title: Hepatic Injury in Nonalcoholic Steatohepatitis Contributes to Altered Intestinal Permeability.
abstract: OBJECTIVE
  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 TNFαproduction yet has no direct effect on intestinal epithelial cells. Although these data suggest a role for hepatic TNFαin 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.
  
  
  CONCLUSIONS
  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 TNFαand MLCK.
authors.affiliation: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jay
authors.initials: J
authors.lastname: Luther
authors.affiliation: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: John J
authors.initials: JJ
authors.lastname: Garber
authors.affiliation: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Hamed
authors.initials: H
authors.lastname: Khalili
authors.affiliation: Division of Gastroenterology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Maneesh
authors.initials: M
authors.lastname: Dave
authors.affiliation: Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, and the Shriners Burns Hospital, Boston, Massachusetts.
authors.forename: Shyam Sundhar
authors.initials: SS
authors.lastname: Bale
authors.affiliation: Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, and the Shriners Burns Hospital, Boston, Massachusetts.
authors.forename: Rohit
authors.initials: R
authors.lastname: Jindal
authors.affiliation: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Motola
authors.affiliation: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Sanjana
authors.initials: S
authors.lastname: Luther
authors.affiliation: Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, and the Shriners Burns Hospital, Boston, Massachusetts.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bohr
authors.affiliation: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Soung Won
authors.initials: SW
authors.lastname: Jeoung
authors.affiliation: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Vikram
authors.initials: V
authors.lastname: Deshpande
authors.affiliation: Department of Pathology, University of Chicago, Chicago, Illinois.
authors.forename: Gurminder
authors.initials: G
authors.lastname: Singh
authors.affiliation: Department of Pathology, University of Chicago, Chicago, Illinois.
authors.forename: Jerrold R
authors.initials: JR
authors.lastname: Turner
authors.affiliation: Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, and the Shriners Burns Hospital, Boston, Massachusetts.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Yarmush
authors.affiliation: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Chung
authors.affiliation: Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, and the Shriners Burns Hospital, Boston, Massachusetts.
authors.forename: Suraj J
authors.initials: SJ
authors.lastname: Patel
keywords: Meta-Analysis; Myosin Light Chain Kinase; Steatosis; Tight Junctions