Metformin Alleviates Neuroinflammation Following Intracerebral Hemorrhage in Mice by Regulating Microglia/Macrophage Phenotype in a Gut Microbiota-Dependent Manner

Abstract

The gut microbiota plays a key role in regulating intracerebral hemorrhage (ICH)-induced neuroinflammation. The anti-neuroinflammatory effects of metformin (Met) have been reported in many central nervous system (CNS) diseases. However, whether Met regulates neuroinflammation through the gut microbiota in ICH-induced brain injury remains unknown. We found that Met treatment substantially alleviated neurological dysfunction and reduced neuroinflammation by inhibiting pro-inflammatory polarization of microglia/macrophages in mice with ICH. Moreover, Met treatment altered the microbiota composition and improved intestinal barrier function. The expression of lipopolysaccharide-binding protein (LBP), a biomarker of intestinal barrier damage, was also significantly reduced by Met treatment. Neuroinflammation was also potently ameliorated after the transplantation of fecal microbiota from Met-treated ICH mice. The neuroprotective effects of fecal microbiota transplantation (FMT) were similar to those of oral Met treatment. However, suppression of the gut microbiota negated the neuroprotective effects of Met in ICH mice. Therefore, Met is a promising therapeutic agent for neuroinflammation owing to ICH-induced imbalance of the gut microbiota.

Gut microbes in cerebrovascular diseases: Gut flora imbalance, potential impact mechanisms and promising treatment strategies

“…(Continued) polarization of microglia/macrophages and has a neuroprotective effect similar to that of microflora transplantation (48). The most widely studied florae are prebiotics and probiotics.…”

“…Proteobacteria and Firmicutes showed an overall increasing trend, while Bacteroidetes showed a decreasing trend, and there were some contradictions in the changes in Actinobacteria ( 20 , 24 , 25 , 27 , 29 , 38 – 61 ). In addition, there were changes in Verrucomicrobia , Lentisphaerae , Candidatus , Parcubacteria , Deferribacteres , and other species of bacteria ( 20 , 27 , 41 – 44 , 48 , 54 ). However, there were some differences in the changes in different bacteria, different species of bacteria, and different lesion periods within each group.…”

“…Studies have reported that Escherichia / Shigella , Peptoniphilus , Ezakiella , and Enterococcus are more abundant in the bacterial flora after IS and ICH ( 29 ). ICH is primarily characterized by increased Actinomycetes , Bacteroidetes , and Firmicutes and minor alterations in other bacteria ( 25 , 40 , 48 ). Moreover, gut microorganisms change over time.…”

“…Metformin possesses potent anti-inflammatory and immunosuppressive properties. In ICH mice, metformin effectively ameliorates neurological dysfunction and lowers neuroinflammation by suppressing the proinflammatory polarization of microglia/macrophages and has a neuroprotective effect similar to that of microflora transplantation ( 48 ). The most widely studied florae are prebiotics and probiotics.…”

Interplay between Gut Microbiota and NLRP3 Inflammasome in Intracerebral Hemorrhage

“…The gut microbiota can affect the outcome of acute brain injury by modulating the immune system [16]. It has been reported that the dysregulation of the gut microbiota triggers neuroinflammation and increases disease severity in animal ICH models [17,18]. Changes in the gut microbiota influence neuroinflammation by activating the NLRP3 inflammasome and promoting the release of inflammatory cytokines.…”