Clostridium difficile toxin B is an inflammatory enterotoxin in human intestine.
OBJECTIVE
Clostridium difficile causes antibiotic-associated diarrhea and pseudomembranous colitis, diseases afflicting millions of people each year. Although C. difficile releases 2 structurally similar exotoxins, toxin A and toxin B, animal experiments suggest that only toxin A mediates diarrhea and enterocolitis. However, toxin A-negative/toxin B-positive strains of C. difficile recently were isolated from patients with antibiotic-associated diarrhea and colitis, indicating that toxin B also may be pathogenic in humans.


METHODS
Here we used subcutaneously transplanted human intestinal xenografts in immunodeficient mice to generate a chimeric animal model for C. difficile toxin-induced pathology of human intestine.


RESULTS
We found that intraluminal toxin B, like equivalent concentrations of toxin A, induced intestinal epithelial cell damage, increased mucosal permeability, stimulated interleukin (IL)-8 synthesis, and caused an acute inflammatory response characterized by neutrophil recruitment and tissue damage. Laser capture microdissection and real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR) showed that intestinal epithelial cell-specific IL-8 gene expression also was increased significantly after luminal exposure to C. difficile toxins in vivo.


CONCLUSIONS
We conclude that C. difficile toxin B, like toxin A, is a potent inflammatory enterotoxin for human intestine. Future therapeutic or vaccine strategies for C. difficile infection therefore need to target both toxins.
Savidge
Tor C
TC
Developmental Gastroenterology Laboratory, Combined Program in Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital and Harvard Medical School, 114 16th Street, Charlestown, Massachusetts 02129, USA. savidge@helix.mgh.harvard.edu
Pan
Wei-Hua
WH
Newman
Paul
P
O'brien
Michael
M
Anton
Pauline M
PM
Pothoulakis
Charalabos
C
D000293:Adolescent; D000818:Animals; D001426:Bacterial Proteins; D001427:Bacterial Toxins / Q000633:toxicity*; D016360:Clostridioides difficile / Q000472:pathogenicity*; D004768:Enterotoxins / Q000633:toxicity*; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D051379:Mice; D016513:Mice, SCID; D010539:Permeability; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis; D014183:Transplantation, Heterologous
D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004768:Enterotoxins; D016209:Interleukin-8; D012333:RNA, Messenger; C031815:toxB protein, Clostridium difficile