Autoinducer-2 and depression

Project Summary Stress often has deleterious effects, particularly in the context of chronic stress, when harm to the individual occurs and often leads to the development of psychiatric diseases. A better understanding of mechanisms mediating stress is critically needed to develop new interventions. In this project, we propose to determine if quorum sensing molecules (QSMs) used by bacteria to communicate, mediate the mammalian stress response. This is particularly relevant in the context of stress as stress has been shown to alter microbiome composition and behaviors. Herein, we propose to determine the physiological role of the QSM, autoinducer-2 (AI-2) in stress- related behaviors. Our overall hypothesis is that AI-2 is key in controlling behaviors because it senses and controls gut bacterial levels and community behavior, as well as integrates and regulates the host response to stress. Specific Aim 1 will test the hypothesis that production of gut bacterial AI-2 is regulated by stress. We will determine whether stress signals produced by the mammalian host (e.g., corticosterone, catecholamines, metabolites) are responsible for the change in AI-2 production by bacteria. Specific Aim 2 will test the contribution of bacterial AI-2 to stress-related behaviors. We will identify bacterial species and metabolites regulated by stress or AI-2 modulation and use engineered E. coli either producing large amount of AI-2 or in contrast scavenging AI-2 from the environment to test their contribution to stress-related behaviors. Finally, Specific Aim 3 will test the hypothesis that bacterial AI-2 induces Th17 cells, microglial changes, and dendritic spine density reduction. We will analyze downstream effectors of bacterial AI-2 on neurobiology, concentrating on the Th17 cells, microglia, and dendritic spine density Altogether, we expect to demonstrate that bacterial AI-2 is a novel signal implicated in the gut-brain axis controlling stress behavioral response. The knowledge gained from these studies might open new avenues for innovative microbiota-based therapeutic strategies for stress-related disorders.