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 Firmicutes/Bacteroidetes 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 Escherichia_Shigella increased in the MET group than the C and CLP groups, while Lactobacillaceae abundance decreased. Furthermore, Prevotella_9, Muribaculaceae, and Alloprevotella related to short-chain fatty acids production increased in the sepsis-related neurodamage of metformin-treated rats. Additionally, Prevotella_9 and Muribaculaceae 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.
Although numerous studies have clarified the synergistic pathogenesis in mouse models of influenza A virus (IAV)-associated dual infections, fewer studies have investigated the influence of intranasal liquid administration on the disease. This study explored the effects of intranasal PBS administration in mouse models of mimic IAV dual infection and the infectious dose of IAV that caused equivalent pathogenesis in different dual infection models. Weights, survival rates, virus loads, lung indexes and lung pathology were compared. We demonstrated that intranasal PBS administration following H1N1 or H3N2 infection increased weight loss, mortality, virus replication and lung damage. No difference was observed if the order was reversed or PBS was given simultaneously with IAV. To induce equivalent virulence, a 20-fold difference in the infectious dose was needed when the H3N2–PBS superinfection and H3N2–PBS coinfection or PBS–H3N2 superinfection groups were compared. Our study demonstrated that the unfavourable effect of intranasal liquid administration should not be neglected and that both the strain and infectious dose of IAV should be considered to avoid an illusion of synergistic pathogenicity when establishing IAV-associated dual infection model. A 20-fold lower dose than that of coinfection may be a better choice for secondary infection following IAV.
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