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(American Journal of Pathology. 2004;164:947-957.)
© 2004 American Society for Investigative Pathology

Epithelia Under Metabolic Stress Perceive Commensal Bacteria as a Threat

Aisha Nazli*, Ping-Chang Yang*, Jennifer Jury*, Kathryn Howe*, James L. Watson*, Johan D. Söderholm{dagger}, Philip M. Sherman{ddagger}, Mary H. Perdue* and Derek M. McKay*

From the Intestinal Disease Research Programme,*McMaster University, Hamilton, Ontario, Canada; the Hospital for Sick Children,{ddagger}University of Toronto, Toronto, Ontario, Canada; and the Department of Surgery,{dagger}University Hospital, Linköping, Sweden

The normal gut flora has been implicated in the pathophysiology of inflammatory bowel disease and there is increased interest in the role that stress can play in gut disease. The chemical stressor dinitrophenol (DNP, uncouples oxidative phosphorylation) was injected into the ileum of laparotomized rats and mitochondria structure, epithelial permeability, and inflammatory cell infiltrate were examined 6 and 24 hours later. Monolayers of human colonic epithelial cells (T84, HT-29) were treated with DNP ± commensal Escherichia coli, followed by assessment of epithelial permeability, bacterial translocation, and chemokine (ie, interleukin-8) synthesis. Delivery of DNP into rat distal ileum resulted in disruption of epithelial mitochondria; similar changes were noted in mildly inflamed ileal resections from patients with Crohn’s disease. Also, DNP-treated ileum displayed increased gut permeability and immune cell recruitment. Subsequent studies revealed deceased barrier function, increased bacterial translocation, increased production of interleukin-8, and enhanced mobilization of the transcription factor AP-1 in the model epithelial cell lines exposed to commensal bacteria (E. coli strains HB101 or C25), but only when the monolayers were pretreated with DNP (0.1 mmol/L). These data suggest that enteric epithelia under metabolic stress perceive a normally innocuous bacterium as threatening, resulting in loss of barrier function, increased penetration of bacteria into the mucosa, and increased chemokine synthesis. Such responses could precipitate an inflammatory episode and contribute to existing enteric inflammatory disorders.




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