Targeting microbially-derived juvenile protective factors to resolve neuroinflammation and delirium

摘要 术后并发症，如精神错乱，是一个巨大的公共卫生挑战，将继续 随着预期寿命和一生中手术次数的不断增加，这一趋势进一步加剧。尽管做出了努力 为了优化预防措施，术后精神错乱的发生率可影响高达87%的老年人， 取决于年龄和手术方式，并且仍然没有有效的治疗方法。患有轻度- 认知障碍(MCI)是发生术后精神错乱的最高风险。即使是常规外科手术 常见的膝关节置换或骨折修复等手术可能会导致危及生命的结果 包括长期认知功能障碍的风险增加。因此，迫切需要新的治疗策略。 需要的。我们的长期目标是定义来自肠道的新的青少年保护因子(JPF) 微生物区系，并确定其防止与衰老有关的发展和进展的能力 神经退行性疾病和围手术期疾病。这里的目标是比较分子签名在 来自健康青少年和有术后精神错乱风险的患者的肠道微生物样本， 包括老年人和患有MCI的成年人。我们的中心假设是幼年相关的肠道 微生物区系产生JPF，使其对年龄相关的神经炎症和术后精神错乱具有弹性。 这一假设将通过追求两个具体目标来检验：1)分析细菌群落及其 在青少年、老年人和MCI粪便样本中的分子特征；以及2)确定不同的功能影响 人类微生物区系对术后神经炎症和失语样行为的影响。的可行性。 收集和分析这些大型数据集和模型是在我们的实验室中由一个独特的 翻译团队。我们的初步数据提供了证据，特定的代谢物，已知可以预防 神经元死亡，在幼年小鼠的粪便中丰富。在这个创新的方法中，我们将移植粪便 将供体人类幼年、老年或MCI患者的样本送入无菌受体小鼠的临床相关研究 手术小鼠术后神经炎症和失语样行为的模型。我们的理论基础是 拟议的研究是，成功完成这项工作将证明与衰老相关的变化之间存在一种新的联系 微生物区系与术后神经炎症和认知缺陷的恢复力。这项工作将是意义重大的 通过提高我们对肠道微生物区系如何控制基本大脑病理的理解(即， 神经炎症和认知功能下降)，这可能揭示出一种独特的有效治疗方法 围手术期神经系统并发症。

ABSTRACT Postoperative complications such as delirium represent an immense public health challenge that will continue to intensify as life-expectancy and the number of surgeries during a lifespan continue to increase. Despite efforts to optimize preventive measures, the incidence of postoperative delirium can affect up to 87% of older adults, depending on age and surgical procedures, and remains without an effective treatment. Patients with mild- cognitive impairment (MCI) are most at risk for developing postoperative delirium. Even routine surgical procedures such as common knee replacement or fracture repair, may result in life-threatening outcomes including increased risk for long-term cognitive dysfunction. Thus, new therapeutic strategies are urgently needed. Our long-term goal is to define novel Juvenile Protective Factors (JPFs) derived from intestinal microbiota and to determine their capacity to protect against the development and progression of aging-related neurodegenerative and perioperative disorders. The objective here is to compare molecular signatures in intestinal microbiome samples from healthy juveniles and patients at risk for developing postoperative delirium, which includes older adults and adults with MCI. Our central hypothesis is that juvenile-associated intestinal microbiota generate JPFs that confer resiliency to age-associated neuroinflammation and postoperative delirium. This hypothesis will be tested by pursuing 2 specific aims: 1) analyze the bacterial communities and their molecular signatures in juvenile, aged, and MCI fecal samples; and 2) determine the functional impact of different human microbiota communities on postoperative neuroinflammation and delirium-like behavior. The feasibility of collecting and analyzing these large datasets and models has been established in our laboratories by a unique translational team. Our preliminary data provide evidence that specific metabolites, known to protect against neuronal death, are enriched in feces from juvenile mice. In this innovative approach, we will transplant fecal samples from donor human juvenile, elderly, or MCI patients into germ-free recipient mice in a clinically-relevant surgical mouse model of postoperative neuroinflammation and delirium-like behaviors. Our rationale for the proposed research is that successful completion will demonstrate a novel link between aging-related changes in microbiota and resiliency to postoperative neuroinflammation and cognitive deficits. This work will be significant by improving our understanding of how intestinal microbiota control fundamental brain pathology (ie, neuroinflammation and cogntive decline) that may reveal a unique approach to effective treatment for perioperative neurologic complications.