Original Research
Hepatic Injury in Nonalcoholic Steatohepatitis Contributes to Altered Intestinal Permeability

https://doi.org/10.1016/j.jcmgh.2015.01.001Get rights and content
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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 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.

Keywords

Meta-Analysis
Myosin Light Chain Kinase
Steatosis
Tight Junctions

Abbreviations used in this paper

ALT
alanine aminotransferase
CI
confidence interval
FITC
fluorescein isothiocyanate
IL
interleukin
MCD
methionine and choline deficient
MLCK
myosin light chain kinase
NAFLD
nonalcoholic fatty liver disease
NASH
nonalcoholic steatohepatitis
NPC
nonparenchymal cells
OR
odds ratio
PBS
phosphate-buffered saline
qRT-PCR
quantitative real-time polymerase chain reaction
TEER
transepithelial electrical resistance
TNFα
tumor necrosis factor-α
ZO-1
zona occludens-1

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Conflicts of interest The authors disclose no conflicts.

Funding This study was funded by a Sheila Sherlock Clinical and Translation Research Award (to J.L.); and the National Institutes of Health NIH R01DK61931 and R01DK68271 (to J.R.T.) and DK078772 (to R.T.C.).

Authors share corresponding authorship.