Novel mechanism in microbiota-brain communication: the role of the hepatoportal region

微生物群-大脑通讯的新机制：肝门区的作用

• 批准号: 10600138
• 负责人: LEVENTE KAPAS
• 金额: $ 38.25万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-05 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10600138
• 关键词: Afferent Neurons; Agonist; Animals; Antibiotic Therapy; Arachidonic Acids; Attenuated; Bacteria; Bacterial Translocation; Brain; Brain Diseases; Brain Stem; Butyrates; Cardiovascular Diseases; Cell Nucleus; Cell Wall; Central Nervous System Diseases; Circulation; Communication; Dichloromethylene Diphosphonate; Diet; Dinoprostone; Dose; EP4 receptor; Elements; Environment; FOS gene; Food Additives; Future; Hepatic; Human; Inflammatory; Injections; Intestines; Knowledge; Kupffer Cells; Lipopolysaccharides; Liposomes; Liver; Macrophage; Measures; Metabolic; Metabolic Diseases; Metabolic syndrome; Mission; Modeling; Neurosciences; Nutritional status; Organism; Pathologic; Pathway interactions; Peptidoglycan; Peripheral; Physiological; Play; Portal vein structure; Predisposition; Production; Prostaglandins; Public Health; Rattus; Respiratory Disease; Role; Signal Transduction; Site; Sleep; Sleep Disorders; Source; Stress; Tissues; Translational Research; United States National Institutes of Health; Vagotomy; Vagus nerve structure; Volatile Fatty Acids; WFDC2 gene; Work; afferent nerve; antagonist; cyclooxygenase 2; disability; experimental study; gut microbiota; immunological status; improvement on sleep; microbial products; microbiota; microbiota-gut-brain axis; novel; prevent; receptor; response; sensor; sleep regulation; translational study

PROJECT SUMMARY Signals from peripheral tissues play an important role in aligning sleep-wake activity with the metabolic, nutri- tional and immune status of the organism. The intestinal microbiota is an essential source of such signals through the production of bacterial metabolites, e.g., short-chain fatty acids (SCFAs), and the release of bacterial cell wall components, lipopolysaccharide (LPS) and peptidoglycans. The long-term objective is to identify mechanisms of microbiota-brain communications and its relevance to sleep regulation. The objective of the present proposal is to investigate the newly discovered sleep-promoting viscerosensory mechanism in the hepatoportal region. Activation of hepatoportal sensors by SCFAs and bacterial cell wall products is a potent sleep-promoting signal. The central hypothesis is that bacterial products, such as LPS that translocate from the intestinal lumen to the liver via the portal vein, activate hepatic macrophages. Macrophages, in turn, secrete prostaglandins locally, which activate the sensory neurons of the hepatic vagus. Vagus carries somnogenic signal to the nucleus tractus solitarius, a component of brain stem sleep circuits. In three specific aims, we will 1) determine the role of hepatic macrophages in LPS-induced sleep in macrophage-depleted rats, 2) determine the contribution of hepatic prostaglandin E2 in sleep signaling 3) determine the contribution of hepatic vagal afferents in hepatoportal sleep induction. The concept of microbiota-gut-brain axis is viewed as a major paradigm shift in neuroscience. Changes in the composition of microbiota as well as increased translocation of microbial products to the systemic circulation are related to pathological conditions, including disorders of the central nervous system. Identifying the role of bacterial products in sleep regulation is important because the gut flora is susceptible to changes in diet, environment, food additives and antibiotic treatment, which could lead to altered sleep, but it can also provide an easily accessible target for translational research to improve sleep.

项目摘要 来自外周组织的信号在将睡眠-觉醒活动与代谢、营养和代谢相结合方面起着重要作用。 生物体的正常和免疫状态。肠道微生物群是这种信号的重要来源 通过产生细菌代谢物，例如，短链脂肪酸（SCFAs）和细菌的释放 细胞壁组分、脂多糖（LPS）和肽聚糖。长期目标是确定 微生物群-大脑通信机制及其与睡眠调节的相关性。的目的 目前的建议是研究新发现的促进睡眠的内脏感觉机制， 肝门区SCFAs和细菌细胞壁产物激活肝门静脉传感器是一种有效的 睡眠促进信号。中心假设是细菌产物，如从大肠杆菌移位的LPS， 肠腔通过门静脉进入肝脏，激活肝脏巨噬细胞。反过来，巨噬细胞分泌 局部激活肝迷走神经的感觉神经元。迷走神经携带催眠 信号到孤束核，脑干睡眠回路的组成部分。在三个具体目标中，我们将 1)确定肝巨噬细胞在巨噬细胞耗竭大鼠中LPS诱导的睡眠中的作用，2）确定 肝脏前列腺素E2在睡眠信号传导中的作用3）决定了肝脏迷走神经的作用 肝门静脉睡眠诱导中的传入神经。微生物群-肠-脑轴的概念被视为一个主要的范式 神经科学的转变微生物群组成的变化以及微生物易位的增加 产品的体循环有关的病理条件，包括疾病的中央 神经系统确定细菌产物在睡眠调节中的作用很重要，因为肠道植物群 易受饮食、环境、食品添加剂和抗生素治疗的影响，这可能导致 睡眠，但它也可以为转化研究提供一个容易获得的目标，以改善睡眠。