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

项目总结/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媒介。心理健康状况的显著变化，包括焦虑、抑郁和认知功能障碍，可与系统性疾病同时发生。这些包括但不限于肠易激综合征、炎性肠病、肝性脑病和糖尿病。至关重要的是，已经描述了在这些疾病期间发生的微生物群的变化。强调微生物群的重要性，由于细菌病原体的挑战而导致的多样性变化可能导致成年小鼠的应激诱导的行为变化。虽然微生物群-肠-脑轴对心理健康的影响正在成年小鼠模型中出现，但目前尚不清楚在发育期间建立该轴的关键因素。 早期生活是一个快速学习和发展的时期。新生儿比成人更容易受到细菌病原体挑战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。在早期生活中以母亲分离的形式暴露于压力与成年后微生物-肠道-大脑轴的改变有关，远远超过了暴露于压力源。这些改变包括抑郁症（通过快感缺乏测量）、焦虑、认知缺陷、急性应激介导的肠功能障碍、对化学诱导的结肠炎的易感性增加、病原体感染和乙醇偏好增加等。因此，影响新生儿时期肠道-大脑-微生物群轴建立的变化可能会对整个生命产生深远的影响，包括心理健康问题。 该项目的总体目标是确定使用细菌病原体挑战新生儿操纵微生物群对微生物群-肠-脑轴发育的影响。这将通过用肠致病性E.大肠杆菌（EPEC）在新生儿中，与行为和认知的变化，评估在成年期，评估潜在的宿主微生物因素，宿主防御因素，包括粘膜屏障功能和模式识别受体。完成这些研究将产生关于微生物-肠道-大脑轴发展的重要信息，并更好地了解心理健康和福祉关键因素的调节。

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.