Division of Gastroenterology and Hepatology, Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota.
Division of Gastroenterology and Hepatology, Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota.
Clin Gastroenterol Hepatol. 2020 Dec;18(13):2962-2970.e6. doi: 10.1016/j.cgh.2020.02.027. Epub 2020 Feb 21.
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.
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.
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.
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.
约三分之一的 IBS-D 患者存在胆汁酸（BA）合成或排泄增加。一项开放标签研究显示，考来维仑可改善肠道功能，这与考来维仑对腔内 BA 的螯合作用一致。我们比较了考来维仑与安慰剂对伴有 IBS-D 的 BA 腹泻患者乙状结肠黏膜症状和基因表达模式的影响。
我们于 2017 年 12 月至 2018 年 12 月在一家中心进行了一项双盲、平行组研究，纳入 30 名 IBS-D 患者，这些患者存在 BA 合成或粪便排泄增加的证据。患者被随机（1:1）分为考来维仑组（每天口服 3 次，每次 3 片，每片 625 mg）或安慰剂组，治疗 4 周。在服用考来维仑或安慰剂之前的 8 天和之后的 28 天，患者使用粪便日记记录肠道功能。收集粪便和空腹血清样本，用于分析粪便 BA 和血清 C4 和 FGF19 水平。我们通过闪烁扫描测量结肠转运，通过体内糖探针排泄测量黏膜通透性，并测量直肠乙状结肠活检的 mRNA 水平。所有测量均在基线和治疗的最后一天进行。主要终点是粪便总 BA 浓度和粪便稠度的变化。
与安慰剂相比，考来维仑治疗与粪便中结合型总 BA 排泄显著变化（P <.001）以及血清 C4 和 FGF19 水平显著变化（均 P <.001）相关，与安慰剂相比，脱氧胆酸水平平均增加 10%（P =.07）。与基线相比，考来维仑降低了结肠黏膜 NR1H4 和 P2RY4 的表达，增加了 GPBAR1 的表达。两组间粪便频率和稠度、结肠转运和通透性无显著差异。考来维仑耐受性良好。
在一项随机试验中，我们发现考来维仑增加了总胆汁酸和次级胆汁酸向粪便中的输送、肝 BA 合成以及调节 BA、法尼酯 X 受体和 GPBAR1 受体的结肠黏膜基因的表达。需要更大规模的研究来确定对临床反应的影响。ClinicalTrials.gov 编号：NCT03270085。
