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Urolithin A (UA) has been well\u2010reported 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\u2010term memory (12\u2010fold), long\u2010term memory (50.32%), social ability (10\u2010fold), and social novelty (12\u2010fold), 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\u2010enriched\n                    <jats:italic>Bacteroids sartorii<\/jats:italic>\n                    and\n                    <jats:italic>Parabacteroids distasonis<\/jats:italic>\n                    , or their derived endocannabinoid\u2010anandamide (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\u2010derived AEA mediates the therapeutic effects of UA on AICSD through the CB1R\u2010DRD2\u2010RAP1 signaling axis, providing valuable insights for UA and microbiome\u2010targeted endocannabinoid interventions against AICSD.\n                  <\/jats:p>","DOI":"10.1002\/advs.202508048","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T15:03:58Z","timestamp":1770131038000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Gut Microbiota\u2010Derived Anandamide Mediates the Therapeutic Effects of Urolithin A on Alcohol\u2010Induced Cognitive and Social Dysfunction via CB1R\u2010DRD2\u2010RAP1 Signaling Axis"],"prefix":"10.1002","volume":"13","author":[{"given":"Hongbo","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Nutrition and Health College of Food Science and Engineering Northwest A&amp;F University  Yangling Shaanxi China"},{"name":"College of Food Science and Engineering Ningxia University  Yinchuan Ningxia China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zibin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Health College of Food Science and Engineering Northwest A&amp;F University  Yangling Shaanxi China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yao","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Health College of Food Science and Engineering Northwest A&amp;F University  Yangling Shaanxi China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji","family":"Bian","sequence":"additional","affiliation":[{"name":"Kolling Institute Sydney Medical School Royal North Shore Hospital University of Sydney  St. Leonards NSW Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caian","family":"He","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Health College of Food Science and Engineering Northwest A&amp;F University  Yangling Shaanxi China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chao","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Novel Food Resources Processing Ministry of Agriculture and Rural Affairs\/Institute of Agro\u2010Food Science and Technology Shandong Academy of Agricultural Sciences  Jinan P. 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