Alanyl-glutamine supplementation of standard treatment for C. difficile infection

项目摘要 C.艰难梭菌（difficile）是腹泻相关性腹泻和医院感染的主要原因。抗生素治疗是 管理C.艰难梭菌感染（CDI），并与高复发率， 65%，取决于既往疾病的数量。丙氨酰-谷氨酰胺阻止C.艰难梭菌毒素诱导 肠细胞系细胞迁移和增殖障碍、动物回肠分泌和组织病理学 组织，并在体外和体内增加细胞凋亡。我们已经证明，在CDI小鼠模型中，丙氨酰- 谷氨酰胺补充剂显著减少了腹泻，体重减轻，组织病理学，复发和死亡， 万古霉素处理的小鼠。一项小型的人体初步研究表明，丙氨酰谷氨酰胺可以预防复发性 CDI治疗后6个月。我们假设补充丙氨酰谷氨酰胺 改善人类CDI治疗结果。为了证明这一假设，我们计划进行一次 随机双盲安慰剂对照试验。该项目的具体目标有三个方面。一要 确定口服丙氨酰谷氨酰胺预防患者复发和死亡的最佳剂量 用标准的抗艰难梭菌药物治疗。其次，我们将证明口服丙氨酰的安全性- 补充谷氨酰胺。第三，我们将测试丙氨酰谷氨酰胺对肠道的影响， 炎症、屏障功能和肠道植物群。这 研究提案将允许进行严格、安全和富有成效的临床试验，以证明 丙氨酰-谷氨酰胺在人类疾病中的益处，可能引入一种治疗CDI的新方法。

PROJECT SUMMARY C. difficile is the 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 high 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 ileal tissues, and increased apoptosis in vitro and in vivo. 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. A small pilot study in human suggests that alanyl-glutamine may prevent recurrent disease up to 6 months after CDI treatment. We hypothesize that supplementation with alanyl-glutamine will improve outcomes of treatment of CDI in humans. To prove this hypothesis, we plan to conduct a randomized, double-blinded, placebo-controlled trial. The specific aims of this project are 3-fold. First, we shall determine the optimal dose of oral alanyl-glutamine on preventing recurrence and deaths in patients treated with standard anti-C.difficile agents. Secondly, we shall demonstrate the safety of oral alanyl- glutamine supplementation. And thirdly, we shall test the effect of alanyl-glutamine on intestinal inflammation, barrier function and gut flora in patients undergoing standard treatment for CDI. This research proposal will allow for a rigorous, safe 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.