Escherichia coli-derived outer-membrane vesicles induce immune activation and progression of cirrhosis in mice and humans
Escherichia coli-derived outer-membrane vesicles induce immune activation and progression of cirrhosis in mice and humans
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DOI：
10.1111/liv.15539
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发表时间：
2023-03-08
影响因子：
6.7
通讯作者：
Terai, Shuji
中科院分区：
文献类型：
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作者：
Natsui, Kazuki;Tsuchiya, Atsunori;Terai, Shuji
背景和目的失代偿性肝硬化伴纤维化进展导致门静脉高压，随后导致肠道水肿。这些情况削弱了肠道针对细菌的屏障功能，这种情况称为肠漏，导致细菌和细菌成分的入侵。在这里，我们研究了大肠杆菌的外膜囊泡（OMV）在肝硬化发病机制中的作用，大肠杆菌是肝硬化患者的代表性致病性肠道来源细菌。方法我们使用人血清和腹水样本研究了 OMV 在人类中的参与，并使用小鼠肝源性细胞和小鼠肝硬化模型研究了来自大肠杆菌的 OMV 在小鼠中的参与。结果在体外，OMVs 诱导巨噬细胞和中性粒细胞的炎症反应，包括上调 C 型凝集素结构域家族 4 成员 E (Clec4e)，并诱导肝细胞中白蛋白产生的抑制，但对肝星状细胞的直接影响相对较小。在小鼠肝硬化模型中，施用 OMV 会导致肝脏炎症增加，特别是影响巨噬细胞的活化，导致纤维化恶化并减少白蛋白产生。白蛋白的施用减弱了这些炎症变化。此外，针对细菌成分的多种抗体随着Child-Pugh分级的进展而增加，并且在失代偿性肝硬化患者的腹水中检测到OMV。结论 总之，OMVs 诱导炎症、纤维化和白蛋白产生抑制，影响肝硬化的发病机制。我们相信我们的研究为未来预防和治疗肝硬化铺平了道路。
Background and AimsDecompensated cirrhosis with fibrosis progression causes portal hypertension followed by an oedematous intestinal tract. These conditions weaken the barrier function against bacteria in the intestinal tract, a condition called leaky gut, resulting in invasion by bacteria and bacterial components. Here, we investigated the role of outer-membrane vesicles (OMVs) of Escherichia coli, which is the representative pathogenic gut-derived bacteria in patients with cirrhosis in the pathogenesis of cirrhosis. MethodsWe investigated the involvement of OMVs in humans using human serum and ascites samples and also investigated the involvement of OMVs from E. coli in mice using mouse liver-derived cells and a mouse cirrhosis model. ResultsIn vitro, OMVs induced inflammatory responses to macrophages and neutrophils, including the upregulation of C-type lectin domain family 4 member E (Clec4e), and induced the suppression of albumin production in hepatocytes but had a relatively little direct effect on hepatic stellate cells. In a mouse cirrhosis model, administration of OMVs led to increased liver inflammation, especially affecting the activation of macrophages, worsening fibrosis and decreasing albumin production. Albumin administration weakened these inflammatory changes. In addition, multiple antibodies against bacterial components were increased with a progressing Child-Pugh grade, and OMVs were detected in ascites of patients with decompensated cirrhosis. ConclusionsIn conclusion, OMVs induce inflammation, fibrosis and suppression of albumin production, affecting the pathogenesis of cirrhosis. We believe that our study paves the way for the future prevention and treatment of cirrhosis.