N-oxide (TMAO) concentrations from baseline to study end. Secondary outcomes included change in serum concentrations of p-cresol sulfate, indoxyl sulfate, kynurenic acid, deoxycholic acid, and inflammatory cytokines (C-reactive protein, IL-6, IL-1β), and change in composition and diversity of fecal microbiota.

Results: A total of 19 patients were randomized to each of the rifaximin and placebo arms, with n=17 and n=14 completing both study visits in these respective groups. We observed no difference in serum TMAO change (post-therapy minus baseline TMAO) between the rifaximin and placebo groups (mean TMAO change -3.9±15.4 for rifaximin versus 0.5±9.5 for placebo, P=0.49). Similarly, we found no significant change in serum concentrations for p-cresol sulfate, indoxyl sulfate, kynurenic acid, deoxycholic acid, and inflammatory cytokines. We did observe differences in colonic bacterial communities, with the rifaximin group exhibiting significant decreases in bacterial richness (Chao1, P=0.02) and diversity (Shannon H, P=0.05), along with altered abundance of several bacterial genera.

Conclusions: Short-term rifaximin treatment failed to reduce gut-derived cardiovascular toxins and inflammatory cytokines in patients with CKD.

Clinical trial registry name and registration number: Rifaximin Therapy in Chronic Kidney Disease, NCT02342639.

Conflict of interest statement

All authors have nothing to disclose.

Figures

Graphical abstract

Figure 1.

Graphical representation of study design showing treatment schedule, timing of biological sample collection, and study endpoints. BID, twice a day; PO, by mouth; rRNA, ribosomal RNA.

Figure 2.

Graphical representation of study participant enrollment, randomization and disposition.

Figure 3.

Rifaximin therapy fails to alter serum levels of gut-derived metabolites or inflammatory cytokines. Pre- and post-treatment concentrations in individual study participants from the rifaximin group (first column) and placebo group (second column), along with a between-group comparison (far right column) of absolute changes for (A–C) trimethylamine N-oxide (TMAO), (D–F) p-cresol sulfate, (G–I) indoxyl sulfate, (J–L) kynurenic acid, (M–O) deoxycholic acid, (P–R) C-reactive protein, (S–U) and IL-6 (error bars represent mean±SD).

Figure 4.

Rifaximin therapy reduces fecal bacterial richness and diversity. (A) Changes in fecal bacterial richness, evenness, and diversity, stratified by treatment arm, assessed by a rank-based nonparametric test; error bars represent point estimates and confidence intervals for relative treatment effects. Average abundance of bacterial genera per group at each study visit depicted as percentage 16S rRNA for each genus relative to the total 16S rRNA count per sample. (B) Average relative abundance of predominant bacterial genera per group at each study visit. Differences in community composition (i.e., β-diversity) after treatment were evaluated by the permutational multivariate ANOVA test. Changes in fecal bacterial richness, evenness, and diversity stratified by treatment arm (error bars represent mean±SD). 1V, baseline visit; 2V, post-therapy visit; Actino, Actinobacteria; Bact, Bacteroidetes; Firm, Firmicutes; Verr, Verrucomicrobia.