PDF(Pubmed)
Abstract：
The intestinal-liver axis is associated with various liver diseases. Here, we verified the role of the gut microbiota and macrophage activation in the progression of pyrrolizidine alkaloids-induced hepatic sinusoidal obstruction syndrome (PA-HSOS), and explored the possible mechanisms and new treatment options.
The HSOS murine model was induced by gavage of monocrotaline (MCT). An analysis of 16S ribosomal DNA (16S rDNA) of the feces was conducted to determine the composition of the fecal microbiota. Macrophage clearance, fecal microbiota transplantation (FMT), and butyrate supplementation experiments were used to assess the role of intestinal flora, gut barrier, and macrophage activation and to explore the relationships among these three variables.
Activated macrophages and low microflora diversity were observed in HSOS patients and murine models. Depletion of macrophages attenuated inflammatory reactions and apoptosis in the mouse liver. Moreover, compared with control-FMT mice, the exacerbation of severe liver injury was detected in HSOS-FMT mice. Specifically, butyrate fecal concentrations were significantly reduced in HSOS mice, and administration of butyrate could partially alleviated liver damage and improved the intestinal barrier in vitro and in vivo. Furthermore, elevated lipopolysaccharides in the portal vein and high proportions of M1 macrophages in the liver were also detected in HSOS-FMT mice and mice without butyrate treatment, which resulted in severe inflammatory responses and further accelerated HSOS progression.
These results suggested that the gut microbiota exacerbated HSOS progression by regulating macrophage M1 polarization via altered intestinal barrier function mediated by butyrate. Our study has identified new strategies for the clinical treatment of HSOS.
The HSOS murine model was induced by gavage of monocrotaline (MCT). An analysis of 16S ribosomal DNA (16S rDNA) of the feces was conducted to determine the composition of the fecal microbiota. Macrophage clearance, fecal microbiota transplantation (FMT), and butyrate supplementation experiments were used to assess the role of intestinal flora, gut barrier, and macrophage activation and to explore the relationships among these three variables.
Activated macrophages and low microflora diversity were observed in HSOS patients and murine models. Depletion of macrophages attenuated inflammatory reactions and apoptosis in the mouse liver. Moreover, compared with control-FMT mice, the exacerbation of severe liver injury was detected in HSOS-FMT mice. Specifically, butyrate fecal concentrations were significantly reduced in HSOS mice, and administration of butyrate could partially alleviated liver damage and improved the intestinal barrier in vitro and in vivo. Furthermore, elevated lipopolysaccharides in the portal vein and high proportions of M1 macrophages in the liver were also detected in HSOS-FMT mice and mice without butyrate treatment, which resulted in severe inflammatory responses and further accelerated HSOS progression.
These results suggested that the gut microbiota exacerbated HSOS progression by regulating macrophage M1 polarization via altered intestinal barrier function mediated by butyrate. Our study has identified new strategies for the clinical treatment of HSOS.
摘要：
■肠肝轴与各种肝脏疾病相关。这里,我们验证了肠道微生物群和巨噬细胞活化在吡咯啶生物碱诱导的肝窦阻塞综合征（PA-HSOS）进展中的作用，并探讨了可能的机制和新的治疗方案。
■通过野百合碱(MCT)的管饲法诱导HSOS小鼠模型。对粪便的16S核糖体DNA(16SrDNA)进行分析以确定粪便微生物群的组成。巨噬细胞清除,粪便微生物移植（FMT），和丁酸盐补充实验用于评估肠道菌群的作用，肠道屏障,和巨噬细胞活化，并探讨这三个变量之间的关系。
■在HSOS患者和小鼠模型中观察到活化的巨噬细胞和低微生物区系多样性。巨噬细胞的消耗减弱了小鼠肝脏中的炎症反应和细胞凋亡。此外，与对照FMT小鼠相比，在HSOS-FMT小鼠中检测到严重肝损伤的加重。具体来说,丁酸盐在HSOS小鼠粪便中的浓度显著降低，给予丁酸盐可以部分减轻肝损伤，改善体内外肠道屏障。此外，在HSOS-FMT小鼠和未经丁酸盐处理的小鼠中也检测到门静脉中脂多糖的升高和肝脏中M1巨噬细胞的高比例，导致严重的炎症反应并进一步加速HSOS进展。
■这些结果表明，肠道微生物群通过丁酸盐介导的改变肠屏障功能调节巨噬细胞M1极化，从而加剧了HSOS的进展。我们的研究确定了HSOS临床治疗的新策略。
■通过野百合碱(MCT)的管饲法诱导HSOS小鼠模型。对粪便的16S核糖体DNA(16SrDNA)进行分析以确定粪便微生物群的组成。巨噬细胞清除,粪便微生物移植（FMT），和丁酸盐补充实验用于评估肠道菌群的作用，肠道屏障,和巨噬细胞活化，并探讨这三个变量之间的关系。
■在HSOS患者和小鼠模型中观察到活化的巨噬细胞和低微生物区系多样性。巨噬细胞的消耗减弱了小鼠肝脏中的炎症反应和细胞凋亡。此外，与对照FMT小鼠相比，在HSOS-FMT小鼠中检测到严重肝损伤的加重。具体来说,丁酸盐在HSOS小鼠粪便中的浓度显著降低，给予丁酸盐可以部分减轻肝损伤，改善体内外肠道屏障。此外，在HSOS-FMT小鼠和未经丁酸盐处理的小鼠中也检测到门静脉中脂多糖的升高和肝脏中M1巨噬细胞的高比例，导致严重的炎症反应并进一步加速HSOS进展。
■这些结果表明，肠道微生物群通过丁酸盐介导的改变肠屏障功能调节巨噬细胞M1极化，从而加剧了HSOS的进展。我们的研究确定了HSOS临床治疗的新策略。
