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

Abstract

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.

Interventional strategies for ischemic stroke based on the modulation of the gut microbiota

“…Huangqi-Honghua (Wang K. et al, 2022) Ruminococcaceae, Bacteroides, Phascolarctobacterium, Desulfovibrionaceae↓ Blautia, Lachnospiraceae, Oscillibacter, Bifidobacterium↑ bile acid receptor FXR activated Huazhuo Jiedu Huoxue Tongluo Prescription (Ni et al, 2022) Firmicutes, Bacteroidetes, Lactobacillus, Prevotella↑ Enterobacteriaceae, Clostridium, Enterococcus↓…”

Cross-Regulation of the Cellular Redox System, Oxygen, and Sphingolipid Signalling

“…Finally, a recent study suggested an indirect link between H 2 S and sphingolipids in a rat model of cerebral ischemia. In that study, the authors orally applied berberine to ischemic rats which improved the neuroinflammation and disease scores in tMCAO-induced cerebral ischemia [ 167 ]. It was shown that oral berberine acted on the gut microbiota and stimulated H 2 S production in the intestine, which subsequently activated the vagus nerve to subsequently alter the cerebral microenvironment resulting in less microglia activation and reduced neuroinflammation.…”

“…Metabolomics analysis of various brain regions revealed changes in sphingolipid metabolism which may mediate the neuroprotection following vagus nerve activation. Notably, sphingosine was strongly increased in the ischemic rat cortex and downregulated by berberine treatment [ 167 ]. These data suggest that microbiota H 2 S production affects cerebral sphingolipid metabolism through vagus nerve activation.…”

Microglial cells: Sensors for neuronal activity and microbiota-derived molecules

“…In line with this observation, in a rat model of transient ischemia, berberine, an alkaloid with weak antibiotic properties, decreased CD86-positive and increased CD163-positive microglial cells in the cerebral cortex, in a microbiota-dependent manner. The authors show that the hydrogen sulfide (H 2 S) derived from microbiota metabolization of berberine, stimulates the vagus nerve through the transient receptor potential vanilloid 1 (TRPV1) and that a cocktail of antibiotics blocked vagal activation, confirming the necessity of a functional metabolizing microbiota ( 128 ).…”