Regulation of Microglia-Mediated Neuroinflammation Post-Intracerebral Hemorrhage by Gut Microbiota and Short-Chain Fatty Acid Metabolism

Intracerebral hemorrhage (ICH) induces alterations in the gut microbiota composition, significantly impacting neuroinflammation post-ICH. However, the impact of gut microbiota absence on neuroinflammation following ICH-induced brain injury remain unexplored. Here, we observed that the gut microbiota absence was associated with reduced neuroinflammation, alleviated neurological dysfunction, and mitigated gut barrier dysfunction post-ICH. In contrast, recolonization of microbiota from ICH-induced SPF mice by transplantation of fecal microbiota (FMT) exacerbated brain injury and gut impairment post-ICH. Additionally, microglia with transcriptional changes mediated the protective effects of gut microbiota absence on brain injury, with Apoe emerging as a hub gene. Subsequently, Apoe deficiency in peri-hematomal microglia was associated with improved brain injury. Finally, we revealed that gut microbiota influence brain injury and gut impairment via gut-derived short-chain fatty acids (SCFA). To investigate the complex modulatory effects of the gut microbiota on microglia following intracerebral hemorrhage, we established a intracerebral hemorrhage collagenase model and corresponding sham surgery controls using antibiotic cocktail-treated ABX mice, germ-free mice, and SPF mice. Subsequently, on days 3 and 7 post-cerebral hemorrhage, we performed RNA sequencing on the microglia surrounding the hematoma using flow cytometry-based cell sorting, and analyzed the RNA-Seq data to obtain gene expression profiles.