Rifaximin-Mediated Gut Microbiota Regulation Modulates the Polarization of Microglia During CUMS in Rat

Abstract Background: Chronic unpredictable mild stress (CUMS) can not only lead to depression-like behavior but also change the composition of the gut microbiome. Regulating the gut microbiome can have an antidepressant effect, but the mechanism by which it improves depressive symptoms is not clear. Short-chain fatty acids (SCFAs) are small molecular compounds produced by the fermentation of non-digestible carbohydrates. SFCAs are ubiquitous in intestinal endocrine and immune cells, making them important mediators of gut microbiome-regulated body functions. Activated M1 microglia can cause pro-inflammatory and neurotoxic effects, while M2 microglia serve anti-inflammatory and neuroprotective functions. The balance between the two phenotypes of microglia plays an important role in the occurrence and treatment of depression caused by chronic stress. We hypothesized that rifaximin exerts an antidepressant effect by changing the abundance of fecal SFCA metabolites and transforming the microglial phenotype. Methods: We administered 150 mg/kg rifaximin intragastrically to rats exposed to CUMS for 4 weeks and investigated the composition of the fecal microbiome, the content of short-chain fatty acids in the serum and brain, microglial phenotypic profiles and hippocampal neurogenesis. Results: Our results show that rifaximin ameliorated depressive-like behavior induced by CUMS, as reflected by sucrose preference, the open field test and the Morris water maze. Rifaximin increased the relative abundance of Ruminococcaceae, which were significantly positively correlated with high levels of butyrate in the brain. Rifaximin also increased the transformation of M1 microglia into the M2 type in the hippocampal dentate gyrus (DG) and ameliorated neurogenic abnormalities and functional deficits caused by CUMS.Conclusions: These results suggest that rifaximin can enhance the neuroprotective effect of microglia to some extent by regulating the gut microbiome and one of its metabolites, butyrate.