Early microbial colonization and development of the microbiota-gut-brain axis

早期微生物定植和微生物群-肠-脑轴的发育

• 批准号: 9126612
• 负责人: Melanie G Gareau
• 金额: $ 27.48万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9126612
• 关键词: Address; Adult; Affect; Amygdaloid structure; Anhedonia; Antibiotics; Anxiety; Bacterial Infections; Behavior; Behavioral; Biological; Biological Assay; Birth; Brain; Brain region; Cd68; Chemicals; Child; Cognition; Cognition Disorders; Cognitive deficits; Colitis; Communication; Communities; Defect; Depressive disorder; Development; Diabetes Mellitus; Dose; Enteral; Ethanol; Event; Exposure to; Foundations; Functional disorder; Gastrointestinal tract structure; Glial Fibrillary Acidic Protein; Goals; Health; Health Status; Hepatic Encephalopathy; Hippocampus (Brain); Host Defense; Immunohistochemistry; Impaired cognition; Individual; Infection; Inflammatory Bowel Diseases; Intestines; Irritable Bowel Syndrome; Lead; Learning; Life; Link; Liver; Measures; Mediating; Mediator of activation protein; Memory Loss; Mental Depression; Mental Health; Metabolism; Microbe; Modeling; Molecular; Mood Disorders; Mus; Names; Neonatal; Neuraxis; Pathway interactions; Pattern recognition receptor; Personal Satisfaction; Physiology; Predisposition; Regulation; Role; Shapes; Signal Transduction; Skin; Staining method; Stains; Stress; Systemic disease; Time; Tissues; Weaning; abstracting; acute stress; behavior change; body system; brain health; cognitive change; cytokine; design; enteropathogenic Escherichia coli; frontal lobe; gut microbiota; maternal separation; microbial colonization; microbial host; microbiota; mouse model; neonatal exposure; neonate; neurogenesis; neuroinflammation; new therapeutic target; pathogen; postnatal; preference; programs; receptor; response; stressor

Project Summary/Abstract The gut-brain-microbiota axis is increasingly being recognized as an important mediator of overall health and well-being. Significant changes in mental health status including anxiety, depression and cognitive dysfunctions can occur concurrently with systemic diseases. These include, but are not limited to, irritable bowel syndrome, inflammatory bowel disease, hepatic encephalopathy, and diabetes. Critically, changes in the microbiota have been described to occur during these maladies. Highlighting the importance of the microbiota, changes in diversity due to challenge with a bacterial pathogen can cause stress-induced behavioral changes in adult mice. While the effects of the microbiota-gut-brain axis on mental health are emerging in adult mouse models, the critical factors responsible for the establishment of the axis during development are currently unknown. Early life is a time of rapid learning and development. Neonates are more susceptible to serious complications arising from challenge with a bacterial pathogen, than adults. Consequently, neonates must be studied appropriately. Exposure to stress in early life in the form of maternal separation is associated with alterations in the microbiota-gut-brain axis in adulthood, well past exposure to the stressor. These alterations include depressive disorders (as measured by anhedonia), anxiety, cognitive deficits, acute stress-mediated intestinal dysfunction, increased susceptibility to chemical-induced colitis, infection with pathogens, and increased ethanol preference, to name a few. Therefore, changes that affect the establishment of the gut-brain-microbiota axis in the neonatal periods may have profound effects, including mental health issues, throughout life. The overall goals of this project are to determine the effect of neonatal manipulation of the microbiota using challenge with a bacterial pathogen on the development of the microbiota-gut-brain axis. This will be achieved via challenge with enteropathogenic E. coli (EPEC) in neonates, with behavioral and cognitive changes assessed in adulthood, assessing potential host microbial factors, and host defense factors including mucosal barrier function and pattern recognition receptors. Completion of these studies will yield important information regarding the development of the microbiota-gut-brain axis and greater understanding of the regulation of key factors in mental health and well-being.

项目概要/摘要 肠道-大脑-微生物群轴越来越被认为是整体健康和福祉的重要调节因素。心理健康状况的显着变化，包括焦虑、抑郁和认知功能障碍，可能与全身性疾病同时发生。这些包括但不限于肠易激综合征、炎症性肠病、肝性脑病和糖尿病。至关重要的是，在这些疾病期间，微生物群发生了变化。细菌病原体的挑战导致的多样性变化可能会导致成年小鼠应激诱导的行为变化，这凸显了微生物群的重要性。虽然微生物群-肠-脑轴对心理健康的影响在成年小鼠模型中正在显现，但在发育过程中负责轴建立的关键因素目前尚不清楚。 早期生活是快速学习和发展的时期。与成人相比，新生儿更容易受到细菌病原体攻击而引起的严重并发症的影响。因此，必须对新生儿进行适当的研究。生命早期暴露于母亲分离形式的压力与成年期微生物群-肠-脑轴的变化有关，而成年后暴露于压力源的时间已经很长了。这些改变包括抑郁症（通过快感缺乏来衡量）、焦虑、认知缺陷、急性压力介导的肠道功能障碍、对化学诱发的结肠炎的易感性增加、病原体感染以及对乙醇的偏好增加等等。因此，影响新生儿期肠道-大脑-微生物群轴建立的变化可能会产生深远的影响，包括终生的心理健康问题。 该项目的总体目标是确定新生儿利用细菌病原体攻击来操纵微生物群对微生物群-肠-脑轴发育的影响。这将通过对新生儿进行肠病性大肠杆菌 (EPEC) 攻击、评估成年期的行为和认知变化、评估潜在的宿主微生物因素和宿主防御因素（包括粘膜屏障功能和模式识别受体）来实现。这些研究的完成将产生有关微生物群-肠-脑轴发育的重要信息，并更好地了解心理健康和福祉关键因素的调节。