Project Summary/Abstract This K01 Mentored Research Scientist Development Award is designed to prepare the candidate to become an independent investigator in the emerging field of the gut microbiome in alcohol use disorder (AUD). AUD is a chronic relapsing disease with a major public health impact. While substantial research has been done to understand the neural circuitry underlying AUD, the role of the periphery and the connections between the periphery and the central nervous system have been understudied. One promising avenue of study is the gut microbiome and the microbiota-gut-brain axis, which have only recently been recognized as contributing to the pathogenesis of AUD. Despite the promise of the microbiota-gut-brain axis as an important contributor to AUD, there have been no comprehensive investigations of the microbiota-gut-brain axis in a single sample of individuals with AUD. Therefore, this proposal seeks to evaluate the relationship between gut dysbiosis, clinical phenomenology of AUD, and a brain-based biomarker in individuals with AUD and matched controls. The research objective of this K01 application is to characterize the microbiome-gut-brain axis across different levels of analysis. Specifically, 64 individuals with AUD and 64 matched healthy controls will provide a fecal sample to localize the effects of chronic alcohol use on the gut microbiome. Participants will also provide a blood sample to evaluate gut permeability through serum biomarkers. Participants will also complete an in- depth neuroscience-informed clinical assessment battery, which will allow for phenotyping individuals into the three domains of the Addiction Neuroclinical Assessment (ANA): incentive salience, negative emotionality, and executive dysfunction. Finally, participants with AUD will complete an alcohol cue-reactivity neuroimaging task to obtain a brain-based biomarker of AUD. The specific aims of the proposed project are: (1) to identify the gut microbiota discriminating individuals with AUD from controls; (2) to evaluate the relationship between the gut microbiome and AUD phenomenology; and (3) to test the relationship between gut microbiota and a brain- based biomarker for AUD. The successful completion of the above aims will provide the first data linking the microbiome-gut-brain axis to AUD in a clinical sample. This K01 award will position the candidate to be at the forefront of the AUD microbiome-gut-brain axis field. The training goals for Dr. Grodin are to gain expertise in (1) the gut-microbiome applied to AUD phenomenology, (2) quantitative methods in machine learning and big data, and (3) professional development as an independent scientist.