Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Biomedical Statistics and Informatics, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Gastroenterology. 2010 Nov;139(5):1549-58, 1558.e1. doi: 10.1053/j.gastro.2010.07.052. Epub 2010 Aug 4.
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).
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.
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).
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.
胆酸钠（CDC）可加速健康人群的结肠转运。本研究旨在探讨胆酸钠在以结肠传输缓慢为特征的便秘型肠易激综合征（IBS-C）患者中的药效学（结肠传输、肠道功能）和药物遗传学。
在一项双盲安慰剂对照研究中，36 名女性 IBS-C 患者被随机分为安慰剂、500mg 胆酸钠和 1000mg 胆酸钠延迟释放口服制剂治疗组，治疗时间为 4 天。我们评估了胃肠道和结肠传输、粪便特征以及传输与空腹血清 7αC4（胆汁酸合成的替代物）和 FGF19（胆汁酸合成的负调节剂）水平之间的相关性。分析了涉及胆汁酸合成调节的候选基因多态性，以评估 IBS-C 患者和 57 名健康志愿者中基因多态性对胆酸钠对传输影响的遗传影响。
与安慰剂组相比，胆酸钠组的总结肠传输和升结肠排空时间（AC t(½)）显著加快（P =.005 和 P =.028）。与安慰剂组相比，胆酸钠组的粪便稠度更松散（P =.003）、粪便频率增加（P =.018）、排便更容易（P =.024）。最常见的副作用是下腹部痉挛/疼痛（P =.01）。空腹血清 7αC4（而非 FGF19）与结肠传输呈正相关（r(s) = 0.749，P =.003，安慰剂组）。FGFR4 基因的遗传变异与对胆酸钠的 AC t(½)反应相关（未经校正 P =.015）；αKlothoβ 变体基于患者亚组显示出基因-治疗相互作用（未经校正 P =.0088）。
胆酸钠可加速女性 IBS-C 患者的结肠转运并改善肠道功能。胆汁酸合成率影响结肠传输。胆汁酸合成负反馈抑制的遗传变异可能影响胆酸钠介导的结肠传输加速。
