Effects of alanyl-glutamine supplementation on C. difficile associated diarrhea

描述(申请人提供)：艰难梭菌是抗生素相关性腹泻和医院感染的主要原因。抗生素治疗是治疗艰难梭菌感染(CDI)的标准方法，根据既往疾病的数量，复发率高达65%。丙氨酰谷氨酰胺可预防艰难梭菌毒素引起的肠道细胞迁移和增殖、动物组织分泌和组织病理学的损害，并增加体内外的细胞凋亡。最近，我们已经证明，在CDI小鼠模型中，补充丙氨酰谷氨酰胺显著减少了万古霉素治疗小鼠的腹泻、体重减轻、组织病理学、复发和死亡。我们假设补充丙氨酰-谷氨酰胺将改善人类CDI的治疗结果。为了证明这一假设，计划中的临床试验将有两个具体目标。首先，我们将测试口服补充丙氨酰-谷氨酰胺对接受标准艰难梭菌药物治疗的患者的腹泻持续时间、复发和死亡的影响。其次，我们将测试丙氨酰谷氨酰胺对接受CDI标准治疗的患者的肠道炎症、屏障功能和肠道菌群的影响。为了充分准备临床试验，这项建议将有以下具体目标：(1)建立和准备运行临床试验的研究团队；(2)开发临床试验所需的文件；以及(3)开发符合以下条件的工具 临床试验评估所需的。计划拨款将使临床试验具有严格、安全、有效和富有成效的表现，以证明丙氨酰-谷氨酰胺的益处。 在人类疾病中，潜在地引入了一种治疗CDI的新方法。

DESCRIPTION (provided by applicant): C. difficile is a leading cause of antibiotic-associated diarrhea and nosocomial infection. Antibiotic treatment is the standard approach in managing C. difficile infection (CDI) and is associated with recurrence rates of up to 65% depending on the number of previous disease. Alanyl-glutamine prevents C. difficile toxin-induced impairment of cell migration and proliferation in intestinal cell lines, secretion and histopathology in animal ieal tissues, and increased apoptosis in vitro and in vivo. Recently, we have shown that in the mouse model of CDI, alanyl-glutamine supplementation significantly reduced diarrhea, weight loss, histopathology, relapse and deaths in vancomycin-treated mice. We hypothesize that supplementation with alanyl-glutamine will improve outcomes of treatment of CDI in humans. To prove this hypothesis, the planned clinical trial will have 2 specific aims. First, we shall test te effect of oral supplementation with alanyl-glutamine on duration of diarrhea, recurrence and deaths in patients treated with standard anti-C.difficile agents. Secondly, we shall test the effec of alanyl-glutamine on intestinal inflammation, barrier function and gut flora in patients undergoing standard treatment for CDI. To adequately prepare for the clinical trial, this proposal will have the following specific aims: (1) Establish and prepare the research team to run the clinical trial; (2) Develop documents needed for the clinical trial; and (3) Develop tools that are required for the evaluation of the clinical trial. The planning grant will allow for a rigorous, sae, effective and productive performance of the clinical trial to prove the benefit of alanyl-glutamine in human disease, potentially introducing a novel approach to treatment of CDI.