Urolithin A protects against alcohol-induced cognitive and social dysfunction through microbiota-mediated AEA-CB1R-D2R signaling

Chronic alcohol consumption disrupts the gut microbiome, leading to alcohol-induced cognitive and social dysfunction (AICSD), which constitutes a primary etiology of early-onset dementia. Urolithin A (UA) has been well-reported as an effective intervention for neurodegenerative diseases. However, the protective efficacy of UA against AICSD, and its underlying mechanisms remain largely elusive. Firstly, our study demonstrates that UA restored AICSD in a microbiota-dependent manner, with reduced synaptic impairments and neuroinflammation by upregulating the dopamine D2 receptor (D2R). Antibiotic treatment and fecal microbiota transplantation experiments confirmed the causality between the host microbiota and behavioral alterations. Furthermore, treatment with UA-enriched Bacteroids sartorii and Parabacteroids distasonis and their derived neurotransmitter anandamide (AEA) also ameliorated AICSD. Finally, AEA inhibited the Rap1 signaling through cannabinoid receptor 1 (CB1R) and D2R interaction, eventually ameliorating AICSD. Collectively, our study elucidates that UA alleviated AICSD through microbiota-mediated AEA-CB1R-D2R signaling, providing valuable insights for UA and microbiome-targeted interventions against AICSD.