Bile acid signaling in the gut-liver-brain axis: from pathogenesis to disease-modifying therapies in Parkinson’s disease

The identification of gastrointestinal prodromal symptoms decades prior to motor onset, combined with the Braak hypothesis of ascending neurodegeneration from the enteric nervous system, has repositioned the gut as a critical origin point in Parkinson’s disease pathophysiology. Within this paradigm, gut microbiota-derived metabolites have emerged as key mediators of disease initiation and progression. Among these, bile acids constitute a particularly compelling mechanistic link, functioning not merely as lipid emulsifiers but as pleiotropic signaling molecules whose metabolic fate is governed by the gut microbiota and whose bioactive derivatives orchestrate systemic processes ranging from mitochondrial bioenergetics and immune homeostasis to neuronal survival. This review systematically integrates the triad of bile acid metabolism, gut microbiota ecology, and neurodegenerative mechanisms within the gut-liver-brain axis framework. We examine how intestinal dysbiosis disrupts enterohepatic bile acid homeostasis, generating a neurotoxic milieu characterized by accumulation of hydrophobic, pro-inflammatory secondary species alongside depletion of hydrophilic, neuroprotective counterparts. We further dissect how these compositional shifts propagate from gut to brain, converging on the core pathological hallmarks that define Parkinson’s disease. Critically, we evaluate the translational trajectory of bile acid-targeted interventions, while addressing the pharmacokinetic barriers of oral bioavailability and blood-brain barrier penetration that currently limit clinical efficacy. By synthesizing preclinical mechanistic insights with emerging clinical biomarker and trial data, this review aims to establish the gut-liver-brain axis as an actionable therapeutic target for disease modification in Parkinson’s disease and related synucleinopathies.