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.
Highlights
Intracerebral hemorrhage (ICH) is a common endovascular disease mainly related to aging and hypertension and shows poor outcomes and high mortality rates (Taylor et al, 2017; Zhu et al, 2019)
We investigated the effect of Met on intracerebral hemorrhage (ICH)-induced neuroinflammation, the changes in the microglial/macrophage phenotype, and the functional changes in the gastrointestinal tract
We examined the transitions in microglial/macrophage phenotypes in the peri-hematoma region using immunofluorescence to explore the effects of Met on the ICH-induced neuroinflammation
Summary
Intracerebral hemorrhage (ICH) is a common endovascular disease mainly related to aging and hypertension and shows poor outcomes and high mortality rates (Taylor et al, 2017; Zhu et al, 2019). ICH causes acute brain injury, which can lead to primary and secondary injuries (Zhu et al, 2019). Metformin Regulating Microglia Phenotype After ICH secondary brain injury involves neuroinflammation, cytotoxicity, oxidative stress, white matter injury, and neuronal apoptosis (Zhao et al, 2014; Duan et al, 2016; Li et al, 2017; Fu et al., 2021b,c). Surgical hematoma evacuation has been associated with protective effects such as the alleviation of mass effects and hematoma-related brain injury. This method fails to improve neurological function in patients with ICH (Mendelow et al, 2013). A new therapeutic strategy for ICH is urgently needed
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