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

Abstract

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.

Nobiletin attenuates Nrf2-Gpx4-regulated ferroptosis in septic liver injury by modulating the gut microbiota

“…Recently, growing evidence has highlighted the cross-talk between the gut microbiota and sepsis [38]. There was convincing evidence indicating the potential of constituting effective and safe therapies for sepsis by targeting the intestinal microbiota [39,40]. However, the detailed roles of the intestinal microbiota during sepsis remain largely unknown, and effective therapeutic strategies for its clinical application are still lacking.…”

Alterations in the gut microbiome and metabolome profiles of septic mice treated with Shen FuHuang formula

“…As expected, SFH could modulate the abundance of Escherichia_Shigella , Escherichia_coli , Blautia , and other bacteria, restoring them to levels similar to those of healthy mice. As Escherichia_Shigella has the ability to invade and destruct human colonic epithelium ( Belotserkovsky and Sansonetti, 2018 ), it may incur sepsis-related neural inflammation ( Zhao et al, 2022 ). Blautia , an anaerobic bacteria with probiotic traits, plays specific roles in metabolic diseases, inflammatory settings, and bio-transformation ( Liu et al, 2021 ).…”

Study on the protective effect of berberine treatment on sepsis based on gut microbiota and metabolomic analysis

“…Additionally, a study reported the negative relevance of Muribaculaceae to IL-6 in the CLP rat brain ( 29 ). In this study, Muribaculaceae was increased in the CLP + BBR group compared to the CLP group.…”

“…The processed samples were injected into the analytical equipment. The nontargeted metabolomics approach had been previously described by Zhao et al ( 29 ). The metabolomics analysis performed by the Gas Chromatography-Time-of-Flight Mass Spectrometry (GC-TOF/MS) platform (Gerstel, Germany) integrated processing samples and issuing reports.…”