Chenodeoxycholate in females with irritable bowel syndrome-constipation: a pharmacodynamic and pharmacogenetic analysis

Abstract

Background & aims: Sodium chenodeoxycholate (CDC) accelerates colonic transit in health. Our aim was to examine pharmacodynamics (colonic transit, bowel function) and pharmacogenetics of CDC in constipation-predominant irritable bowel syndrome (IBS-C).

Methods: In a double-blind placebo-controlled study, 36 female patients with IBS-C were randomized to treatment with delayed-release oral formulations of placebo, 500 mg CDC, or 1000 mg CDC for 4 days. We assessed gastrointestinal and colonic transit, stool characteristics, and associations of transit with fasting serum 7αC4 (surrogate of bile acid synthesis) and FGF19 (negative regulator of bile acid synthesis) levels. Candidate genetic polymorphisms involved in regulation of bile acid synthesis were analyzed in the 36 patients with IBS-C and 57 healthy volunteers to assess genetic influence on effects of CDC on transit.

Results: Overall colonic transit and ascending colon emptying (AC t(½)) were significantly accelerated in the CDC group compared with placebo (P = .005 and P = .028, respectively). Looser stool consistency (P = .003), increased stool frequency (P = .018), and greater ease of passage (P = .024) were noted with CDC compared with placebo. The most common side effect was lower abdominal cramping/pain (P = .01). Fasting serum 7αC4 (but not FGF19) was positively associated with colonic transit (r(s) = 0.749, P = .003, placebo group). Genetic variation in FGFR4 was associated with AC t(½) in response to CDC (uncorrected P = .015); αKlothoβ variant showed a gene-by-treatment interaction based on patient subgroup (uncorrected P = .0088).

Conclusions: CDC accelerates colonic transit and improves bowel function in female patients with IBS-C. The rate of bile acid synthesis influences colonic transit. Genetic variation in negative feedback inhibition of bile acid synthesis may affect CDC-mediated acceleration of colonic transit.

Figure 1

Illustration of bile acid enterohepatic circulation and homeostasis and relevant proteins with genetic variation tested in this study.

Figure 2

Study flow chart and patient demographics.

Figure 3

Effects of placebo or CDC on overall colonic transit and time for AC emptying. ^*Overall significant difference among placebo and CDC groups (ANCOVA P = .005 for GC 24 and P = .028 for AC t_½).

Figure 4

Correlation between gastric emptying and colonic transit for each treatment group.

Figure 5

Effects of treatment on AC colon emptying in relation to genotype. The upper panel shows results by genotype in the entire cohort (health and IBS-C). The lower panel shows results for KLB for the different phenotype subgroups and illustrates the genotype-by-treatment-by-phenotype interaction.