Therapeutically Modified Gut Bacteria for Treatment of Obesity

用于治疗肥胖症的治疗性修饰肠道细菌

• 批准号: 8843716
• 负责人: SEAN Stephen DAVIES
• 金额: $ 35.94万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8843716
• 关键词: Acyltransferase; Adherence; Adverse effects; American; Animals; Arabidopsis; Award; Bacteria; Behavior; Biochemical; Body Composition; Body Weight decreased; Body fat; Calories; Calorimetry; Cardiovascular Diseases; Cells; Cholecystokinin; Consumption; Data; Diabetes Mellitus; Diet; Dietary Intervention; Disease; Eating; Effectiveness; Energy Metabolism; Engineering; Enteroendocrine Cell; Escherichia coli; Exposure to; Family; Fatty acid glycerol esters; Feedback; Feeding behaviors; Food; Food Energy; Genetic; Health; Hormones; Human; Hunger; Individual; Inflammation; Intake; Intestines; Life Style; Lipids; Measures; Mediating; Medical; Metabolic Diseases; Metabolism; Methods; Modeling; Molecular; Molecular Mechanisms of Action; Monitor; Mus; Myocardial Infarction; Neurons; Neurosecretory Systems; Obesity; PPAR alpha; Pharmaceutical Preparations; Phosphatidylethanolamine; Predisposition; Probiotics; Process; Regimen; Rewards; Satiation; Signal Transduction; Signaling Molecule; Testing; Therapeutic; Treatment Protocols; United States; United States National Institutes of Health; Weight; Withholding Treatment; drinking water; energy balance; feeding; follow-up; food surveillance; glucagon-like peptide 1; glucose monitor; glucose tolerance; gut microbiota; improved; novel strategies; obesity treatment; prevent; public health relevance; receptor; response; success; treatment strategy

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.

描述（由申请人提供）：包括肥胖、糖尿病和心血管疾病在内的代谢紊乱在美国已变得普遍。不幸的是，由于限制食物热量时不能满足饥饿感以及食物和血糖监测的劳动密集性，导致代谢紊乱的有效医疗和生活方式治疗方案的依从性往往较差。因此，迫切需要简单的治疗策略，不需要忽视饥饿驱动或进行劳动密集型监测和药物治疗。 由于肠道微生物群的组成最近被证明会影响代谢疾病的易感性，因此我们采取了一种新的策略，对肠道微生物群进行基因改造以分泌饱腹感因子。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，而不需要接受治疗的个体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，当给喂食高脂肪饮食的小鼠喂食经修饰可分泌 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，在停止施用修饰细菌后，这种针对肥胖的保护作用持续了 4 周的随访期，这表明至少实现了一定水平的稳定定植。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。 该提案的目的是：确定用 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可口的饮食或遗传而引起的已经存在的肥胖。 确定 NAPE 分泌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 分泌细菌在肠道中作用的分子机制。 如果我们成功完成这些研究，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类中取得成功，并且我们将更好地了解肠道微生物群如何与其宿主相互作用以调节宿主代谢过程。