Vagus nerve stimulated by microbiota‐derived hydrogen sulfide mediates the regulation of berberine on microglia in transient middle cerebral artery occlusion rats

• Published in: Phytotherapy research Vol. 36; no. 7; pp. 2964 - 2981
• Main Authors: Ni, Sai‐jia, Yao, Zeng‐Ying, Wei, Xiaotong, Heng, Xia, Qu, Shu‐Yue, Zhao, Xin, Qi, Yi‐Yu, Ge, Ping‐Yuan, Xu, Cai‐Ping, Yang, Nian‐Yun, Cao, Yi, Zhu, Hua‐Xu, Guo, Rui, Zhang, Qi‐Chun
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01-07-2022; Wiley Subscription Services, Inc
• Subjects: Antibiotics; Berberine; Brain; Capsaicin receptors; Capsazepine; Cerebral blood flow; Cerebral cortex; Cerebrospinal fluid; Hydrogen sulfide; Inflammation; Ischemia; Lipid metabolism; Metabolism; Metabolomics; Microbiota; Microenvironments; Microglia; Molybdate; Nerves; Occlusion; Polarization; Receptors; Sensory neurons; Signal transmission; Sodium molybdate; Sulfate reduction; Sulfation; Transient receptor potential proteins; Vagus nerve; microbiota; vagus nerve; hydrogen sulfide; microglia; berberine
• ISSN: 0951-418X; 1099-1573
• DOI: 10.1002/ptr.7490

Amelioration of neuroinflammation via modulating microglia is a promising approach for cerebral ischemia therapy. The aim of the present study was to explore gut–brain axis signals in berberine‐modulating microglia polarization following cerebral ischemia. The potential pathway was determined through analyzing the activation of the vagus nerve, hydrogen sulfide (H2S) 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‐induced H2S 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‐fos 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‐dependent manner. H2S stimulates the vagus nerve through TRPV1 is responsible for the berberine‐induced gut–brain axis signal transmission. Sphingolipid metabolism might mediate the neuroinflammation amelioration following vagus afferent fiber activation.