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

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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.