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

项目总结 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)的标准方法与UP的高复发率相关 至65%，具体取决于既往患病人数。丙氨酰谷氨酰胺预防艰难梭菌毒素诱导 动物回肠肠道细胞系迁移、增殖、分泌及组织病理学的损害 组织，并增加了体外和体内的细胞凋亡。我们已经证明，在CDI的小鼠模型中，丙氨酰- 补充谷氨酰胺显著减少腹泻、体重减轻、组织病理学、复发和死亡 万古霉素处理的小鼠。一项对人类的小型先导性研究表明，丙氨酰谷氨酰胺可以防止复发 疾病在CDI治疗后长达6个月。我们假设补充丙氨酰-谷氨酰胺会 改善人类CDI的治疗结果。为了证明这一假设，我们计划进行一项 随机、双盲、安慰剂对照试验。这个项目的具体目标有三个方面。首先，我们将 口服丙氨酰谷氨酰胺预防患者复发和死亡的最佳剂量 用标准的艰难梭菌抗菌剂治疗。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 接受CDI标准治疗的患者的炎症、屏障功能和肠道菌群。这 研究提案将允许临床试验的严格、安全和富有成效的表现，以证明 丙氨酰谷氨酰胺对人类疾病的益处，潜在地引入了一种治疗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.