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

项目总结/摘要 增加血脑屏障（BBB）渗透性有助于衰老过程的速度和衰老过程的发生。 与年龄有关的疾病的发展。小胶质细胞介导的炎症是一个关键因素， BBB通透性的发展导致脑损伤并促进许多脑损伤的进展， 疾病通过靶向小胶质细胞而不诱导副作用来恢复受损的BBB功能， 这是一个重大的进步。令人信服的证据表明，健康的食用植物具有重要的 它对正常脑功能具有生理作用，可以预防神经炎症过程而无副作用。 姜黄根和生姜，用于药物几个世纪以来，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 姜黄根（TELN）选择性地被小胶质细胞摄取，它们的组成microRNA抑制小胶质细胞的增殖。 衰老相关炎症感受体基因（包括S100 A8和TLR 4）的表达，从而增强BBB 功能另外，S100 A8被释放的代谢物异戊胺（IAA）和巴豆酸（CA）诱导 来自细菌瘤胃球菌科，由于肌病毒科的减少，其在老年小鼠中过度生长 家庭的生姜提取物（GELNs）能抑制瘤胃球菌的生长，降低内源IAA水平 和CA，从而减少感觉体炎症以及增加紧密连接基因Cldn 5和 内皮细胞中的Ocln。在这项研究中，我们将提供细胞和分子的见解，如何ELN调节， 通过靶向小胶质细胞和瘤胃球菌科，通过肠-脑轴调节脑功能， 个脑袋我们的假设是，老年小鼠受损的脑功能可以通过TELN和GELN恢复， 以及通过抑制感觉体促炎基因的表达而抑制肠道细菌的增殖， 减少瘤胃球菌科的IAA和CA的产生。我们将通过两个测试来验证我们的假设。 具体目标。(1)我们将研究TELN microRNAs靶向的S100 A8/TLR 4通路在 （2）我们将确定口服给予GELN和GELN是否能从老年小鼠的认知衰退中恢复; 肌尾病毒科（Myoviridae family）病毒通过减少肌尾病毒的产生，对改善认知能力下降具有有益作用。 的IAA和CA代谢产物。目标将在小鼠模型中进行， 人类的衰老过程这项研究的完成将导致确定新的治疗靶点， 开发基于ELN的干预治疗BBB通透性和脑炎症的潜力。 此外，本研究结果将为进一步研究口服定制ELN是否 分离自不同植物的化合物将与肠道有益益生菌在预防或 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.