Saturday, May 17, 2025
5/17/2025
Extracellular RNA carrier subclasses in processes relevant to Substance Use Disorders or HIV infection - Abstract/Project Summary Emerging preclinical data and clinical evidence support the existence of a bidirectional communication between the gut microbiome and the central nervous system. Recently, the gut microbiome has been shown to play a critical role in the development and function of the central nervous system (CNS). While advanced age as well as immune and metabolic alterations can lead to increased permeability of tissue barriers, evidence shows gut microbes signal to the brain even in young, healthy humans and in animal models. Signaling through the vagal nerve may play a role in these situations, but the exact mechanism of this communication remains to be confirmed. Bacterial extracellular vesicles (BEVs) have recently been shown to carry information over long- distances modulating interkingdom communication within the gut microbiota brain axis. Both gram negative and more recently gram-positive bacteria have been shown to release extracellular vesicles. These vesicles have been shown to contain a variety of biomolecules, such as proteins, lipids, nucleic acids, and small-molecule metabolites and play a key role in the biology of bacteria. BEVs has been postulated to be the key underlying mechanisms behind harmful or beneficial effects of many pathogenic, symbiont, and probiotic bacteria. Opioid use disorders have been associated with dramatic alteration in the gut microbiome with the expansion of gram- positive bacteria. Similarly, in humans and in animal models HIV infection is associated with microbial changes resulting in elevated systemic endotoxin levels-a signature marker for HIV co-morbidity. Opioid abuse exacerbates these effects both in PLWH and in animal models of HIV and substance use. The role of bacterial extracellular vesicles in modulating the gut brain axis under these conditions has not been investigated. This high risk, high reward R21 proposal is a pilot grant to establish proof of concept. Based on preliminary data and published studies, we hypothesize that microbial dysbiosis associated with opioid use and in the context of HIV, results in the expansion of distinct pathogenic bacterial communities leading to the secretion of BEVs which acts as mediators that communicates with both immune cells and microglial cells to disrupt the gut-brain-axis. Two specific aims are proposed to test this novel hypothesis. Specific Aim 1: Determine if bacterial EV’s derived from fecal samples from Control, Morphine dependent, HIV/ART and Morphine dependent/HIV/ART treated mice a) disrupt gut epithelial and brain endothelial barriers and b) cross gut epithelial and blood brain barriers using in vitro gut epithelial and blood brain barrier models. We will further investigate if BEVs modulate macrophage and microglial gene expression in co-cultures. Specific Aim 2: Determine if Extracellular vesicles isolated from fecal samples from Control, Morphine dependent, HIV/ART and Morphine dependent/HIV/ART treated mice a) disrupt epithelial barrier b) increase gut epithelial permeability and c) cross gut epithelial barrier and Blood brain barrier in vivo. The clinical relevance of these studies is that BEVs can be exploited for therapeutic purposes to deliver nano pharmaceuticals systemically and to the CNS.
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