Hepatic Injury in Nonalcoholic Steatohepatitis Contributes to Altered Intestinal Permeability

作者：Jay Luther, John J. Garber, Hamed Khalili, Maneesh Dave, Shyam Sundhar Bale, Rohit Jindal, Daniel Motola, Sanjana Luther, Stefan Bohr, Soung Won Jeoung, Vikram Deshpande, Gurminder Singh, Jerrold R. Turner, Martin L. Yarmush, Raymond T. Chung, Suraj J. Patel · 发表于：Cellular and Molecular Gastroenterology and Hepatology · 年份：2015 · DOI：10.1016/j.jcmgh.2015.01.001 · 被引用次数：278 · 研究领域：Liver Disease Diagnosis and Treatment、Drug Transport and Resistance Mechanisms、Alcohol Consumption and Health Effects

Background & Aims 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. Methods 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. Results 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 intesti...