Intestinal Microbiota Mediates the Susceptibility to Polymicrobial Sepsis-Induced Liver Injury by Granisetron Generation in Mice
Intestinal Microbiota Mediates the Susceptibility to Polymicrobial Sepsis-Induced Liver Injury by Granisetron Generation in Mice
复制标题
肠道微生物区系介导格拉司琼诱导的小鼠多菌素脓毒症肝损伤易感性
DOI：
10.1002/hep.30361
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发表时间：
2019-04-01
期刊：
影响因子：
13.5
通讯作者：
Chen, Peng
中科院分区：
文献类型：
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作者：
Gong, Shenhai;Yan, Zhengzheng;Chen, Peng
脓毒症所致的肝损伤被认为是重症监护病房的一个关键问题。肠道微生物区系一直被吹捧为肝脏疾病发展的重要介质；然而，肠道微生物区系在调节脓毒症所致肝损伤中的确切作用尚不清楚。在此，我们旨在研究肠道微生物区系在脓毒症所致肝损伤中的作用及其潜在机制。采用盲肠结扎穿刺术(CLP)诱导多菌败血症及相关肝损伤。粪便微生物区系移植(FMT)用于验证肠道微生物区系在这些病理过程中的作用。代谢组学分析用来表征败血症抵抗(RES；在CLP后存活到7天)和脓毒症敏感(SEN；在CLP前或大约24小时前或大约24小时死亡)小鼠之间的代谢谱差异。用Sen小鼠的粪便灌胃的小鼠表现出比用RES小鼠的粪便灌胃的小鼠更严重的肝脏损伤。SEN和RES小鼠的肠道微生物代谢谱不同。特别是，RES小鼠的微生物群比SEN小鼠的微生物群产生更多的格拉司琼，这是一种5-羟色胺3(5-HT3)受体拮抗剂。格拉司琼对CLP诱导的小鼠死亡和肝脏损伤具有保护作用。此外，在格拉司琼存在下，巨噬细胞在脂多糖(LPS)刺激后的促炎细胞因子的表达明显减少。使用格拉司琼和基因敲除细胞中的5-HT3A受体均可抑制核因子kappaB(NF-kB)的反式激活和巨噬细胞中磷酸化p38(p-p38)的积累。脓毒症患者肠道微生物格拉司琼水平与血浆丙氨酸氨基转移酶(ALT)/天冬氨酸氨基转移酶(AST)水平呈显著负相关。结论：肠道微生物区系在脓毒症所致肝损伤的致敏过程中起关键作用，格拉司琼在脓毒症的发展过程中起到保护肝脏的作用。
Sepsis-induced liver injury is recognized as a key problem in intensive care units. 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 used 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 hours 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 cytokine expression by macrophages after lipopolysaccharide (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 nuclear factor kappa B (NF-kB) transactivation and phosphorylated p38 (p-p38) accumulation in macrophages. Gut microbial granisetron levels showed a significantly negative correlation with plasma alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels in septic patients. Conclusion: Our study indicated that gut microbiota plays a key role in the sensitization of sepsis-induced liver injury and associates granisetron as a hepatoprotective compound during sepsis development.