Hepatic Injury in Nonalcoholic Steatohepatitis Contributes to Altered Intestinal Permeability.
Hepatic Injury in Nonalcoholic Steatohepatitis Contributes to Altered Intestinal Permeability.
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DOI：
10.1016/j.jcmgh.2015.01.001
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发表时间：
2015-03
影响因子：
7.2
通讯作者：
Patel SJ
中科院分区：
文献类型：
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作者：
Luther J;Garber JJ;Khalili H;Dave M;Bale SS;Jindal R;Motola DL;Luther S;Bohr S;Jeoung SW;Deshpande V;Singh G;Turner JR;Yarmush ML;Chung RT;Patel SJ
新出现的数据表明，肠道通透性的变化和肠道微生物易位的增加有助于参与非酒精性脂肪性肝炎（NASH）发展的炎症途径。许多研究已经调查了增加的肠通透性和NASH之间的关联。我们对这种关联的荟萃分析研究了潜在的机制。进行了一项荟萃分析，以比较NASH患者和健康对照者的肠通透性增加率。为了进一步阐明潜在的作用机制，我们研究了饮食诱导（蛋氨酸和胆碱缺乏; MCD）NASH小鼠模型中肠道通透性的变化。还进行了体外研究，以研究MCD培养基在细胞水平对肝细胞、枯否细胞和肠上皮细胞的影响。非酒精性脂肪性肝病（NAFLD）患者，特别是NASH患者，与健康对照组相比，更有可能增加肠道通透性。我们将这一临床观察结果与体内数据相关联，体内数据显示喂食MCD饲料的小鼠在肝损伤和肿瘤坏死因子-α（TNFα）诱导的初始阶段后出现肠通透性变化。体外研究表明，MCD培养基诱导肝损伤和TNFα产生，但对肠上皮细胞无直接影响。尽管这些数据表明肝脏TNFα在改变肠通透性中的作用，但我们发现，喂食MCD饲料的对TNFα-肌球蛋白轻链激酶（MLCK）诱导的肠通透性变化具有遗传抗性的小鼠仍会出现通透性增加和肝损伤。我们的临床和实验结果加强了肠通透性增加和NASH之间的联系，也表明肝损伤和炎症的早期阶段以独立于TNFα和MLCK的方式有助于改变肠通透性。
Emerging data suggest that changes in intestinal permeability and increased gut microbial translocation contribute to the inflammatory pathway involved in nonalcoholic steatohepatitis (NASH) development. Numerous studies have investigated the association between increased intestinal permeability and NASH. Our meta-analysis of this association investigates the underlying mechanism. A meta-analysis was performed to compare the rates of increased intestinal permeability in patients with NASH and healthy controls. To further address the underlying mechanism of action, we studied changes in intestinal permeability in a diet-induced (methionine-and-choline-deficient; MCD) murine model of NASH. In vitro studies were also performed to investigate the effect of MCD culture medium at the cellular level on hepatocytes, Kupffer cells, and intestinal epithelial cells. Nonalcoholic fatty liver disease (NAFLD) patients, and in particular those with NASH, are more likely to have increased intestinal permeability compared with healthy controls. We correlate this clinical observation with in vivo data showing mice fed an MCD diet develop intestinal permeability changes after an initial phase of liver injury and tumor necrosis factor-α (TNFα) induction. In vitro studies reveal that MCD medium induces hepatic injury and TNFα production yet has no direct effect on intestinal epithelial cells. Although these data suggest a role for hepatic TNFα in altering intestinal permeability, we found that mice genetically resistant to TNFα-myosin light chain kinase (MLCK)–induced intestinal permeability changes fed an MCD diet still develop increased permeability and liver injury. Our clinical and experimental results strengthen the association between intestinal permeability increases and NASH and also suggest that an early phase of hepatic injury and inflammation contributes to altered intestinal permeability in a fashion independent of TNFα and MLCK.