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Indomethacin-induced translocation of bacteria across enteric epithelia is reactive oxygen species-dependent and reduced by vitamin C
Gastrointestinal Research Group, Department of Physiology and Pharmacology, The Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Alberta, Canada.ORCID iD: 0000-0002-8391-1576
Gastrointestinal Research Group, Department of Physiology and Pharmacology, The Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Alberta, Canada.
Gastrointestinal Research Group, Department of Physiology and Pharmacology, The Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Alberta, Canada.
Gastrointestinal Research Group, Department of Physiology and Pharmacology, The Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Alberta, Canada.
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2012 (English)In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 303, no 5, G536-G545 p.Article in journal (Refereed) Published
Abstract [en]

The enteric epithelium must absorb nutrients and water and act as a barrier to the entry of luminal material into the body; this barrier function is a key component of innate immunity. Nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy occurs via inhibition of prostaglandin synthesis and perturbed epithelial mitochondrial activity. Here, the direct effect of NSAIDs [indomethacin, piroxicam (cyclooxygenase 1 and 2 inhibitors), and SC-560 (a cyclooxygenase 1 inhibitor)] on the barrier function of human T84 epithelial cell line monolayers was assessed by transepithelial electrical resistance (TER) and internalization and translocation of a commensal Escherichia coli. Exposure to E. coli in the presence and absence of drugs for 16 h reduced TER; however, monolayers cotreated with E. coli and indomethacin, but not piroxicam or SC-560, displayed significant increases in internalization and translocation of the bacteria. This was accompanied by increased reactive oxygen species (ROS) production, which was also increased in epithelia treated with E. coli only. Colocalization revealed upregulation of superoxide synthesis by mitochondria in epithelia treated with E. coli + indomethacin. Addition of antioxidants (vitamin C or a green tea polyphenol, epigallocathechin gallate) quenched the ROS and prevented the increase in E. coli internalization and translocation evoked by indomethacin, but not the drop in TER. Evidence of increased apoptosis was not observed in this model. The data implicate epithelial-derived ROS in indomethacin-induced barrier dysfunction and show that a portion of the bacteria likely cross the epithelium via a transcellular pathway. We speculate that addition of antioxidants as dietary supplements to NSAID treatment regimens would reduce the magnitude of decreased barrier function, specifically the transepithelial passage of bacteria.

Place, publisher, year, edition, pages
2012. Vol. 303, no 5, G536-G545 p.
Keyword [en]
permeability; nonsteroidal anti-inflammatory drug; mitochondria; intestine
National Category
Gastroenterology and Hepatology Physiology
Research subject
Physiology
Identifiers
URN: urn:nbn:se:oru:diva-40007DOI: 10.1152/ajpgi.00125.2012ISI: 000308464800002PubMedID: 22700821OAI: oai:DiVA.org:oru-40007DiVA: diva2:774698
Note

Funding Agency:

Canadian Institutes of Health Research MOP-171492

Available from: 2014-12-28 Created: 2014-12-28 Last updated: 2018-01-11Bibliographically approved

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