Therapeutically Modified Gut Bacteria for Treatment of Obesity

描述（由申请人提供）：代谢性疾病包括肥胖、糖尿病和心血管疾病在美国已经变得很普遍。不幸的是，对代谢紊乱的有效医疗和生活方式治疗方案的坚持往往很差，因为在限制食物卡路里和食物和葡萄糖监测的劳动强度时，不能满足饥饿感。因此，不需要忽视饥饿驱动或进行劳动密集型监测和药物治疗的简单治疗策略是至关重要的。由于肠道菌群组成最近被证明会影响对代谢性疾病的易感性，我们已经寻求了一种新的策略，通过基因修饰肠道菌群来分泌饱腹感因子。由于肠道细菌的稳定性，这种策略可以提供高度可持续的食物摄入量减少，而不需要治疗个体忽略饥饿驱动或执行劳动密集型药物治疗方案。我们的初步数据表明，当喂食高脂肪饮食的小鼠给予大肠杆菌Nissle 1917，这些小鼠可以分泌n -酰基磷脂酰乙醇胺（NAPE），这些小鼠可以防止肥胖。重要的是，这种对肥胖的保护在停止给药后的4周随访期间持续存在，这表明至少达到了一定程度的稳定定植。这些令人兴奋的结果证明了这种方法的可行性，但也提出了一些重要的问题，这些问题的答案将帮助我们了解这种策略是否可以用于治疗人类肥胖。这项提议的目的是：确定NAPE分泌细菌治疗所提供的保护持续时间，以及这是否会逆转由于高度美味的饮食或遗传而产生的已经建立的肥胖。确定NAPE分泌菌对调节摄食行为的短期和长期神经元过程的影响。确定这些NAPE分泌菌在肠道中的作用分子机制。如果我们成功地完成这些研究，我们将知道这种重塑肠道微生物群的策略是否可能在肥胖人群中成功，我们将更好地了解肠道微生物群如何与宿主相互作用以调节宿主代谢过程。

DESCRIPTION (provided by applicant): Metabolic disorders including obesity, diabetes, and cardiovascular disease have become widespread in the United States. Unfortunately, adherence to effective medical and lifestyle treatment regimens for metabolic disorders is often poor as the result of poorly satisfying the hunger drive when limiting food calories and the labor intensiveness of food and glucose monitoring. Therefore, simple treatments strategies that do not require ignoring hunger drive or performing labor intensive monitoring and medication are vitally needed. Because gut microbiota composition has recently been shown to impact susceptibility to metabolic disease, we have pursued a novel strategy of genetically modifying the gut microbiota to secrete satiety factors. Because of the stability of gut bacteria, this stratgy may provide highly sustainable reductions in food intake without requiring treated individuals to ignore hunger drive or to perform labor intensive medication regimens. Our preliminary data demonstrate that when mice fed a high fat diet were administered E. coli Nissle 1917 modified to secrete N-acylphosphatidylethanolamine (NAPE), these mice were protected against obesity. Importantly, this protection against obesity was sustained for the 4 week follow-up period after stopping administration of the modified bacteria demonstrating that at least some level of stable colonization was achieved. These exciting results demonstrate the feasibility of this approach, but also raise important questions, the answers to which will help us understand whether this strategy could be used to treat human obesity. The aims of this proposal are: To determine the duration of protection afforded by treatment with NAPE secreting bacteria and if this will reverse already established obesity that arises both as the result of highly palatable diets or genetics. To determine the effect of the NAPE secreting bacteria on both short and long term neuronal processes regulating feeding behavior. To determine the molecular mechanism of action in the intestine of these NAPE secreting bacteria. If we successfully complete these studies, we will know if this strategy to remodel the gut microbiota is likely to \be successful i obese humans and we will have a better understanding of how gut microbiota interact with their host to regulate host metabolic processes.