AUTHOR=Zhao Huayan , Lyu Yuanjun , Zhai Ruiqing , Sun Guiying , Ding Xianfei 

TITLE=Metformin Mitigates Sepsis-Related Neuroinflammation via Modulating Gut Microbiota and Metabolites

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.797312

DOI=10.3389/fimmu.2022.797312

ISSN=1664-3224

ABSTRACT=<p>Gut microbiota affects the functions of brains. However, its mechanism in sepsis remains unclear. This study evaluated the effect of metformin on ameliorating sepsis-related neurodamage by regulating gut microbiota and metabolites in septic rats. Cecal ligation and puncture (CLP) was used to establish the sepsis-related neurodamage animal models. Metformin therapy by gavage at 1 h after CLP administration was followed by fecal microbiota transplantation (FMT) to ensure the efficacy and safety of metformin on the sepsis-related neurodamage by regulating gut microbiota. The gut microbiota and metabolites were conducted by 16S rRNA sequencing and liquid chromatography-tandem mass spectrometry metabolomic analysis. The brain tissue inflammation response was analyzed by histopathology and reverse transcription-polymerase chain reaction (RT-PCR). This study reported brain inflammatory response, hemorrhage in sepsis-related neurodamage rats compared with the control group (C group). Surprisingly, the abundance of gut microbiota slightly increased in sepsis-related neurodamage rats than C group. The ratio of <italic>Firmicutes/Bacteroidetes</italic> was significantly increased in the CLP group than the C group. However, no difference was observed between the CLP and the metformin-treated rats (MET group). Interestingly, the abundance of <italic>Escherichia_Shigella</italic> increased in the MET group than the C and CLP groups, while <italic>Lactobacillaceae</italic> abundance decreased. Furthermore, <italic>Prevotella_9</italic>, <italic>Muribaculaceae</italic>, and <italic>Alloprevotella</italic> related to short-chain fatty acids production increased in the sepsis-related neurodamage of metformin-treated rats. Additionally, <italic>Prevotella_9</italic> and <italic>Muribaculaceae</italic> correlated positively to 29 metabolites that might affect the inflammatory factors in the brain. The FMT assay showed that metformin improved sepsis-related neurodamage by regulating the gut microbiota and metabolites in septic rats. The findings suggest that metformin improves the sepsis-related neurodamage through modulating the gut microbiota and metabolites in septic rats, which may be an effective therapy for patients with sepsis-related neurodamage.</p>