Corticotropin-releasing hormone (CRH) requirement in Clostridium difficile toxin A-mediated intestinal inflammation.
Clostridium difficile, the causative agent of antibiotic-associated colitis, mediates inflammatory diarrhea by releasing toxin A, a potent 308-kDa enterotoxin. Toxin A-induced inflammatory diarrhea involves many steps, including mucosal release of substance P (SP) corticotropin-releasing hormone (CRH) and neutrophil transmigration. Here we demonstrate that, compared with wild type, mice genetically deficient in CRH (Crh(-/-)) have dramatically reduced ileal fluid secretion, epithelial cell damage, and neutrophil transmigration 4 h after intraluminal toxin A administration. This response is associated with diminished mucosal activity of the neutrophil enzyme myeloperoxidase compared with that of wildtype mice. In wild-type mice, toxin A stimulates an increase in intestinal SP content compared with buffer administration. In contrast, toxin A administration in Crh(-/-) mice fails to result in an increased SP content. Moreover, immunohistochemical experiments showed that CRH and SP are colocalized in some enteric nerves of wild-type mice, and this colocalization is more evident after toxin A administration. These results provide direct evidence for a major proinflammatory role for CRH in the pathophysiology of enterotoxin-mediated inflammatory diarrhea and indicate a SP-linked pathway.
Anton
Pauline M
PM
Division of Gastroenterology, Beth Israel Deaconess Medical Center, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Gay
Jerome
J
Mykoniatis
Andreas
A
Pan
Amy
A
O'Brien
Michael
M
Brown
Daniel
D
Karalis
Katia
K
Pothoulakis
Charalabos
C
D000818:Animals; D001427:Bacterial Toxins / Q000378:metabolism*; D016360:Clostridioides difficile / Q000378:metabolism*; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D003967:Diarrhea / Q000382:microbiology* / Q000503:physiopathology; D004768:Enterotoxins / Q000378:metabolism*; D007082:Ileum / Q000294:innervation / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D066298:In Vitro Techniques; D007249:Inflammation / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009412:Nerve Fibers / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D013373:Substance P / Q000378:metabolism
D001427:Bacterial Toxins; D004768:Enterotoxins; C041348:tcdA protein, Clostridium difficile; D013373:Substance P; D003346:Corticotropin-Releasing Hormone; D009195:Peroxidase