The microbiota-gut-brain axis in Alzheimers disease

阿尔茨海默病中的微生物群-肠-脑轴

基本信息

批准号：
10283496
负责人：
Melanie G Gareau
金额：
$ 32.74万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10283496
关键词：
Address Adult Aging Alzheimer&apos s Disease Anti-Anxiety Agents Antibiotics Behavior Behavioral Brain Brain Pathology Butyrates Butyric Acids Cecum Cells Child Cognition Disorders Cognitive deficits Colon Coupled Defect Development Disease Disease model Elderly Epithelial Cells Esters Functional disorder Gastrointestinal tract structure Genetic Germ-Free Goals Human Immune Impaired cognition Impairment Individual Infection Inflammation Intestines Knowledge Lactobacillus Lead Learning Life Mediating Memory Modeling Mucous Membrane Mus Neonatal Nerve Degeneration Neurodegenerative Disorders Neurons Onset of illness Pathology Pathway interactions Physiology Predisposition Prefrontal Cortex Probiotics Process Rattus Role Severities Signal Transduction Stress Testing Time Volatile Fatty Acids Weaning anxiety-like behavior brain behavior commensal microbes critical developmental period dysbiosis gastrointestinal gut colonization gut dysbiosis gut microbiota gut-brain axis host-microbe interactions ileum microbiota microbiota-gut-brain axis motor deficit motor disorder myelination neonatal period neonate neurodevelopment neurogenesis neuroinflammation new therapeutic target pathogenic bacteria prevent receptor restoration symptomatic improvement trauma exposure tributyrin

项目摘要

ABSTRACT Host-microbe interactions are paramount for maintaining normal physiology of the human host, including the brain and behavior. Bacterial colonization of the gastrointestinal (GI) tract, formation of GI mucosal barrier function, neurogenesis, and myelination of neurons all occur during a critical developmental window in early life. Thus, exposure to trauma such as stress, infection or inflammation during neonatal life could detrimentally impact the developing microbiota, gut and brain (MGB) axis. Disrupted MGB axis signaling, including dysbiosis, mucosal barrier defects and/or changes in behavior, occur in multiple diseases, including Alzheimer’s disease. Antibiotics (Abx) are administered to children more frequently than adults, due to increased susceptibility to bacterial pathogens. Since the MGB axis is developing during this critical time, Abx administration may have long-lasting effects. Beneficial bacterial metabolites, including short chain fatty acids (SCFAs) can ameliorate numerous pathologies, including dysbiosis, mucosal barrier dysfunction, inflammation and behavioral defects. We have demonstrated that modifying the gut microbiota, for example using Lactobacillus-containing probiotics, can prevent stress-induced MGB axis deficits following infection with a bacterial pathogen. We hypothesize that administration of specific SCFAs can prevent neonatal Abx-induced deficits in the adult MGB axis. Therefore, our primary objective is to address the effects of neonatal dysbiosis on the development of the MGB axis using a model of neonatal Abx administration. Our overall goal is to determine whether intestinal dysbiosis disrupts the gut-brain axis, and whether administration of SCFAs beneficially modulates the MGB axis. This goal will be accomplished by the following Specific Aims: (1) Neonatal dysbiosis disrupts myelination leading to neurodegeneration and (2) SCFAs regulate the MBG axis via myelination Taken together, these proposed studies will demonstrate whether neonatal dysbiosis disrupts the developing MGB axis, impacting the microbiota composition, altering myelination in the brain, and causing behavioral deficits in late adulthood. Furthermore, we will determine whether administering select SCFAs ameliorates these effects, in part restoration of impaired myelination in the brain. Finally, our results may promote use of SCFAs to prevent development MGB axis deficits, particularly in older adults.

抽象的宿主 - 微生物相互作用对于维持人类宿主的正常生理学至关重要，包括大脑和行为。胃肠道（GI）的细菌定植，形成GI粘膜屏障神经元的功能，神经发生和髓鞘形成都在早期的关键发育窗口中发生生活。那就是暴露于新生儿生活期间压力，感染或注射等创伤可能会降低影响发育中的微生物群，肠道和大脑（MGB）轴。 MGB轴信令中断，包括多种疾病发生，包括阿尔茨海默氏病。抗生素（ABX）比成年人更频繁地给儿童施用，因为对细菌病原体。由于MGB轴在此关键时期正在发展，因此ABX给药可能具有长期效果。有益的细菌代谢物，包括短链脂肪酸（SCFA）可以改善许多病理，包括营养不良，粘膜屏障功能障碍，炎症和行为缺陷。我们已经证明了修改肠道微生物群，例如使用含乳杆菌的益生菌，可以防止感染细菌病原体后压力诱导的MGB轴定义。我们假设给药特定的SCFA可以防止成年MGB的新生儿ABX诱导的缺陷轴。因此，我们的主要目标是解决新生儿营养不良对发展的影响使用新生儿ABX给药模型的MGB轴。我们的总体目标是确定肠道是否营养不良破坏肠脑轴，以及SCFA的给药是否有益地调节 MGB轴。该目标将通过以下特定目的来实现：（1）新生儿失调中断导致神经退行性的髓鞘化，（2）SCFA通过髓鞘轴调节MBG轴综上所述，这些提出的研究将证明新生儿营养不良是否会破坏开发MGB轴，影响菌群组成，改变大脑的髓鞘形成并引起行为定义在成年后期。此外，我们将确定是否管理选择SCFA 改善这些作用，部分恢复了大脑中髓鞘的受损。最后，我们的结果可能促进使用SCFA来防止MGB轴定义的开发，特别是在老年人中。