Berberine alleviates visceral hypersensitivity in rats by altering gut microbiome and suppressing spinal microglial activation

摘要

Accumulating evidence shows that agents targeting gut dysbiosis are effective for improving symptoms of irritable bowel syndrome (IBS).However,the potential mechanisms remain unclear.In this study we investigated the effects of berberine on the microbiota-gut-brain axis in two rat models of visceral hypersensitivity,i.e.,specific pathogen-free SD rats subjected to chronic water avoidance stress (WAS) and treated with berberine (200 mg·kg-1 ·d-1,ig,for 10 days) as well as germ-free (GF) rats subjected to fecal microbiota transplantation (FMT) from a patient with IBS (designated IBS-FMT) and treated with berberine (200 mg.kg-1·d-1,ig,for 2 weeks).Before the rats were sacrificed,visceral sensation and depressive behaviors were evaluated.Then colonic tryptase was measured and microglial activation in the dorsal lumbar spinal cord was assessed.The fecal microbiota was profiled using 16S rRNA sequencing,and short chain fatty acids (SCFAs) were measured.We showed that berberine treatment significantly alleviated chronic WAS-induced visceral hypersensitivity and activation of colonic mast cells and microglia in the dorsal lumbar spinal cord.Transfer of fecal samples from berberine-treated stressed donors to GF rats protected against acute WAS.FMT from a patient with IBS induced visceral hypersensitivity and pro-inflammatory phenotype in microglia,while berberine treatment reversed the microglial activation and altered microbial composition and function and SCFA profiles in stools of IBS-FMT rats.We demonstrated that berberine did not directly influence LPS-induced microglial activation in vitro.In both models,several SCFA-producing genera were enriched by berberine treatment,and positively correlated to the morphological parameters of microglia.In conclusion,activation of microglia in the dorsal lumbar spinal cord was involved in the pathogenesis of IBS caused by dysregulation of the microbiota-gut-brain axis,and the berberine-altered gut microbiome mediated the modulatory effects of the agent on microglial activation and visceral hypersensitivity,providing a potential option for the treatment of IBS.