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The aim of the present study was to explore gut\u2013brain axis signals in berberine\u2010modulating microglia polarization following cerebral ischemia. The potential pathway was determined through analyzing the activation of the vagus nerve, hydrogen sulfide (H\n                    <jats:sub>2<\/jats:sub>\n                    S) metabolism, and cysteine persulfides of transient receptor potential vanilloid 1 (TRPV1) receptor. The cerebral microenvironment feature was explored with a metabolomics assay. The data indicated that berberine ameliorated behavioral deficiency in transient middle cerebral artery occlusion rats through modulating microglia polarization and neuroinflammation depending on microbiota. Enhanced vagus nerve activity following berberine treatment was blocked by antibiotic cocktails, capsazepine, or sodium molybdate, respectively. Berberine\u2010induced H\n                    <jats:sub>2<\/jats:sub>\n                    S production was responsible for vagus nerve stimulation achieved through assimilatory and dissimilatory sulfate reduction with increased synthetic enzymes. Sulfation of the TRPV1 receptor resulted in vagus nerve activation and promoted the c\u2010fos and ChAT in the nucleus tractus solitaries with berberine. Sphingolipid metabolism is the primary metabolic characteristic with berberine in the cerebral cortex, hippocampus, and cerebral spinal fluid disrupted by antibiotics. Berberine, in conclusion, modulates microglia polarization in a microbiota\u2010dependent manner. H\n                    <jats:sub>2<\/jats:sub>\n                    S stimulates the vagus nerve through TRPV1 is responsible for the berberine\u2010induced gut\u2013brain axis signal transmission. Sphingolipid metabolism might mediate the neuroinflammation amelioration following vagus afferent fiber activation.\n                  <\/jats:p>","DOI":"10.1002\/ptr.7490","type":"journal-article","created":{"date-parts":[[2022,5,18]],"date-time":"2022-05-18T10:04:26Z","timestamp":1652868266000},"page":"2964-2981","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Vagus nerve stimulated by microbiota\u2010derived hydrogen sulfide mediates the regulation of berberine on microglia in transient middle cerebral artery occlusion rats"],"prefix":"10.1002","volume":"36","author":[{"given":"Sai\u2010jia","family":"Ni","sequence":"first","affiliation":[{"name":"Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy Nanjing University of Chinese Medicine  Nanjing 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