Atorvastatin alleviates microglia-mediated neuroinflammation via modulating the microbial composition and the...

Our previous work has shown that atorvastatin exerts anti-inflammatory properties in ischemic stroke, and recent studies have revealed that intestinal microbiota plays a vital role in the pathogenesis of stroke. However, it is not clear whether the anti-inflammatory effects of atorvastatin against ischemic stroke is related to gut function and microbiota. We report herein that atorvastatin significantly ameliorated the defects in sensorimotor behaviors and reduced microglia-mediated neuroinflammation by inhibiting proinflammatory polarization of microglia in the peri-infarct cortex of the mice with permanent middle cerebral artery occlusion (pMCAO). Moreover, atorvastatin reversed microbial composition (characterized by increased abundance of Firmicutes and Lactobacillus and decreased Bacteroidetes abundance), increased fecal butyrate level, promoted intestinal barrier function (elevated protein levels of claudin-1, occludin and mucoprotein 2), as well as regulated intestinal immune function (decreased MCP-1, TNF-α and increased IL-10). Atorvastatin also significantly reduced the level of circulating endotoxin (lipopolysaccharide-binding protein), which is a biomarker of leaky gut. Transplantation of fecal microbiota collected from atorvastatin treated mice potently attenuated neuroinflammation in pMCAO mice, and the anti-inflammatory effects of fecal microbiota transplantation were similar to those of oral atorvastatin administration. These results suggested that the atorvastatin-mediated restoration of gut microbiota, improvement of intestinal barrier function and regulation of intestinal immunity were involved in the anti-inflammatory function in stroke mice.