Therapeutically Modified Gut Bacteria for Treatment of Obesity

描述(申请人提供)：包括肥胖、糖尿病和心血管疾病在内的代谢紊乱在美国已经变得很普遍。不幸的是，由于限制食物卡路里时的饥饿感以及食物和血糖监测的劳动密集度，代谢紊乱的有效医疗和生活方式治疗方案的坚持性往往很差。因此，非常需要简单的治疗策略，既不需要忽视饥饿驱动力，也不需要进行劳动密集型监测和药物治疗。由于肠道微生物区系的组成最近被证明影响代谢性疾病的易感性，我们一直在寻求一种新的策略，通过遗传修饰肠道微生物区系来分泌饱腹感因子。由于肠道细菌的稳定性，这一策略可能会提供高度可持续的食物摄入量减少，而不需要接受治疗的个人忽视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，当喂食高脂饮食的小鼠服用经过改造以分泌N-酰基磷脂酰乙醇胺(NAPE)的大肠杆菌Nissle 1917时，这些小鼠可以免受肥胖的影响。重要的是，这种对肥胖的保护在停止给药后的4周内持续存在，这表明至少实现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，这些问题的答案将有助于我们理解这种策略是否可以用于治疗人类肥胖症。这项提议的目的是：确定使用分泌NAPE的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基因导致的已经确定的肥胖。确定分泌NAPE的细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分泌菌在肠道中的分子作用机制。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区系的策略是否有可能在肥胖者身上取得成功，我们将更好地了解肠道微生物区系如何与宿主相互作用来调节宿主的代谢过程。

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.