Intestinal dysbiosis augments liver disease progression via NLRP3 in a murine model of primary sclerosing cholangitis
Intestinal dysbiosis augments liver disease progression via NLRP3 in a murine model of primary sclerosing cholangitis
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DOI：
10.1136/gutjnl-2018-316670
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发表时间：
2019-08-01
期刊：
影响因子：
24.5
通讯作者：
Trautwein, Christian
中科院分区：
文献类型：
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作者：
Liao, Lijun;Schneider, Kai Markus;Trautwein, Christian
目的探讨人胆汁淤积性肝病（CLD）与炎症性肠病的相关性。然而，CLD中肠道微生物群和炎性小体介导的先天免疫反应的功能意义仍然难以捉摸。本研究在类似人类原发性硬化性胆管炎（PSC）的小鼠Mdr2敲除（Mdr2(-/-)）模型中，研究了肠-肝串扰对CLD的功能作用。雄性Mdr2（-/-）、Mdr2（-/-）与肝细胞特异性缺失caspase-8 (Mdr2（-/-)/Casp8(Delta hepa)）杂交的Mdr2（-/-）和野生型（WT）对照小鼠分别饲养8周或52周，以表征Mdr2缺失对肝脏和肠道的影响，包括胆酸和微生物群谱。为了阻断caspase的激活，给药一种泛caspase抑制剂（IDN-7314）。最后，通过微生物群转移实验研究Mdr2（-/-）相关肠道生态失调的功能作用。结果Mdr2（-/-）小鼠表现出不利的肠道微生物群特征，并在肠-肝轴内显著激活NLRP3炎性体。Mdr2（-/-）小鼠肠道生态失调导致肠道屏障功能障碍和细菌易位增加，放大了肝脏nlrp3介导的先天免疫反应。将Mdr2（-/-）微生物群转移到健康的WT对照小鼠中，在受体小鼠中引起了显著的肝损伤，突出了肠道生态失调对疾病进展的因果作用。引人注目的是，IDN-7314抑制炎性体激活，改善肝损伤，逆转血清胆汁酸谱和胆汁淤积相关微生物群特征。结论：mdr2相关性胆汁淤积可引发肠道生态失调。反过来，内毒素易位进入门静脉和随后的NLRP3炎性体激活导致肝损伤加重。这个过程基本上不依赖于肝细胞中的caspase-8，但可以被IDN-7314阻断。
Objective There is a striking association between human cholestatic liver disease (CLD) and inflammatory bowel disease. However, the functional implications for intestinal microbiota and inflammasome-mediated innate immune response in CLD remain elusive. Here we investigated the functional role of gut-liver crosstalk for CLD in the murine Mdr2 knockout (Mdr2(-/-)) model resembling human primary sclerosing cholangitis (PSC).Design Male Mdr2(-/-), Mdr2(-/-) crossed with hepatocyte-specific deletion of caspase-8 (Mdr2(-/-)/Casp8(Delta hepa)) and wild-type (WT) control mice were housed for 8 or 52 weeks, respectively, to characterise the impact of Mdr2 deletion on liver and gut including bile acid and microbiota profiling. To block caspase activation, a pan-caspase inhibitor (IDN-7314) was administered. Finally, the functional role of Mdr2(-/-)-associated intestinal dysbiosis was studied by microbiota transfer experiments.Results Mdr2(-/-) mice displayed an unfavourable intestinal microbiota signature and pronounced NLRP3 inflammasome activation within the gut-liver axis. Intestinal dysbiosis in Mdr2(-/-) mice prompted intestinal barrier dysfunction and increased bacterial translocation amplifying the hepatic NLRP3-mediated innate immune response. Transfer of Mdr2(-/-) microbiota into healthy WT control mice induced significant liver injury in recipient mice, highlighting the causal role of intestinal dysbiosis for disease progression. Strikingly, IDN-7314 dampened inflammasome activation, ameliorated liver injury, reversed serum bile acid profile and cholestasis-associated microbiota signature.Conclusions MDR2-associated cholestasis triggers intestinal dysbiosis. In turn, translocation of endotoxin into the portal vein and subsequent NLRP3 inflammasome activation contribute to higher liver injury. This process does not essentially depend on caspase-8 in hepatocytes, but can be blocked by IDN-7314.