Original article—alimentary tract
Effects of Chenodeoxycholate and a Bile Acid Sequestrant, Colesevelam, on Intestinal Transit and Bowel Function

https://doi.org/10.1016/j.cgh.2009.10.020Get rights and content

Background & Aims

Di-α hydroxy bile salt, sodium chenodeoxycholate (CDC), and bile acid binding have unclear effects on colonic transit in health and disease.

Methods

We performed 2 randomized, double-blind, placebo-controlled studies. In healthy volunteers (20 per group), we evaluated the effects of oral placebo, 500 mg, or 1000 mg of CDC (delayed-release, each given for 4 days) on gastrointestinal and colonic transit. A second trial compared the effects of colesevelam (1.875 g, twice daily) versus placebo in 24 patients (12 per group) with diarrhea-predominant irritable bowel syndrome (IBS-D) on transit, daily bowel frequency and consistency, and colonic mucosal permeability. Serum fasting 7α-hydroxy-4-cholesten-3-one (7αC4) was measured to screen for bile acid malabsorption. Effects of treatments on transit were compared using analysis of covariance with body mass index and 7αC4 as covariates.

Results

In healthy volunteers, CDC significantly accelerated colonic transit (at 24 and 48 hours, P = .01 and P < .0001, respectively), increased stool frequency and ease of passage (both P < .001), and evacuation (P = .02), and decreased stool consistency (P < .001). Four of the 24 IBS-D patients had increased serum 7αC4 levels. In IBS-D, colesevelam modestly affected overall colonic transit (24 h; P = .22). Emptying of the ascending colon took an average of 4 hours longer in patients given colesevelam compared with placebo; treatment effect was associated with baseline serum 7αC4 levels (P = .0025). Colesevelam was associated with greater ease of stool passage (P = .048) and somewhat firmer stool consistency (P = .12). No effects on mucosal permeability or safety were identified.

Conclusions

Sodium chenodeoxycholate in health and colesevelam in IBS-D patients have opposite effects on colonic transit and fecal parameters.

Section snippets

Study Design, Randomization, Medication, and Measurements

We conducted 2 double-blind, placebo-controlled, parallel-group, randomized studies evaluating the effects of oral sodium CDC or placebo, once daily for 4 days, in healthy volunteers. In a second trial, oral colesevelam hydrochloride or placebo was administered for 12 to 14 days in patients with IBS-D. The study was approved by the Mayo Clinic Institutional Review Board and all participants signed informed consent. The trial in patients with IBS-D is listed in ClinicTrials.gov (//www.clinicaltrials.gov/ct2/show/NCT00911612?term=welchol%26rank=2

Participants, Study Conduct, and Completion

All medical records were screened for major exclusion criteria (ie, prior gastrointestinal surgery and concomitant medications). Patients' responses to the bowel disease questionnaire, Hospital Anxiety and Depression scores, and SCL-90 also excluded the presence of significant gastrointestinal symptoms in the healthy volunteers or anxiety, depression, poor quality of life, or psychopathology that could act as confounders in our assessment of the effects of the administered CDC or colesevelam.

Discussion

We used 2 approaches to assess the effect of bile acids on colonic transit and of binding bile acids in the treatment of bowel dysfunction in unselected patients with IBS-D in whom indirect serum markers of bile acid synthesis were measured.

Conclusions

In summary, our studies show that the acceleration of overall colonic transit at 24 and 48 hours induced by sodium CDC is significant and comparable with the effects observed with a variety of pharmacologic agents (eg, prucalopride, lubiprostone, linaclotide) using the same colonic transit measurement. In addition, a subgroup of patients with IBS-D has amelioration of transit in response to colesevelam, fasting serum 7αC4 may predict responsiveness to bile acid binding in patients with IBS-D,

Acknowledgments

The excellent secretarial support of Mrs Cindy Stanislav is gratefully acknowledged.

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    Conflicts of interest These authors disclose the following: the Mayo Clinic has filed a provisional patent application (inventors: Michael Camilleri and Duane Burton) related to this technology (no. 61/143,727). The remaining authors disclose no conflicts.

    Funding Dr Camilleri is supported by a National Institutes of Health grant (DK-54681).

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