Taylor Lehner, Darleen A Sandoval, Rebecca L McCullough
Alcohol use disorder (AUD) is a leading contributor to global morbidity and mortality, yet current treatments remain underutilized and only partially effective. Although AUD has traditionally been conceptualized as a brain-centered disorder, emerging evidence supports an integrative framework in which peripheral physiological signals influence central neural circuits that regulate motivation, affect, and reinforcement. This review examines the effects of alcohol on the gut-vagal-brain axis and evaluates the role of vagal signaling in the development and maintenance of AUD. Chronic alcohol exposure disrupts intestinal barrier integrity, alters microbiome composition, and promotes systemic inflammation, generating inflammatory and metabolic signals that can engage vagal sensory pathways. However, the direct effects of these alcohol-associated peripheral adaptations on vagal signaling and downstream CNS circuits in AUD remain incompletely defined. Preclinical studies demonstrate that surgical and pharmacological manipulation of vagal signaling alters alcohol intake, relapse-like behavior, and stress responsivity, supporting a functional role for vagal pathways in alcohol-related behaviors. Clinical studies similarly report reduced vagal tone and autonomic imbalance in individuals with AUD, suggesting translational relevance. Emerging neuromodulatory approaches, including invasive and transcutaneous vagus nerve stimulation (VNS), show promise for reducing craving and improving affective symptoms; however, current evidence remains limited. In this review, we synthesize current evidence examining how chronic alcohol exposure may disrupt gut-vagal-brain communication and discuss the potential contribution of these changes to alcohol use disorder. We identify potential mechanistic pathways and knowledge gaps, and highlight the need for more circuit-specific and longitudinal studies to evaluate vagal pathways as therapeutic targets for AUD.