The gut-liver-brain axis in alcohol use disorder: The emerging role of bile acid dysregulation.

Abstract

Alcohol use disorder (AUD) is a chronic, relapsing neuropsychiatric disorder with limited treatment options. The gut-liver-brain axis has emerged as an important contributor to alcohol addiction. Within this axis, bile acids, important signaling molecules that connect the gut, liver, and central nervous system (CNS), have received increasing attention, as their metabolic dysregulation is closely associated with AUD. This review systematically elucidates the physiological metabolic processes of bile acids and the mechanisms by which chronic alcohol consumption disrupts their homeostasis. We propose a bidirectional pathological cycle model in which chronic alcohol consumption disrupts bile acid homeostasis via multiple pathways, resulting in a dysregulated bile acid profile characterized by an increase in total bile acids, a significant reduction in the proportion of secondary bile acids (SBAs), and an increased proportion of hydrophobic species. This disrupted profile impairs intestinal barrier integrity, triggering systemic inflammation and neuroinflammation via Toll-like receptor 4 (TLR4) signaling, and promotes blood-brain barrier (BBB) dysfunction. Critically, these brain dysfunctions drive compulsive alcohol-seeking behavior, thereby resulting in excessive alcohol consumption, which in turn exacerbates bile acid dysregulation, thus forming a self-reinforcing cycle that accelerates the progression of AUD. Furthermore, we evaluated the therapeutic potential of bile acid-related interventions, including farnesoid X receptor (FXR)/Takeda G protein-coupled receptor 5 (TGR5) agonists and gut microbiota modulation. This review provides an integrated framework for understanding AUD pathophysiology from a gut-liver-brain axis perspective.