Multidisciplinary Characterization of the Gut-Brain Axis in Addiction

Project Summary Addiction and substance use disorders (SUDs) affect more than 27 million people in the United States, with an estimated $740 billion annual cost due to crime, lost work productivity, and health care expenses. Unfortunately, these numbers continue to increase and even more, since the pandemic, unleashing an alarming

health and social burden. Despite worldwide efforts, no successful treatments have been developed to better deal with this chronic and relapsing disease. In the past years, the gut microbiota and its composition has been associated with different adult behaviors and diverse neuropsychological diseases, including SUDs. However,

the mechanism by which the gut microbiota influences these pathologies remains elusive, with most of the available data originating from associations between human patients or animal models and their fecal microbiome profiles. There is an urgent need to push the field toward more mechanistic studies to find actual

communication pathways and molecular mediators behind these gut-brain connections. Therefore, the goal of this project is to identify and characterize relevant interactions between different members of the gut microbiota, psychostimulant exposure, and vulnerability to develop SUDs. To this end, we will apply a conceptually and

technically innovative approach that really bridges the fields of neuroscience and microbiology. We will use metagenomics and metabolomics to identify psychostimulant-induced alteration in microbial composition and gut milieu. We will then apply pharmacological and microbiological techniques to modulate gut physiology and

bacterial genetics to validate identified host signals and characterize bacteria-sensing pathways that are impacted by the drug. To understand how the microbiome influences the progression to disease, we will combine gut microbial manipulations with well-established animal models to determine the impact of these manipulations

on addiction. We will leverage the availability of genetically tractable hosts (mice) and human gut bacterial strains to build up in vitro and in vivo models that will allow us to better understand the molecular mechanisms involved in this interkingdom communication. This project is only possible because we have developed the protocols and

the technical resources to accurately manipulate and investigate bacterial physiology while also following neurobehavioral alterations associated with psychiatric diseases. We have the experience and the equipment to run a battery of behavioral tests under microbiologically controlled conditions. Our approach provides an exciting

opportunity for acquiring new knowledge regarding addiction, gut microbiome physiology, and their interaction, that can make a vertical leap in the field. |Contact PD/PI: Cuesta, Santiago