Epithelia under metabolic stress perceive commensal bacteria as a threat.
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.
Nazli
Aisha
A
Intestinal Disease Research Programme, McMaster University, Hamilton, Ontario, Canada.
Yang
Ping-Chang
PC
Jury
Jennifer
J
Howe
Kathryn
K
Watson
James L
JL
Söderholm
Johan D
JD
Sherman
Philip M
PM
Perdue
Mary H
MH
McKay
Derek M
DM
D000818:Animals; D001422:Bacterial Adhesion / Q000187:drug effects; D018988:Bacterial Translocation / Q000187:drug effects*; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D003424:Crohn Disease / Q000473:pathology; D004140:Dinitrophenols / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli / Q000502:physiology*; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology*; D008297:Male; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological / Q000378:metabolism / Q000382:microbiology; D018808:Transcription Factor AP-1 / Q000096:biosynthesis / Q000187:drug effects; D014475:Uncoupling Agents / Q000494:pharmacology
D004140:Dinitrophenols; D016209:Interleukin-8; D018808:Transcription Factor AP-1; D014475:Uncoupling Agents