Randomized placebo-controlled trial of glutamine for patients with IBS

描述(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。肠易激综合征患者的生活质量明显下降，并利用了大量的医疗资源。IBS患者遭受与腹泻、便秘和/或腹胀相关的慢性腹痛(Verne&Cerda，1997)。最近的几项研究表明，以腹泻为主的肠易激综合征(D-IBS)患者的肠道通透性增加，可能导致慢性胃肠道症状(Dunlop等人，2006；Spiller 2000；2007；周等人，2009 b)。我们实验室最近评估了以腹泻为主的IBS患者，并报告他们的细胞膜通透性增加(周等人，2009b)。我们现在已经获得了口服谷氨酰胺可以恢复这些IBS患者的细胞膜通透性和改善慢性胃肠道症状的初步证据。此前，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)。到目前为止，还没有发表的研究支持使用谷氨酰胺治疗肠易激综合征。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，肯定需要研究测试口服谷氨酰胺是否是治疗肠易激综合征的有效方法。基于这些新的发现，我们假设口服谷氨酰胺可以改善以腹泻为主的IBS患者的IBS症状严重程度，并恢复肠膜通透性。我们建议在100名腹泻型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10g，po，tid与安慰剂10g，tid，为期8周的比较。这将导致以下具体目标：具体目标1：确定口服谷氨酰胺是否会改善IBS患者的IBS症状严重程度评分。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症状严重程度评分的变化。主要的结果衡量标准将是从IBS症状严重程度量表的基线评分开始，对e50治疗的改善或临床显著反应。具体目的2：确定口服谷氨酰胺是否能恢复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，以慢性腹痛为特征，伴随着腹泻和/或便秘的排便习惯改变。有腹泻的IBS患者被证明有一种“渗漏的肠道”，细菌和毒素可能会穿透肠壁，称为膜通透性增加。目前的提案将研究口服谷氨酰胺补充剂作为一种治疗腹泻为主的IBS患者的症状和“肠漏”的方法。

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.