Rifaximin is associated with modest, transient decreases in multiple taxa in the gut microbiota of patients with diarrhoea-predominant irritable bowel syndrome

Abstract

Rifaximin, a non-systemic antibiotic, is efficacious for the treatment of diarrhoea-predominant irritable bowel syndrome (IBS-D). Given the emerging association between the gut microbiota and IBS, this study examined potential effects of rifaximin on the gastrointestinal microbial community in patients with IBS-D. TARGET 3 was a randomised, double-blind, placebo-controlled, phase 3 study. Patients with IBS-D initially received open-label rifaximin 550 mg 3 times daily (TID) for 2 weeks. Patients who responded to the initial treatment and then relapsed were randomised to receive 2 repeat courses of rifaximin 550 mg TID or placebo for 2 weeks, with each course separated by 10 weeks. Stool samples were collected at the beginning and end of open-label treatment, at the beginning and end of the first double-blind treatment, and at the end of the study. As a secondary analysis to the TARGET 3 trial, the composition and diversity of the gut microbiota were assessed, from a random subset of patients, using variable 4 hypervariable region 16S ribosomal RNA gene sequencing. Samples from 103 patients were included. After open-label rifaximin treatment for 2 weeks, 7 taxa (e.g. Peptostreptococcaceae, Verrucomicrobiaceae, Enterobacteriaceae) had significantly lower relative abundance at a 10% false discovery rate threshold. The effects of rifaximin were generally short-term, as there was little evidence of significantly different changes in taxa relative abundance at the end of the study (up to 46 weeks) versus baseline. The results suggest that rifaximin has a modest, largely transient effect across a broad range of stool microbes. Future research may determine whether the taxa affected by rifaximin are causally linked to IBS-D. ClinicalTrials.gov identifier number: NCT01543178.

Keywords: Antibiotic therapy; colonic microflora; diarrhoea; gastrointestinal immune response; irritable bowel syndrome.

Figures

Figure 1.

Study design. Adapted with permission from Lembo, et al. EOS, end of study; TID: 3 times daily, V: clinic visit

Figure 2.

Multidimensional scaling (MDS) ordination at the family level for all samples colored by visit (left panel) and batch (right panel). Batch 1 and batch 2 show substantial overlap, as do batch 3 and batch 4. Tests from 9999 ADONIS permutations yielded a significant difference (p = 0.016) for V3 vs V4 and the effect of patient (p

Figure 3.

Rifaximin induces a small, transient reduction in the relative abundance of multiple taxa. (A) For 74 non‒rare taxa observed in ≥10% of all samples, the mean relative abundance of each taxon is shown in V3 (n = 101) and V4 (n = 102) samples. (B) For the same taxa, the mean relative abundance of taxa is shown in V3 and V11. The symbols in red indicate taxa that were significantly different in paired Wilcoxon test comparisons of log-transformed data (Supplementary Table S3). The black line is the identity line (V3 = V4). V: clinic visit

Figure 4.

The number of taxa observed as different from V3 to V4 (A) and to V11 (B) using smaller sample sizes. At each sample size, the number of patients indicated on the x-axis was subsampled 50 times (without replacement). The mean and SD of the number of taxa that were detected at a 10% FDR by the paired t-test are shown for taxa with relative abundances that were depressed (black) or enhanced (red) in association with rifaximin treatment. FDR: false discovery rate; SD: standard deviation; V: clinic visit

Figure 5.

Comparison between the first (V3–V4) and second (V6–V7) treatment of uncorrected p values for non‒rare taxa for the null hypothesis that patients responded to rifaximin (A) or placebo (B) as evaluated by the paired t-test. The y-axis shows the p value for the null hypothesis that treatment had no effect for each taxa for the V6–V7 time point (second treatment) where patients were treated at this time point with either rifaximin (A) or placebo (B). The x-axis shows the results of evaluation of the null hypothesis for the V3 and V4 time points (first treatment), where all patients were treated with rifaximin. To distinguish the direction of response of each treatment, if the mean after treatment was higher than before treatment, the log p value was multiplied by –1. Only patients for whom the researchers had samples for all 4 time points were included in this analysis (33 patients treated with rifaximin for V6–V7; 30 patients in the placebo group for V6–V7) V: clinic visit