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ACS Infect Dis. 2018 Jan 12;4(1):46-52. doi: 10.1021/acsinfecdis.7b00139. Epub 2017 Nov 10.

Nonsteroidal Anti-Inflammatory Drug-Induced Leaky Gut Modeled Using Polarized Monolayers of Primary Human Intestinal Epithelial Cells.

Author information

1
Department of Chemistry, University of North Carolina , 250 Bell Tower Drive, Chapel Hill, North Carolina 27599-3290, United States.
2
Translational Pathology Laboratory, Lineberger Comprehensive Cancer Center, University of North Carolina , 160 North Medical Drive, Chapel Hill, North Carolina 27599-7525, United States.
3
Department of Biomedical Engineering, University of North Carolina , Chapel Hill, North Carolina 27599, United States , and North Carolina State University, Raleigh, North Carolina 27607, United States.
4
Departments of Medicine, Cell Biology and Physiology, University of North Carolina , 111 Mason Farm Road, Chapel Hill, North Carolina 27599-7032, United States.
5
Department of Genetics, University of North Carolina , 120 Mason Farm Road, Chapel Hill, North Carolina 27599-7264, United States.
6
Lineberger Comprehensive Cancer Center, University of North Carolina , 450 West Drive, Chapel Hill, North Carolina 27599, United States.
7
Departments of Biochemistry and Biophysics, and Microbiology and Immunology, and the Integrated Program for Biological and Genome Science, University of North Carolina , 250 Bell Tower Drive, Chapel Hill, North Carolina 27599-3290, United States.

Abstract

The intestinal epithelium provides a critical barrier that separates the gut microbiota from host tissues. Nonsteroidal anti-inflammatory drugs (NSAIDs) are efficacious analgesics and antipyretics and are among the most frequently used drugs worldwide. In addition to gastric damage, NSAIDs are toxic to the intestinal epithelium, causing erosions, perforations, and longitudinal ulcers in the gut. Here, we use a unique in vitro human primary small intestinal cell monolayer system to pinpoint the intestinal consequences of NSAID treatment. We found that physiologically relevant doses of the NSAID diclofenac (DCF) are cytotoxic because they uncouple mitochondrial oxidative phosphorylation and generate reactive oxygen species. We also find that DCF induces intestinal barrier permeability, facilitating the translocation of compounds from the luminal to the basolateral side of the intestinal epithelium. The results we outline here establish the utility of this novel platform, representative of the human small intestinal epithelium, to understand NSAID toxicity, which can be applied to study multiple aspects of gut barrier function including defense against infectious pathogens and host-microbiota interactions.

KEYWORDS:

NSAIDs; bacterial translocation; leaky gut; mitochondria; small intestine; superoxide

PMID:
29094594
PMCID:
PMC6013262
DOI:
10.1021/acsinfecdis.7b00139
[Indexed for MEDLINE]
Free PMC Article

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