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.

Methods

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.

Results

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.

Conclusions

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

中文翻译：

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在一项随机试验中考来维仑对胆汁酸腹泻患者的肠道症状、生物标志物和结肠粘膜基因表达的影响。

背景与目标

大约三分之一的 IBS 腹泻 (IBS-D) 患者的胆汁酸 (BA) 合成或排泄增加。一项开放标签研究表明，考来维仑对肠道功能有益，这与考来维仑对肠腔 BA 的隔离作用一致。我们比较了考来维仑与安慰剂对 IBS-D 相关 BA 腹泻患者乙状结肠黏膜症状和基因表达模式的影响。

方法

我们对 2017 年 12 月至 2018 年 12 月在单个中心对 30 名患有 IBS-D 且 BA 合成或粪便排泄增加的证据进行了双盲、平行组研究。患者被随机分配 (1:1) 到服用考来维仑（3 片，每片 625 毫克）或匹配的安慰剂组，每天口服两次，持续 4 周。粪便日记记录了考来维仑或安慰剂治疗前 8 天和治疗期间 28 天的肠道功能。收集粪便和空腹血清样品用于分析粪便 BA 和 C4 和 FGF19 的血清水平。我们通过闪烁扫描法测量了结肠传输，通过体内糖探针的分泌测量了粘膜通透性，以及直肠乙状结肠活检中的 mRNA 水平。所有测量均在基线和治疗的最后几天进行。主要终点是总粪便 BA 浓度和粪便稠度的变化。

结果

与安慰剂相比，考来维仑与隔离粪便总 BA 排泄量 ( P < .001) 和血清 C4 和 FGF19 水平（均P < .001）以及粪便中脱氧胆酸水平平均增加相关 (10 %；P = .07) 与安慰剂相比。与基线相比，考来维仑降低了NR1H4和P2RY4的结肠粘膜表达并增加了GPBAR1 的表达。大便频率和稠度、结肠传输和通透性在组间没有显着差异。考来维仑的耐受性良好。

结论

在一项随机试验中，我们发现考来维仑增加了总 BA 和继发性 BA 向粪便的递送、肝脏 BA 的合成以及调节 BA、法尼醇 X 和 GPBAR1 受体的基因的结肠粘膜表达。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