Effects of purified Clostridium difficile toxin A in the small intestine of the rat in vivo.
The action of highly purified Clostridium difficile toxin A was studied in the jejunum of rats in vivo. C. difficile toxin A reversed dose-dependently net fluid absorption into net fluid secretion, accompanied by an increase in prostaglandin E2 but not 5-hydroxytryptamine output into the gut lumen. Accordingly, indomethacin but not the 5-hydroxytryptamine receptor antagonists ketanserin plus tropisetron were able to inhibit toxin A-induced fluid secretion. Atropine and hexamethonium were without effect on the action of toxin A, such excluding a nervous mechanism. The cyclic nucleotides cyclic AMP and cyclic GMP appear not to be involved in the mediation of the secretory response. The reduced cyclic GMP levels are most likely the result of a complete destruction of the villus membranes, where the guanylate cyclase is located. Histological studies revealed massive damage to intestinal villi, whereas the majority of the crypts seem to be unaffected. In conclusion, toxin A-induced intestinal fluid secretion appears to be caused mainly by severe mucosal damage. PGE2-release may be the consequence of the inflammation accompanying this damage. The mechanism seems to be completely different to those of cholera toxin or Escherichia coli heat stable enterotoxin.
Beubler
E
E
Department of Experimental and Clinical Pharmacology, Karl-Franzens University of Graz, Austria.
Schirgi-Degen
A
A
Pabst
M A
MA
Pothoulakis
C
C
LaMont
J T
JT
D000818:Animals; D001427:Bacterial Toxins / Q000633:toxicity*; D016360:Clostridioides difficile / Q000472:pathogenicity*; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004768:Enterotoxins / Q000633:toxicity*; D005260:Female; D006162:Guanylate Cyclase / Q000378:metabolism; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009712:Nucleotides, Cyclic / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism
D001427:Bacterial Toxins; D004768:Enterotoxins; D009712:Nucleotides, Cyclic; C041348:tcdA protein, Clostridium difficile; D012701:Serotonin; D006162:Guanylate Cyclase; D015232:Dinoprostone