Gut Microbiota‐Derived Anandamide Mediates the Therapeutic Effects of Urolithin A on Alcohol‐Induced Cognitive and Social Dysfunction via CB1R‐DRD2‐RAP1 Signaling Axis

ABSTRACT Chronic alcohol consumption disrupts the gut microbiome, exacerbating 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. First, our study demonstrates that UA significantly enhances work memory (60.43%), short‐term memory (12‐fold), long‐term memory (50.32%), social ability (10‐fold), and social novelty (12‐fold), while concurrently reducing synaptic impairments and neuroinflammation. Moreover, UA restores AICSD by upregulating the dopamine D2 receptor (DRD2) via RAP1 signaling. Furthermore, antibiotic treatment and fecal microbiota transplantation experiments confirm the causality between the host microbiota and behavioral alterations. Treatment with UA‐enriched Bacteroids sartorii and Parabacteroids distasonis , or their derived endocannabinoid‐anandamide (AEA), also ameliorates AICSD. Finally, AEA inhibits the Rap1 signaling through cannabinoid receptor 1 (CB1R) and DRD2 interaction, eventually ameliorating AICSD. Collectively, our study elucidates that microbiota‐derived AEA mediates the therapeutic effects of UA on AICSD through the CB1R‐DRD2‐RAP1 signaling axis, providing valuable insights for UA and microbiome‐targeted endocannabinoid interventions against AICSD.