Hepatic Injury in Nonalcoholic Steatohepatitis Contributes to Altered Intestinal Permeability

Jay Luther, John J. Garber, Hamed Khalili, Maneesh Dave, Shyam Sundhar Bale, Rohit Jindal, Daniel L. Motola, Sanjana Luther, Stefan Bohr, Soung Won Jeoung, Vikram Deshpande, Gurminder Singh, Jerrold R. Turner, Martin L. Yarmush, Raymond T. Chung, Suraj J. Patel

Research output: Contribution to journalArticlepeer-review

119 Scopus citations

Abstract

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. Invitro 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 invivo 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. Invitro 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. 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 TNFα and MLCK.

Original languageEnglish (US)
Pages (from-to)222-232.e2
JournalCMGH
Volume1
Issue number2
DOIs
StatePublished - Mar 1 2015
Externally publishedYes

Keywords

  • Meta-Analysis
  • Myosin Light Chain Kinase
  • Steatosis
  • Tight Junctions

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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