Leptin mediates Clostridium difficile toxin A-induced enteritis in mice.
OBJECTIVE
Leptin regulates energy homeostasis and participates in the regulation of the hypothalamic-pituitary-adrenal axis. Although hyperleptinemia is described in experimental colitis, its role in the pathophysiology of enterotoxin-mediated diarrhea and inflammation remains unclear. We examined the role of leptin in the inflammatory diarrhea induced by toxin A from Clostridium difficile, the causative agent of antibiotic-related colitis.


METHODS
Toxin A (10 microg) or buffer were administered in ileal loops of leptin-deficient (ob/ob), leptin-resistant (db/db), or wild-type mice and enterotoxic responses were measured.


RESULTS
In toxin A-treated wild-type mice, circulating leptin and corticosterone levels were increased compared with buffer-injected animals. Toxin A also stimulated increased mucosal expression of the Ob-Rb at the messenger RNA (mRNA) and protein level. Ob/ob and db/db mice were partially protected against toxin A-induced intestinal secretion and inflammation, and this effect was reversed by leptin administration in ob/ob, but not db/db, mice. Basal- and toxin A-stimulated plasma corticosterone levels in ob/ob and db/db mice were higher compared with toxin A-treated wild-type mice. To assess whether the effect of leptin in intestinal inflammation is mediated by corticosteroids we performed adrenalectomy experiments in db/db and wild-type mice. Our results suggested that the diminished intestinal response to toxin A in db/db mice was related only in part to increased levels of corticosteroids.


CONCLUSIONS
Leptin plays an important role in regulating the severity of enterotoxin-mediated intestinal secretion and inflammation by activating both corticosteroid-dependent and -independent mechanisms.
Mykoniatis
Andreas
A
Divisions of Gastroenterology and Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
Anton
Pauline M
PM
Wlk
Michael
M
Wang
Chi Chung
CC
Ungsunan
Linda
L
Blüher
Susann
S
Venihaki
Maria
M
Simeonidis
Simos
S
Zacks
Jeff
J
Zhao
Dezheng
D
Sougioultzis
Stavros
S
Karalis
Katia
K
Mantzoros
Christos
C
Pothoulakis
Charalabos
C
D000818:Animals; D001427:Bacterial Toxins; D001826:Body Fluids / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D004351:Drug Resistance; D004751:Enteritis / Q000209:etiology* / Q000378:metabolism; D004768:Enterotoxins; D020738:Leptin / Q000097:blood / Q000172:deficiency / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011956:Receptors, Cell Surface / Q000378:metabolism; D054411:Receptors, Leptin
D001427:Bacterial Toxins; D004768:Enterotoxins; D020738:Leptin; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; C041348:tcdA protein, Clostridium difficile; D003345:Corticosterone