Diet-Induced Dysbiosis and Genetic Background Synergize With Cystic Fibrosis Transmembrane Conductance Regulator Deficiency to Promote Cholangiopathy in Mice
Diet-Induced Dysbiosis and Genetic Background Synergize With Cystic Fibrosis Transmembrane Conductance Regulator Deficiency to Promote Cholangiopathy in Mice
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DOI：
10.1002/hep4.1266
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发表时间：
2018-12-01
影响因子：
5.1
通讯作者：
Housset, Chantal
中科院分区：
文献类型：
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作者：
Debray, Dominique;El Mourabit, Haquima;Housset, Chantal
囊性纤维化 (CF) 相关肝病最典型的表现是胆管病，可进展为肝硬化。我们的目的是确定环境和遗传因素对小鼠 CF 相关胆管病发生的潜在影响。囊性纤维化跨膜电导调节剂 (Cftr)(-/-) 小鼠和同源 C57BL/6J 背景中的 Cftr(+/+) 同窝小鼠喂食高中链甘油三酯 (MCT) 饮食。对 3 个月大雄性的肝脏组织病理学、粪便微生物群、肠道炎症和屏障功能、胆汁酸稳态和肝脏转录组进行了分析。随后，将MCT饮食改为含有聚乙二醇（PEG）的饲料，并将遗传背景改为混合C57BL/6J；129/Ola背景（由三个回交产生），以测试它们对表型的影响。采用 MCT 饮食的 C57BL/6J Cftr(-/-) 小鼠出现了与菌群失调（主要是大肠杆菌富集）和低度肠道炎症相关的胆管病特征。与 Cftr(+/+) 同窝小鼠相比，它们表现出肠道通透性增加、次级胆汁酸缺乏以及回肠胆汁酸转运蛋白表达低。饮食引起的（含 PEG 饲料）肠道微生物群组成的变化在很大程度上阻止了 Cftr(-/-) 小鼠胆管病的发生。无论 Cftr 状态如何，混合 C57BL/6J;129/Ola 背景的小鼠在 MCT 饮食下出现脂肪肝。与同类小鼠相比，混合背景中的 Cftr(-/-) 小鼠没有表现出胆管病，这不能用肠道微生物群或肠道通透性的差异来解释。对肝脏的转录组分析揭示了同类小鼠与混合背景小鼠中的差异表达，特别是免疫相关基因的表达。总之，我们的研究结果表明，CFTR 缺陷会导致肠道通透性异常，再加上饮食引起的菌群失调和免疫相关的遗传易感性，会促进 CF 相关的胆管病。
The most typical expression of cystic fibrosis (CF)-related liver disease is a cholangiopathy that can progress to cirrhosis. We aimed to determine the potential impact of environmental and genetic factors on the development of CF-related cholangiopathy in mice. Cystic fibrosis transmembrane conductance regulator (Cftr)(-/-) mice and Cftr(+/+) littermates in a congenic C57BL/6J background were fed a high medium-chain triglyceride (MCT) diet. Liver histopathology, fecal microbiota, intestinal inflammation and barrier function, bile acid homeostasis, and liver transcriptome were analyzed in 3-month-old males. Subsequently, MCT diet was changed for chow with polyethylene glycol (PEG) and the genetic background for a mixed C57BL/6J;129/Ola background (resulting from three backcrosses), to test their effect on phenotype. C57BL/6J Cftr(-/-) mice on an MCT diet developed cholangiopathy features that were associated with dysbiosis, primarily Escherichia coli enrichment, and low-grade intestinal inflammation. Compared with Cftr(+/+) littermates, they displayed increased intestinal permeability and a lack of secondary bile acids together with a low expression of ileal bile acid transporters. Dietary-induced (chow with PEG) changes in gut microbiota composition largely prevented the development of cholangiopathy in Cftr(-/-) mice. Regardless of Cftr status, mice in a mixed C57BL/6J;129/Ola background developed fatty liver under an MCT diet. The Cftr(-/-) mice in the mixed back-ground showed no cholangiopathy, which was not explained by a difference in gut microbiota or intestinal permeability, compared with congenic mice. Transcriptomic analysis of the liver revealed differential expression, notably of immune-related genes, in mice of the congenic versus mixed background. In conclusion, our findings suggest that CFTR deficiency causes abnormal intestinal permeability, which, combined with diet-induced dysbiosis and immune-related genetic susceptibility, promotes CF-related cholangiopathy.