Effects of Colesevelam on Bowel Symptoms, Biomarkers, and Colonic Mucosal Gene Expression in Patients With Bile Acid Diarrhea in a Randomized Trial

Abstract

Background & aims: Approximately one-third of patients with IBS-diarrhea (IBS-D) have increased bile acid (BA) synthesis or excretion. An open-label study showed benefits of colesevelam on bowel functions, consistent with luminal BA sequestration by colesevelam. We compared the effects of colesevelam vs placebo on symptoms and gene expression patterns in the sigmoid colon mucosa in patients with BA diarrhea associated with IBS-D.

Methods: We performed a double-blind, parallel-group study of 30 adults with IBS-D and evidence of increased BA synthesis or fecal excretion, from December 2017 through December 2018 at a single center. Patients were randomly assigned (1:1) to groups given colesevelam (3 tablets, 625 mg each) or matching placebo, orally twice daily for 4 weeks. Stool diaries documented bowel functions for 8 days before and 28 days during colesevelam or placebo. Stool and fasting serum samples were collected for analyses of fecal BAs and serum levels of C4 and FGF19. We measured colonic transit by scintigraphy, mucosal permeability by in vivo excretion of saccharide probes, and mRNA levels in rectosigmoid biopsies. All measurements were made at baseline and on the last days of treatment. The primary endpoints were change in total fecal BA concentration and stool consistency.

Results: Compared with placebo, colesevelam was associated with significant changes in sequestered fecal total BA excretion (P < .001) and serum levels of C4 and FGF19 (both P < .001), and with a mean increase in fecal level of deoxycholic acid (10%; P = .07) compared to placebo. Colesevelam decreased colon mucosal expression of NR1H4 and P2RY4 and increased expression of GPBAR1, compared with baseline. Stool frequency and consistency, colonic transit, and permeability did not differ significantly between groups. Colesevelam was well tolerated.

Conclusions: In a randomized trial, we found that colesevelam increases delivery of total and secondary BAs to stool, hepatic BA synthesis, and colonic mucosal expression of genes that regulate BA, farnesoid X, and GPBAR1 receptors. Larger studies are needed to determine the effects on clinical responses. ClinicalTrials.gov no: NCT03270085.

Keywords: bile acid-binding; cholesterol; hepatic synthesis; sequestrant.

Conflict of interest statement

Conflicts of interest:

Michael Camilleri has received funding from Allergan, NGM Pharmaceuticals and Novartis to study treatment of patients with bile acid disorders and irritable bowel syndrome and from Takeda for studies in gastroparesis; he has no other personal conflicts of interest. The other authors have no conflicts of interest.

Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1.

Experimental design

Figure 2.

CONSORT flow chart and participant disposition

Figure 3.

Effects of colesevelam on stool frequency and consistency in patients with diarrhea-predominant irritable bowel syndrome and bile acid diarrhea. Same color lines within each cohort represent the same patient.

Figure 4.

Expression of genes of interest in sigmoid colonic mucosa comparing two treatment groups for post- / pre-mRNA expression