Gastroenterology

Gastroenterology

Volume 124, Issue 3, March 2003, Pages 683-691
Gastroenterology

Basic–Alimentary Tract
Leptin mediates Clostridium difficile toxin A–induced enteritis in mice,☆☆

https://doi.org/10.1053/gast.2003.50101Get rights and content

Abstract

Background & Aims: 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 μg) 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.

GASTROENTEROLOGY 2003;124:683-691

Section snippets

Materials and methods

Toxin A was purified from culture supernatants of C. difficile strain 10,463 as previously described.30 Protein concentrations were determined with the DC protein assay (Bio-Rad Laboratories, Hercules, CA).

Reduced toxin A–induced fluid secretion and intestinal inflammation in leptin-deficient and leptin-resistant mice

To assess directly the role of leptin in the toxin A model of intestinal inflammation, we injected ileal loops of anesthetized wild-type, leptin-deficient (ob/ob), and leptin-resistant (db/db) mice, with either buffer or purified toxin A and, after 4 hours, we measured toxin A–associated ileal responses. Basal fluid secretion in response to buffer injection was comparable between wild-type and ob/ob and db/db mice (Figure 1A).

. (A) Reduced toxin A–induced ileal fluid secretion in db/db and ob/ob

Discussion

We have reported previously that C. difficile toxin A stimulates fluid secretion and elicits an acute inflammatory response in animal intestine characterized by neutrophil infiltration and epithelial cell destruction.5 The results presented here show that animals either genetically lacking leptin itself or resistant to leptin's effects have substantially reduced responses to toxin A, which is normalized in response to the administration of leptin in leptin-deficient ob/ob mice but not in

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    Supported by research grants PO DK33506 (to C.P.), PO 1 DK 56116 (to C.M.), RO1 DK 58785 (to C.M.), MO RR 01032 (to C.M.), and a Pilot Feasibility Study from P30 DK 40561 from the National Institutes of Health. This study also was supported by a research grant from the Crohn's and Colitis Foundation.

    ☆☆

    Address requests for reprints to: Charalabos Pothoulakis, M.D., Beth Israel Deaconess Medical Center, Division of Gastroenterology, Dana 501, 330 Brookline Avenue, Boston, Massachusetts 02215. e-mail: [email protected]; fax: (617) 667-2767.

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