Phase I: Safety and Tolerance of Lactobactocillus reuteri in Adults

描述(由申请人提供)：将进行一项第一阶段研究，以确定每天10^8CFU的路氏乳杆菌DSM 17938在治疗健康成年人方面的安全性和耐受性。根据FDA的要求，在进行婴儿绞痛研究之前，我们必须进行一项第一阶段研究，展示路氏杆菌(葵花籽油)滴剂在成人中的安全性和有效性。这项研究包括每天5×10^8，5滴罗伊氏杆菌的单剂量；我们将确定在接受推荐制造剂量的受试者中的效果。这项研究将在一年内进行，前两个月是最关键的。在头两个月，患者将参加7次预定的预约，并保持每两周一次的日记、血清化学检查以及3个月和6个月的随访。不良事件将被记录下来。我们已于2009年4月24日收到IRB对该项目的最终批准(#08-0266)。这项研究的结果预计将显示安全性和耐受性，并将使FDA能够批准对患有绞痛(和其他疾病)的婴儿进行路氏杆菌的研究。 长期目标是阐明儿童(0-18岁)肠道疾病的机制，并确定可行的治疗方法。与美国国立卫生研究院的任务相关，这项建议被设计为健康成人测试路支杆菌的有效性和耐受性的第一阶段研究。但此外，我们还将确定LR对PMA加离子霉素刺激后外周血单个核细胞(PBMC)中细胞因子水平的影响；人PBMC中TLR2和TLR4的表达；人PBMC中Treg细胞的数量；以及粪便钙保护蛋白检测。我们还希望对胃肠道疾病的益生菌治疗干预进行未来的研究。还需要更多的信息来描述复杂的肠道菌群免疫系统与新生儿胃肠疾病(如绞痛)相关的特征。 公共卫生相关性： 我们的研究将为益生菌的安全性提供证据，更具体地说，是L。有证据可以确定胃肠道疾病的早期发病，如肠易激综合征。鲁氏乳杆菌可能具有预防急性腹泻和过敏性疾病的作用。我们将证明罗伊氏杆菌在健康成人中的治疗是否显示出有效性和耐受性。此外，如果从生理上讲，路支杆菌对人类系统有自身免疫作用，更具体地说，是Toll样受体和细胞因子，识别特定菌株是促炎还是抗炎。可以确定一种特定益生菌的机制及其对胃肠道系统的影响。

DESCRIPTION (provided by applicant): A Phase 1 Study will be conducted in order to determine safety and tolerability of L. reuteri DSM 17938, 10^8 CFU daily, in treating healthy adults. It is required by the FDA that we conduct a Phase 1 study showing the safety and efficacy of L. reuteri (in sunflower oil) drops in adults before conducting our infant colic study. The study includes a single dose 5 x 10^8, 5 drops daily of L. reuteri; and we will determine the effects, if any, in subjects receiving recommended manufactured dose. This study will be conducted over a one year period with the first two months being the most critical. During the first two months, patients will attend 7 scheduled appointments and maintain bi-weekly diaries, serum chemistries, and 3 and 6-month follow-up visits. Adverse events will be recorded. We have received final IRB approval of this project on 4/24/2009 (#08-0266). Results of this study are expected to show safety and tolerability and will enable the FDA to approve studies of L. reuteri in infants with colic (and other illnesses). The long term goals are to elucidate mechanisms of intestinal disease in children ages (0 - 18 years) and identify viable treatments. Relevant to the NIH mission, this proposal is designed as a Phase I Study in Healthy Adults testing the efficacy and tolerability of L. reuteri. But in addition, we will determine effects of LR on baseline and stimulated levels of a cytokine panel in peripheral blood mononuclear cells (PBMC) after stimulation by PMA plus ionomycin; TLR2 and TLR4 expression in human PBMC; number of Treg cells in human PBMC; and fecal calprotectin assay. We also hope to conduct future research on probiotic therapeutic interventions in gastrointestinal diseases. Much more information is needed to characterize the complex gut microflora-immune system in association with gastrointestinal conditions in newborns such as colic. Public Health Relevance: Our studies would provide evidence for safety of probiotics, more specifically l. reuteri. Evidence could identify the early onset of gastrointestinal conditions, such as Irritable Bowel Syndrome. L. reuteri could possibly assist in the prevention of acute diarrhea and allergic disease. We will demonstrate if treatment of l. reuteri in healthy adults shows efficacy and tolerability. Also if physiologically, l. reuteri has an autoimmune effect on the human system, more specifically toll like receptors and cytokines identifying the specific strain as pro-inflammatory or anti-inflammatory. A mechanism could be identified for a particular probiotic and its effects on the gastrointestinal system.