Prenatal Alcohol and Neuroimmunity

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7. Project Summary/Abstract Studies in both animal models and human cohorts have demonstrated broad impacts of prenatal alcohol exposure (PAE) on immune function. We showed, for the first time that PAE results in a more severe and prolonged course of inflammation in response to immune challenge in adulthood, which appears to have its origins in a proinflammatory bias that is present from birth. Inflammation, increased gut permeability, and changes in gut microbiota composition have been implicated in the pathogenesis of wide range of diseases/ disorders, including depression and anxiety. Notably, approximately 90% of individuals with Fetal Alcohol Spectrum Disorders (FASD) experience mental health problems at some point in their lives, with depression and anxiety being the most common. Yet links between immune/inflammatory function and mental health outcomes are not well studied in the FASD field, and to date there are no publications examining PAE effects on gut structure, function, and microbiota composition, nor whether such changes may underlie alterations in immune function. The present proposal will fill these gaps by exploring the complex interplay among PAE-induced alterations in gut structure, function, and microbiota composition, immune function, and emotional dysregulation (operationalized here as adverse mental health outcomes). The potential beneficial impact(s) of intervention strategies including pharmacological treatments and fecal transplant will be explored, and a translational experiment will investigate possible associations between PAE-induced emotional dysregulation and altered gut microbiota composition in a human cohort. Our goal is to explore potential novel biomarkers of PAE and inform future clinical strategies to improve health and well-being of individuals with FASD. Our Specific Aims are to: 1) Determine the effects of PAE on gut structure, function and microbiota composition and how these may affect immune function and set the stage for risk for/resilience to emotional dysregulation; 2) Investigate the effectiveness of pharmacological treatments in ameliorating PAE-induced alterations in gut structure, function, microbiota composition, immune function, and emotional dysregulation; 3) Evaluate the efficacy of fecal microbiota transplantation in ameliorating PAE-induced alterations in gut structure, function, microbiota composition, immune function, and emotional dysregulation; and 4) Translate this work to a human cohort by investigating associations among PAE-induced alterations in gut permeability, microbiota composition, and emotional dysregulation in adults with FASD. Our working hypothesis is that PAE: impacts structure and function of the gut barrier, leading to increased permeability to luminal products; causes a shift in gut microbiota composition and altered signaling in the gut-brain axis; and together, these changes may be key drivers of the early proinflammatory bias and lifelong perturbations in immune function that ultimately negatively impact mental health status. This research will provide unique insight into factors underlying PAE-related risk and resilience.