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

摘要 有大量证据表明胃肠道(GI)微生物区系与肥胖有关。无菌(GF) 当喂食高脂肪(HF)食物时，小鼠不会增加体重。微生物区系组成迅速变化以响应 HF喂养和在具有肥胖微生物群的GF动物中的定植导致供体的重述 表型。这一数据表明，不利的微生物区系足以导致肥胖，然而 机制和途径尚不清楚。能量摄入过多是肥胖的主要原因。食物摄入量 受到动态平衡和享乐主义暗示的调节。享乐式饮食指的是“为了快乐”而食用食物，在 缺乏或超出能量需求，与前脑中的奖赏信号有关。食物消费， 尤其是HF食物，会导致大脑中多巴胺的释放，导致该系统的高敏感和低敏感 与不正常的体重增加有关。微生物区系此前已被证明可以改变神经 大脑的发育和基因表达。然而，微生物区系对奖赏的潜在影响 信号和食欲还有待研究。使用生长在瘦肉型或非瘦肉型动物体内的微生物群 肥胖的捐赠者我们将测试微生物区系减少核内多巴胺释放的假设 伏隔增加动力和对脂肪的偏好。为了帮助微生物区系的发展- 在治疗的基础上，有必要了解微生物区系与大脑沟通的途径。 有证据表明，微生物区系到大脑的信号是由支配胃肠道的迷走神经传入传递的，但我们的 对这一途径的了解有限，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区系组成。在这项提案的第二个目标中， 我们将使用一种核糖体失活蛋白来消融定植动物的迷走神经传入信号。我们的目标是 证明微生物区系到大脑的交流是通过迷走神经调节的。从这项提案中了解到的知识将 支持针对食物成瘾和减肥的微生物区系疗法的开发。微生物区系 与中枢靶点相比，迷走神经信号更容易被操控，副作用更少。

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.