Microbiome-Vagal-Brain signaling: impact on the reward system and food intake

微生物组-迷走神经-大脑信号传导：对奖励系统和食物摄入的影响

• 批准号: 9166919
• 负责人: Claire de La Serre
• 金额: $ 19.64万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9166919
• 关键词: Ablation; Adverse effects; Affect; Afferent Neurons; Animals; Anxiety; Appetite Stimulants; Appetitive Behavior; Bacteria; Behavior; Blood - brain barrier anatomy; Body Weight decreased; Brain; Brain Stem; Brain region; Capsaicin; Cell Nucleus; Chronic; Communication; Corpus striatum structure; Cues; Data; Development; Dopamine; Dorsal; Drug Design; Eating; Energy Intake; Etiology; Exhibits; Fatty acid glycerol esters; Food; Food Preferences; Gastrointestinal tract structure; Gene Expression; Germ-Free; High Fat Diet; Hyperphagia; Hypersensitivity; Hypothalamic structure; Inflammation; Infusion procedures; Intake; Knowledge; Link; Mediating; Microdialysis; Motivation; Mus; Neurons; Neuropeptides; Nucleus Accumbens; Obesity; Pathway interactions; Phenotype; Physiology; Population; Probiotics; Prosencephalon; Proteins; Rattus; Regulation; Research; Rewards; Ribosomes; Role; Route; Satiation; Signal Transduction; Specificity; Stimulus; System; Techniques; Testing; Vagotomy; Vagus nerve structure; Weight Gain; Work; base; feeding; food addiction; food consumption; gastrointestinal; gut microbiota; hedonic; innovation; interest; mesolimbic system; microbiome; microbiota; neurochemistry; neurodevelopment; novel; pathogenic bacteria; pleasure; prebiotics; preference; prevent; response; tool

ABSTRACT There is substantial evidence linking the gastrointestinal (GI) microbiota and obesity. Germ free (GF) mice do not gain weight when fed a high fat (HF) diet. Microbiota composition rapidly changes in response to HF feeding and colonization of GF animals with an “obese” microbiota results in recapitulation of the donor phenotype. This data suggest that an unfavorable microbiota is sufficient to cause obesity, however the mechanisms and pathways remain unclear. Excessive energy intake is the main cause for obesity. Food intake is regulated by homeostatic and hedonic cues. Hedonic eating refers to consumption of food “for pleasure”, in the absence of or beyond energy needs and is linked to reward signaling in the forebrain. Food consumption, particularly HF food, leads to the release of dopamine in the brain, hyper- and hyposensitivity of this system have been linked to abnormal weight gain. The microbiota has previously been shown to alter neural development and gene expression in the brain. However the potential influence of the microbiota on reward signaling and appetitive eating has yet to be studied. Using GF animals colonized with microbiota from lean or obese donors we will test the hypothesis that the microbiota reduces dopamine release in the nucleus accumbens to increase motivation and preference for fat. In order to aid in the development of microbiota- based therapies, it is necessary to understand the route by which the microbiota communicates to the brain. There is evidence that microbiota to brain signaling is relayed by vagal afferents innervating the GI tract but our understanding of the pathway is limited, partially because traditional techniques, such as vagotomy and capsaicin, lack specificity and can indirectly alter microbiota composition. In the second aim of this proposal, we will use a ribosome inactivating protein to ablate vagal afferent signaling in colonized animals. We aim to demonstrate that microbiota to brain communication is vagally mediated. Knowledge from this proposal will support the development of microbiota-based therapies aimed at food addiction and weight loss. Microbiota and vagal signaling could be more easily manipulated with fewer side effects than central targets.

摘要 有大量证据表明胃肠道（GI）微生物群与肥胖有关。无菌（GF） 当喂食高脂肪（HF）饮食时，小鼠不增重。微生物群组成迅速变化， HF喂养和具有“肥胖”微生物群的GF动物的定殖导致供体的重演 表型这些数据表明，不利的微生物群足以导致肥胖，然而， 机制和途径仍不清楚。能量摄入过多是肥胖的主要原因。食物摄入 是由自我平衡和享乐的线索来调节的。享乐饮食是指“为了快乐”而食用食物， 缺乏或超出能量需求，并与前脑中的奖励信号有关。食物消费， 特别是HF食物，会导致大脑中多巴胺的释放， 与体重异常增加有关微生物群先前已被证明可以改变神经系统 大脑中的发育和基因表达。然而，微生物群对奖励的潜在影响 信号和食欲的关系还有待研究。使用GF动物，其用来自瘦肉型或瘦肉型的微生物群定殖， 我们将测试微生物群减少细胞核中多巴胺释放的假设 增加动机和偏好脂肪的食谱。为了帮助微生物群的发展- 基于治疗，有必要了解微生物群与大脑沟通的途径。 有证据表明，微生物群到大脑的信号传导是通过神经支配胃肠道的迷走神经传入传递的，但我们的研究表明， 对该途径的理解是有限的，部分原因是传统技术，如迷走神经切断术和 辣椒素缺乏特异性，可以间接改变微生物群的组成。在本建议的第二个目标中， 我们将使用核糖体失活蛋白来消除定殖动物的迷走神经传入信号。我们的目标是 表明微生物群与大脑的交流是迷走神经介导的。从本提案中获得的知识将 支持开发针对食物成瘾和减肥的微生物疗法。菌群 迷走神经信号比中枢靶点更容易操纵，副作用更少。