Randomized placebo-controlled trial of glutamine for patients with IBS

描述（由申请人提供）：肠易激综合征（IBS）是一种常见的胃肠道疾病，估计影响20%的美国人口。IBS患者的生活质量显著下降，并使用大量的医疗保健资源。IBS患者患有与腹泻、便秘和/或腹胀相关的慢性腹痛（Verne和塞尔达，1997）。最近的几项研究表明，以大肠杆菌为主的IBS（D-IBS）患者具有增加的肠通透性，这可能导致慢性胃肠道症状（Dunlop等人，2006; Spiller 2000; 2007; Zhou等人，2009年b）。我们的实验室最近评估了以大肠杆菌为主的IBS患者，并报告他们的膜通透性增加（Zhou et al，2009 b）。我们现在已经获得了初步的证据，口服谷氨酰胺补充剂恢复膜通透性，改善这些IBS患者的慢性胃肠道症状。以前，已经确定谷氨酰胺缺乏可能导致膜通透性增加，补充谷氨酰胺可以恢复肠膜通透性（Souba，1990; Klimberg & Souba，1990; Labow & Souba，2000）。迄今为止，尚无已发表的研究支持谷氨酰胺用于肠易激综合征。然而，鉴于我们的初步数据和谷氨酰胺对胃肠道的作用机制，研究测试口服谷氨酰胺是否是肠易激综合征的有效治疗是绝对必要的。基于这些新的发现，我们假设口服谷氨酰胺补充剂将改善肠易激综合征症状严重程度量表，并恢复肠粘膜通透性在肠易激综合征患者为主。我们建议在100例以肠易激综合征为主的IBS患者中进行一项随机、双盲、安慰剂对照的临床试验，研究谷氨酰胺10 g po tid与安慰剂10 g po tid相比，持续8周。这将导致以下具体目标：具体目标1：确定口服谷氨酰胺补充剂是否会改善IBS患者的IBS症状严重程度量表。为了实现这一目标，我们将测量口服谷氨酰胺补充剂或安慰剂治疗后IBS症状严重程度量表的变化。主要结局指标将是IBS症状严重程度量表上e50相对于基线评分的改善或临床显著的治疗应答。具体目标2：确定口服谷氨酰胺补充剂是否会恢复IBS患者的肠膜通透性。为了实现这一目标，我们将测量口服谷氨酰胺补充剂或安慰剂治疗后肠膜通透性的变化。 公共卫生相关性：肠易激综合征（IBS）是一种常见的胃肠道疾病，其特征是与腹泻和/或便秘的排便习惯改变相关的慢性腹痛。患有腹泻的IBS患者已被证明具有"肠漏"，其中细菌和毒素可穿透肠壁，称为膜通透性增加。目前的建议将调查口服谷氨酰胺补充剂作为治疗症状和“漏肠”在肠易激综合征患者占主导地位。

DESCRIPTION (provided by applicant): Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that is estimated to affect 20% of the US population. IBS patients have significantly decreased quality of life and utilize large amounts of health care resources. IBS patients suffer from chronic abdominal pain associated with diarrhea, constipation, and/or bloating (Verne & Cerda, 1997). Several recent studies have shown that diarrhea-predominant IBS (D-IBS) patients have increased intestinal permeability that may lead to chronic gastrointestinal symptoms (Dunlop et al., 2006; Spiller 2000; 2007; Zhou et al., 2009b). Our laboratory recently evaluated diarrhea-predominant IBS patients and reported that they have increased membrane permeability (Zhou et al, 2009b). We now have obtained preliminary evidence that oral glutamine supplementation restores membrane permeability and improves chronic gastrointestinal symptoms in these IBS patients. Previously, it has been well established that deficiencies in glutamine may lead to increased membrane permeability and supplementation with glutamine can restore intestinal membrane permeability (Souba,1990; Klimberg & Souba, 1990; Labow & Souba, 2000). There are no published studies to date to support the use of glutamine for Irritable Bowel Syndrome. However, given our preliminary data and the mechanisms of action of glutamine on the gastrointestinal tract, research testing whether oral glutamine is an effective therapy in Irritable Bowel Syndrome is definitely needed. Based on these new findings, we hypothesize that oral glutamine supplementation will improve the IBS Symptom Severity Scale and restore intestinal membrane permeability in diarrhea-predominant IBS patients. We propose to conduct a randomized, double-blind, placebo-controlled clinical trial studying glutamine 10 g po tid compared to placebo 10 g po tid for 8 weeks in 100 diarrhea-predominant IBS patients. This will lead to the following specific aims: Specific Aim 1: To determine if oral glutamine supplementation will improve the IBS Symptom Severity Scale in IBS patients. To accomplish this aim, we will measure the change in the IBS Symptom Severity Scale following treatment with either oral glutamine supplementation or placebo. The primary outcome measure will be an improvement or clinically significant response to treatment of e50 from the baseline score on the IBS Symptom Severity Scale. Specific Aim 2: To determine if oral glutamine supplementation will restore intestinal membrane permeability in IBS patients. To accomplish this aim, we will measure the change in the intestinal membrane permeability following treatment with either oral glutamine supplementation or placebo. PUBLIC HEALTH RELEVANCE: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by chronic abdominal pain associated with an alteration in bowel habits with diarrhea and/or constipation. IBS patients with diarrhea have been shown to have a "leaky gut" in which bacteria and toxins may penetrate the gut wall, termed increased membrane permeability. The current proposal will investigate oral glutamine supplementation as a treatment of symptoms and "leaky gut" in diarrhea-predominant IBS patients.