ABSTRACT
BACKGROUND: Protein products of klothoß (KLB) and fibroblast growth factor receptor 4 (FGFR4) impact fibroblast growth factor 19-mediated feedback inhibition of hepatic bile acid (BA) synthesis. Variants of KLB and FGFR4 influence colonic transit (CT) in diarrhea-predominant irritable bowel syndrome (IBS-D). AIM: The purpose of this study was to test the hypothesis that colesevelam's slowing effects on CT in IBS-D patients is influenced by genetic variants in KLB and FGFR4. METHODS: We examined pharmacogenetic effects of KLB and FGFR4 coding variants (SNPs) on scintigraphic CT response to the BA sequestrant, colesevelam 1.875 g b.i.d. versus placebo (PLA) for 14 days in 24 female IBS-D patients. RESULTS: FGFR4 rs351855 and KLB rs497501 were associated with differential colesevelam effects on ascending colon (AC) half-emptying time (t(1/2), P = 0.046 and P = 0.085 respectively) and on overall CT at 24 h (geometric center, GC24: P = 0.073 and P = 0.042, respectively), with slower transit for rs351855 GA/AA (but not for GG) and rs497501 CA/AA (but not CC) genotypes. CONCLUSION: FGFR4 rs351855 and KLB rs4975017 SNPs may identify a subset of IBS-D patients with beneficial response to colesevelam.
Subject(s)
Allylamine/analogs & derivatives , Bile Acids and Salts , Diarrhea , Gastrointestinal Transit/genetics , Irritable Bowel Syndrome , Membrane Proteins/genetics , Receptor, Fibroblast Growth Factor, Type 4/genetics , Adult , Allylamine/administration & dosage , Allylamine/pharmacokinetics , Anticholesteremic Agents/administration & dosage , Anticholesteremic Agents/pharmacokinetics , Bile Acids and Salts/biosynthesis , Bile Acids and Salts/genetics , Biotransformation , Colesevelam Hydrochloride , Colon/metabolism , Colon/physiopathology , Diarrhea/drug therapy , Diarrhea/etiology , Diarrhea/genetics , Diarrhea/physiopathology , Feedback, Physiological/drug effects , Female , Fibroblast Growth Factors/metabolism , Humans , Irritable Bowel Syndrome/complications , Irritable Bowel Syndrome/drug therapy , Irritable Bowel Syndrome/genetics , Irritable Bowel Syndrome/physiopathology , Klotho Proteins , Pharmacogenetics , Polymorphism, Single NucleotideABSTRACT
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); αKlothoß 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.
Subject(s)
Chenodeoxycholic Acid/pharmacokinetics , Gastrointestinal Agents/pharmacokinetics , Gastrointestinal Transit/physiology , Irritable Bowel Syndrome/drug therapy , Administration, Oral , Adult , Bile Acids and Salts/biosynthesis , Chenodeoxycholic Acid/administration & dosage , Cholestenones/metabolism , Chromatography, High Pressure Liquid , DNA/genetics , Delayed-Action Preparations , Dose-Response Relationship, Drug , Double-Blind Method , Enzyme-Linked Immunosorbent Assay , Female , Fibroblast Growth Factors/biosynthesis , Fibroblast Growth Factors/genetics , Follow-Up Studies , Gastrointestinal Agents/administration & dosage , Gastrointestinal Transit/drug effects , Gene Frequency , Genetic Variation , Genotype , Humans , Irritable Bowel Syndrome/genetics , Irritable Bowel Syndrome/metabolism , Mass Spectrometry , Middle Aged , Polymorphism, Genetic , Receptor, Fibroblast Growth Factor, Type 4/biosynthesis , Receptor, Fibroblast Growth Factor, Type 4/genetics , Retrospective Studies , Treatment OutcomeABSTRACT
BACKGROUND & AIMS: Di-alpha 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 7alpha-hydroxy-4-cholesten-3-one (7alphaC4) was measured to screen for bile acid malabsorption. Effects of treatments on transit were compared using analysis of covariance with body mass index and 7alphaC4 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 7alphaC4 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 7alphaC4 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.