Alteration of Gut Microbiome Induced by Berberine Improves Visceral Hypersensitivity via Inhibiting Activation of Microglia

Background: Accumulating evidence indicates that agents targeting gut dysbiosis are effective on improving symptoms in irritable bowel syndrome (IBS). However, the potential mechanisms remain unclear. Here, we investigated the roles of berberine in modulating the microbiota-gut-brain axis in models of IBS. Methods: Two models were used to mimic brain-gut axis dysfunction. Specific pathogen-free Sprague Dawley (SD) rats were subjected to water avoidance stress (WAS) and berberine treatment, and germ-free (GF) SD rats underwent fecal microbiota transplantation (FMT) from patient with IBS, followed by berberine or rifaximin gavage. Visceral sensation and depressive behaviors were assessed, colonic tryptase was measured, and microglial activation was evaluated. The fecal microbiota was profiled by 16S rRNA sequencing, and short chain fatty acids (SCFAs) were measured. Findings: Berberine alleviated stress-induced visceral hypersensitivity and activation of colonic mast cells and microglia. Transfer of fecal samples from berberine-treated stressed donors to GF rats showed protective effects against WAS. IBS-FMT induced visceral hypersensitivity and a pro-inflammatory phenotype of microglia. Berberine, not rifaximin, significantly reversed the activation of microglia, as well as altered microbial composition and function and SCFA profiles in stools of IBS-FMT rats. Pearson correlation analysis revealed positive correlations between SCFA-producing genera or probiotics and the morphological parameters of microglia. Interpretation: Berberine-altered gut microbiota mediated the modulating effects of the agent on microglial activation and visceral hypersensitivity, providing a potential option for the treatment of IBS. Funding Statement: National Natural Science Foundation of China (No.81670491) and Capital’s Funds for Health Improvement and Research (No.2016-2-4093). Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: All protocols were approved by the Laboratory Animal Welfare Ethics branch of the Biomedical Ethics Committee of Peking University (approval no. LA2016230).