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

项目摘要/摘要 肠道-脑-微生物群轴越来越被认为是整体健康和福祉的重要中介。心理健康状况的重大变化，包括焦虑、抑郁和认知功能障碍，可能与系统性疾病同时发生。这些疾病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。关键的是，微生物区系的变化被描述为在这些疾病期间发生的。突显微生物区系重要性的是，由于细菌病原体的挑战而导致的多样性变化可以引起成年小鼠应激诱导的行为变化。虽然在成年小鼠模型中，微生物-肠道-脑轴对心理健康的影响正在显现，但在发育过程中负责建立该轴的关键因素目前尚不清楚。 早期生活是一个快速学习和发展的时期。与成年人相比，新生儿更容易受到细菌病原体攻击而产生的严重并发症的影响。因此，必须对新生儿进行适当的研究。在早年以母体分离的形式暴露于压力下，与成年后微生物-肠道-脑轴的变化有关，而成年后很久就已经暴露于应激源了。这些变化包括抑郁障碍(以快感缺失衡量)、焦虑、认知障碍、急性应激介导的肠道功能障碍、对化学诱导的结肠炎的易感性增加、病原体感染以及对酒精的偏好增加，仅举几例。因此，在新生儿期影响肠道-脑-微生物区轴建立的变化可能会在一生中产生深远的影响，包括心理健康问题。 该项目的总体目标是确定利用细菌病原体挑战新生儿对微生物区系的操纵对微生物区系-肠道-脑轴发育的影响。这将通过在新生儿中挑战产肠病原性大肠杆菌(EPEC)来实现，成年后评估行为和认知变化，评估潜在的宿主微生物因素，以及宿主防御因素包括粘膜屏障功能和模式识别受体。这些研究的完成将提供有关微生物-肠道-脑轴发育的重要信息，并更好地理解心理健康和福祉中的关键因素的调节。

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.