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Abstract：
BACKGROUND: Dysbiosis of gut microbiota is frequent in liver cirrhosis (LC) patients, and splenectomy (SP) has been reported to improve LC. Herein, we report the effects of SP on gut microbiota, especially on Veillonella parvula, a Gram-negative coccus of the gastrointestinal tract, in LC mice, and the underlying mechanism.
METHODS: LC mice models were induced by tail vein injection of concanavalin A (ConA), followed by SP. 16 s rRNA sequencing was conducted to analyze the effects of ConA induction and SP on mouse gut microbiota and the gene expression affected by gut microbiota. LC mice receiving SP were gavaged with Veillonella parvula. Likewise, hepatic stellate cells (HSC) and hepatocytes (HC) were induced with conditioned medium (CM) of Veillonella parvula.
RESULTS: SP alleviated LC in mice by restoring gut barrier function and maintaining gut microbiota balance, with Veillonella as the key genus. The Veillonella parvula gavage on LC mice reversed the ameliorative effect of SP. The CM of Veillonella parvula promoted the activation of HSC and the release of IL-6, IL-1β, and TNF-α. Also, the CM of Veillonella parvula induced HC pyroptosis and the release of ALT and AST. Veillonella parvula represented an imbalance in the gut microbiota, thus enhancing gut-derived endotoxins in the liver with the main target being Tlr4/Nlrp3. Inhibition of Tlr4 blocked Veillonella parvula-induced HC damage, HSC activation, and subsequent LC progression.
CONCLUSIONS: SP-mediated gut microbiota regulation ameliorates ConA-related LC progression by inhibiting Tlr4/Nlrp3 in the liver.
METHODS: LC mice models were induced by tail vein injection of concanavalin A (ConA), followed by SP. 16 s rRNA sequencing was conducted to analyze the effects of ConA induction and SP on mouse gut microbiota and the gene expression affected by gut microbiota. LC mice receiving SP were gavaged with Veillonella parvula. Likewise, hepatic stellate cells (HSC) and hepatocytes (HC) were induced with conditioned medium (CM) of Veillonella parvula.
RESULTS: SP alleviated LC in mice by restoring gut barrier function and maintaining gut microbiota balance, with Veillonella as the key genus. The Veillonella parvula gavage on LC mice reversed the ameliorative effect of SP. The CM of Veillonella parvula promoted the activation of HSC and the release of IL-6, IL-1β, and TNF-α. Also, the CM of Veillonella parvula induced HC pyroptosis and the release of ALT and AST. Veillonella parvula represented an imbalance in the gut microbiota, thus enhancing gut-derived endotoxins in the liver with the main target being Tlr4/Nlrp3. Inhibition of Tlr4 blocked Veillonella parvula-induced HC damage, HSC activation, and subsequent LC progression.
CONCLUSIONS: SP-mediated gut microbiota regulation ameliorates ConA-related LC progression by inhibiting Tlr4/Nlrp3 in the liver.
摘要：
背景：在肝硬化（LC）患者中，肠道微生物群的菌群失调很常见，据报道，脾切除术（SP）可以改善LC。在这里，我们报道了SP对肠道微生物群的影响，尤其是在小风韦洛内菌身上,胃肠道的革兰氏阴性球菌，在LC小鼠中，以及潜在的机制。
方法：尾静脉注射伴刀豆球蛋白A(ConA)诱导LC小鼠模型,其次是SP。进行16srRNA测序以分析ConA诱导和SP对小鼠肠道菌群的影响以及受肠道菌群影响的基因表达。将接受SP的LC小鼠用细小Veillonella灌胃。同样，肝星状细胞（HSC）和肝细胞（HC）用条件培养基（CM）诱导。
结果：SP通过恢复肠道屏障功能和维持肠道菌群平衡减轻小鼠的LC，以Veillonella为关键属。对LC小鼠进行小维洛氏杆菌灌胃可逆转SP的改善作用。小维肠杆菌的CM促进HSC的活化和IL-6、IL-1β的释放,和TNF-α。此外，小维肠杆菌的CM诱导的HC焦亡和ALT和AST的释放。细小韦洛氏菌代表了肠道微生物群的不平衡，从而增强肝脏中的肠源性内毒素,其主要靶标是Tlr4/Nlrp3。抑制Tlr4阻断小静脉菌诱导的HC损伤，HSC激活,以及随后的LC进展。
结论：SP介导的肠道菌群调节通过抑制肝脏中的Tlr4/Nlrp3改善ConA相关的LC进展。
方法：尾静脉注射伴刀豆球蛋白A(ConA)诱导LC小鼠模型,其次是SP。进行16srRNA测序以分析ConA诱导和SP对小鼠肠道菌群的影响以及受肠道菌群影响的基因表达。将接受SP的LC小鼠用细小Veillonella灌胃。同样，肝星状细胞（HSC）和肝细胞（HC）用条件培养基（CM）诱导。
结果：SP通过恢复肠道屏障功能和维持肠道菌群平衡减轻小鼠的LC，以Veillonella为关键属。对LC小鼠进行小维洛氏杆菌灌胃可逆转SP的改善作用。小维肠杆菌的CM促进HSC的活化和IL-6、IL-1β的释放,和TNF-α。此外，小维肠杆菌的CM诱导的HC焦亡和ALT和AST的释放。细小韦洛氏菌代表了肠道微生物群的不平衡，从而增强肝脏中的肠源性内毒素,其主要靶标是Tlr4/Nlrp3。抑制Tlr4阻断小静脉菌诱导的HC损伤，HSC激活,以及随后的LC进展。
结论：SP介导的肠道菌群调节通过抑制肝脏中的Tlr4/Nlrp3改善ConA相关的LC进展。
