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Elevated lipopolysaccharide (LPS) levels, a Gram\u2010negative bacteria component, are found in AD brains, but how LPS breaches the blood\u2013brain barrier (BBB) remains unclear. Hypotheses suggest that bacteria\u2010derived extracellular vesicles (bEVs) may transport LPS across the BBB.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>bEVs were extracted from human and mouse feces and blood, and LPS levels were measured. In vivo imaging and immunofluorescence confirmed the transport of blood LPS\u2010carrying bEVs across the BBB. The role of these bEVs in microglia was investigated both in vivo and in vitro.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Elevated LPS\u2010containing bEVs were detected in the plasma of AD patients compared to healthy individuals. These bEVs activated microglial Piezo1, consequently precipitating an excessive synaptic pruning process mediated by the C1q\u2010C3 complement pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>DISCUSSION<\/jats:title><jats:p>These findings illuminate the complex interplay between the gut microbiota, bEVs, neuroinflammation, and synaptic plasticity \u2013 a key early event in AD \u2013 offering insights for potential therapeutic interventions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>GM\u2010derived bEVs can traverse the BBB.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>LPS was necessary for bEVs\u2019 penetration into the brain, and bEVs might be closely related to AD progression.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>bEVs mediated microglial activation and synaptic pruning via C1q\u2010C3 complement pathway.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Microglia Piezo1 was involved in bEV\u2010induced excessive synaptic pruning.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.70331","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T03:04:55Z","timestamp":1753844695000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Gut\u2010derived bacterial vesicles carrying lipopolysaccharide promote microglia\u2010mediated synaptic pruning"],"prefix":"10.1002","volume":"21","author":[{"given":"Xiaoduo","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Pathology, The First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou Zhejiang China"},{"name":"Nanhu Brain\u2010computer Interface Institute  Hangzhou Zhejiang 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Zhejiang University School of Medicine  Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shilong","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Pathology, The First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shangfei","family":"Luo","sequence":"additional","affiliation":[{"name":"Lingnan Medical Research Center Guangzhou University of Chinese Medicine Guangzhou Guangdong China"},{"name":"The First Affiliated Hospital Guangzhou University of Chinese Medicine  Guangzhou Guangdong China"},{"name":"Innovation Research Center Shandong University of Traditional Chinese Medicine  Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Can","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology, The First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoping","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital Zhejiang University School of Medicine Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[{"name":"Lingnan Medical Research Center Guangzhou University of Chinese Medicine Guangzhou Guangdong China"},{"name":"The First Affiliated Hospital Guangzhou University of Chinese Medicine  Guangzhou Guangdong China"},{"name":"Innovation Research Center Shandong University of Traditional Chinese Medicine  Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 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