Grant: Discovery Grants Program - Individual

The gut microbiome host crosstalk has been extensively reported as a bidirectional communication mediated through metabolic, immunological, endocrine, and neuronal pathways. The gut microbiome produces a broad spectrum of neuroactive metabolites, particularly neurotransmitters (i.e., g-aminobutyric acid (GABA), serotonin, dopamine, norepinephrine, etc.) that could impact brain functions and physiology. Despite recent research progress, multiple questions surrounding gut neuromicrobiology remain unsolved. It has long been thought that GABA, for instance, is unable to cross the blood-brain barrier, but the studies that have built this paradigm are often contradictory and range widely in their employed methods. Accumulating evidence suggests that microbiome-secreted extravesicles (MEVs) are significant mediators in the intercellular signaling mechanism that could be an integral part of microbiome-host communications. MEVs are small membrane-bound phospholipid vesicles that encase a spectrum of biologically active molecules (i.e., proteins, nucleic acids, carbohydrates, and lipids) that protect them from lytic enzymes and RNases in the extracellular environment and facilitate their horizontal transfer across both short and distant locations, such as the brain. MEVs are involved in numerous processes, such as quorum sensing, biofilm formation, relief of environmental stresses, and host immunomodulation. Latest research findings portend that MEVs may act as inter-bacterial and microbe-host signaling pathways that regulate intestinal homeostasis and host physiology. Therefore, MEVs should be considered of utmost importance delivery vehicles for host neuromodulating metabolites to the intestinal mucosa and other organs in the body, thus, affecting the host's physiology. In this research, we will investigate MEVs as a shuttle for neuroactive metabolites and the involved pathway mechanisms by which the microbiome interacts with the gut-brain axis, with two specific objectives: (I) to characterize the diversity and chemical composition of EVs released by the gut microbiome and gut-isolated psychobiotics, and their role as shuttles for neuroactive molecules; (II) to mechanistically understand the impact of EVs on the gut microbiome ex vivo and host physiology in vitro and in vivo. We will apply molecular biology, cell biology, metabolomics, genomics, and biochemistry approaches along with high throughput and classical microbiology techniques to achieve these objectives. The proposed research program will provide groundbreaking mechanistic advances in our understanding of these important aspects of microbial neuro-signaling.