Edible Plant-derived exosome-like nanoparticles (ELNs) and phage inhibit brain inflammation by targeting microglia and gut microbiota

项目摘要/摘要 增加血脑屏障(BBB)的通透性有助于加速衰老过程，并 与年龄有关的疾病的发展进展。小胶质细胞介导的炎症是 血脑屏障通透性的发展，导致脑损伤，促进许多脑的进展 疾病。通过靶向小胶质细胞恢复受损的血脑屏障功能而不会产生副作用 因此，这将是一个重大进步。令人信服的证据表明，健康的可食用植物具有重要的 对于正常的大脑功能具有生理作用，并可防止神经炎症过程，而不会产生副作用。 姜黄根和生姜在医药中使用了几个世纪，显示出多种健康益处，包括 抑制阿尔茨海默病的发展。我们已经证明，来自外部的类外泌体纳米颗粒(ELN) 姜黄根(TELN)被小胶质细胞选择性摄取，其组成的microRNAs抑制 增龄相关炎症感受器基因S100A8和TLR4的表达，从而增强血脑屏障 功能。此外，S100A8由释放的代谢物异戊胺(IAA)和巴豆酸(CA)诱导 来自瘤胃球菌科的细菌科，由于肌病毒科的减少而在老龄小鼠中过度生长 家族噬菌体。从生姜提取的ELNS(GELNS)能抑制瘤胃球菌科的生长，降低IAA水平。 和CA，从而减轻感觉性炎症，增加紧密连接基因Cldn5和 Ocln表达于内皮细胞。在这项研究中，我们将提供细胞和分子方面的见解，了解ELN是如何调节的 通过以小胶质细胞和反刍球菌科为靶点，通过肠道-脑轴发挥大脑功能，从而使 大脑。我们的假设是，老年小鼠受损的脑功能可以通过TELN和GELN恢复， 和肠道细菌噬菌体通过抑制感觉性促炎基因和 反刍球菌科植物体内IAA和CA产量的减少。我们将通过两个例子来检验我们的假设 明确的目标。(1)我们将研究TELN microRNAs靶向的S100A8/TLR4通路在 老年小鼠认知功能衰退的恢复；(2)我们将确定口服GELNS和 Myoviridae家族噬菌体通过减少产量改善认知功能衰退 瘤胃球菌科IAA和CA代谢物的研究。这些目标将在一个模仿的小鼠模型中实现 人类的衰老过程。这项研究的完成将导致新的治疗靶点的确定和 开发基于ELN的干预措施治疗血脑屏障通透性和脑部炎症的潜力。 此外，这些发现将为进一步研究是否口服定制ELN奠定了基础 从不同植物中分离出来的噬菌体与肠道有益的噬菌体具有协同/相加作用，可预防或 治疗慢性炎症性脑相关疾病。

Project Summary/Abstract Increasing blood-brain barrier (BBB) permeability contributes to the speed of the aging process and the progression of the development of age-related diseases. Microglia-mediated inflammation is a key element in the development of BBB permeability which results in brain injury and promotes the progression of many brain diseases. Restoring impaired BBB function by targeting microglial cells without inducing side effects would therefore be a major advance. Compelling evidence shows that healthy edible plants have important physiological roles for normal brain function and can prevent neuroinflammatory processes without side-effects. Turmeric root and ginger, used in medicines for centuries, display a multitude of health benefits including inhibiting the progression of Alzheimer’s disease. We have shown that exosome-like nanoparticles (ELNs) from turmeric root (TELNs) are selectively taken up by microglial cells and their constituent microRNAs inhibit the expression of aging related inflammatory sensome genes including S100A8 and TLR4, thus enhancing BBB function. Additionally, S100A8 is induced by metabolites isoamylamine (IAA) and crotonic acid (CA) released from the bacterial family Ruminococcaceae which is overgrown in aged mice due to a reduction of the Myoviridae family phages. ELNs from ginger (GELNs) can inhibit the growth of Ruminococcaceae, reduce the levels of IAA and CA, thus decreasing sensome inflammation as well as increasing expression tight junction genes Cldn5 and Ocln in endothelial cells. In this study, we will provide cellular and molecular insight into how ELNs modulate brain function via the gut-brain axis by targeting microglial cells and the Ruminococcaceae to the benefit of the brain. Our hypothesis is that impaired brain function in aged mice can be restored by TELNs and GELNs, and gut bacterial phages through inhibition of expression of sensome proinflammatory genes and reduction in production of IAA and CA from Ruminococcaceae. We will test our hypothesis through two specific aims. (1) We will investigate the role of the S100A8/TLR4 pathway targeted by TELN microRNAs in recovery from cognitive decline in aged mice; (2) We will determine whether oral administration of GELNs and Myoviridae family phages has a beneficial effect on improving cognitive decline through reducing the production of IAA and CA metabolites from Ruminococcaceae. The Aims will be performed in a mouse model that mimics the human aging process. The completion of this study will lead to identification of new therapeutic targets and potential for the development of ELN based interventions for treating BBB permeability and brain inflammation. In addition, the findings will provide a foundation to further study whether oral administration of customized ELNs isolated from different plants will have a synergistic/additive effect with gut beneficial phages in preventing or treating chronic inflammatory brain related diseases.