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Intestinal microbiota mediates the susceptibility to polymicrobial sepsis‐induced liver injury by granisetron generation in mice
DOI: 10.1002/hep.30361
Abstract & Authors
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Abstract:
Sepsis‐induced liver injury is recognized as a key problem in intensive care units (ICUs). The gut microbiota has been touted as an important mediator of liver disease development; however, the precise roles of gut microbiota in regulating sepsis‐induced liver injury are unknown. Here, we aimed to investigate the role of the gut microbiota in sepsis‐induced liver injury and the underlying mechanism. Cecal ligation and puncture (CLP) was employed to induce polymicrobial sepsis and related liver injury. Fecal microbiota transplantation (FMT) was used to validate the roles of gut microbiota in these pathologies. Metabolomics analysis was performed to characterize the metabolic profile differences between sepsis‐resistant (Res, survived to 7 days after CLP) and sepsis‐sensitive (Sen, moribund before or approximately 24 h after CLP) mice. Mice gavaged with feces from Sen mice displayed more severe liver damage than did mice gavaged with feces from Res mice. The gut microbial metabolic profile between Sen and Res mice was different. In particular, the microbiota from Res mice generated more granisetron, a 5‐hydroxytryptamine 3 (5‐HT3) receptor antagonist, than the microbiota from Sen mice. Granisetron protected mice against CLP‐induced death and liver injury. Moreover, proinflammatory cytokines expression by macrophages after LPS challenge was markedly reduced in the presence of granisetron. Both treatment with granisetron and genetic knockdown of the 5‐HT3A receptor in cells suppressed NF‐кB transactivation and p‐p38 accumulation in macrophages. Gut microbial granisetron levels showed a significantly negative correlation with plasma ALT/AST levels in septic patients. Conclusion: Our study revealed that gut microbiota plays a key role in the sensitization of sepsis‐induced liver injury and identified granisetron as a novel hepatoprotective compound during sepsis development.
First Authors:
Shenhai Gong,Zhengzheng Yan,Zhanguo Liu,Mengwei Niu
Correspondence:
Ping Chang,Yong Jiang,Peng Chen
All Authors:
Shenhai Gong,Zhengzheng Yan,Zhanguo Liu,Mengwei Niu,Heng Fang,Na Li,Chenyang Huang,Lei Li,Guiming Chen,Haihua Luo,Xiaojiao Chen,Hongwei Zhou,Jingjuan Hu,Wei Yang,Qiaobing Huang,Bernd Schnabl,Ping Chang,Timothy R Billiar,Yong Jiang,Peng Chen
2018-12-01Article
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