Effects of purified Clostridium difficile toxin A on rabbit distal colon.
OBJECTIVE
Antibiotic-associated pseudomembranous colitis in humans is caused by proliferation of Clostridium difficile, which elaborates an enterotoxin toxin A that causes epithelial damage and altered motility in rabbit small intestine. The aim of this study was to assess the effects of toxin A on rabbit distal colonic motility and to relate this to histological damage and inflammatory mediator production.


METHODS
Two hundred micrograms per milliliter of toxin A was placed in a distal colonic loop in anesthetized rabbits, and myoelectric activity was recorded for the following 7 hours. The colon was histologically evaluated and assayed for eicosanoid production. The effects of toxin A on longitudinal and circular muscle were also assessed in vitro.


RESULTS
Beginning 1 hour after instillation, toxin A caused a significant increase in the number of spike bursts without altering slow wave frequency; this was associated with an increase in mucosal neutrophils and increased production of prostaglandin E2 and leukotrienes B4 and C4/D4/E4. Seven hours after administration of toxin A, mediator levels and myoelectric activity remained increased but significant mucosal damage was now also present. Toxin A did not affect longitudinal or circular muscle in vitro.


CONCLUSIONS
C. difficile toxin A caused a significant neutrophil infiltration and an increased myoelectric activity before producing mucosal damage. The myoelectric effect may be indirect, resulting from the production of motility-altering arachidonic acid metabolites.
Burakoff
R
R
Department of Pathology, Winthrop-University Hospital, Mineola, New York, USA.
Zhao
L
L
Celifarco
A J
AJ
Rose
K L
KL
Donovan
V
V
Pothoulakis
C
C
Percy
W H
WH
D000818:Animals; D001427:Bacterial Toxins / Q000302:isolation & purification / Q000494:pharmacology*; D016360:Clostridioides difficile; D003092:Colitis / Q000473:pathology; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015232:Dinoprostone / Q000378:metabolism; D004594:Electrophysiology; D004768:Enterotoxins / Q000302:isolation & purification / Q000494:pharmacology*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D015289:Leukotrienes / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D011817:Rabbits
D001427:Bacterial Toxins; D004768:Enterotoxins; D015289:Leukotrienes; C041348:tcdA protein, Clostridium difficile; D015232:Dinoprostone