Metformin attenuated sepsis-related liver injury by modulating gut microbiota

Abstract

Increased evidence shows that gut microbiota acts as the primary regulator of the liver; however, their role in sepsis-related liver injury (SLI) in the elderly is unclear. This study assessed whether metformin could attenuate SLI by modulating gut microbiota in septic aged rats. Cecal ligation and puncture (CLP) was used to induce SLI in aged rats. Fecal microbiota transplantation (FMT) was used to validate the roles of gut microbiota in these pathologies. The composition of gut microbiota was analyzed by 16S rRNA sequencing. Moreover, the liver and colon tissues were analyzed by histopathology, immunofluorescence, immunohistochemistry,and reverse transcription polymerase chain reaction (RT-PCR). Metformin improved liver damage, colon barrier dysfunction in aged SLI rats. Moreover, metformin improved sepsis-induced liver inflammation and damage under the presence of gut microbiota. Importantly, FMT assay showed that rats gavaged with feces from metformin-treated SLI rats displayed fewer-severe liver damage and colon barrier dysfunction than did rats gavaged with feces from SLI rats.The gut microbiota composition among the sham-operated, CLP-operated and metformin-treated SLI rats were different. In particular, the proportion of Klebsiella and Escherichia_Shigella was higher in SLI rats than sham-operated and metformin-treated SLI rats;while metformin could increased the proportion of Bifidobacterium, Muribaculaceae, Parabacteroides_distasonis and Alloprevitella in aged SLI rats. Additionally, Klebsiella and Escherichia_Shigella correlated positively with the inflammatory factors in the liver. Our findings suggest that metformin may improve the liver injury by regulating the gut microbiota and alleviating colon barrier dysfunction in septic aged rats, which may be an effective therapy for SLI.

Keywords

• sepsis-related liver injury
• aged rats
• metformin
• gut microbiota