You could be reading the full-text of this article now if you...

If you have access to this article through your institution,
you can view this article in

Lipopolysaccharide exposure is linked to activation of the acute phase response and growth failure in pediatric Crohn's disease and murine colitis

Pasternak, Brad A. MD1; D'Mello, Sharon MD2; Jurickova, Ingrid I. MD2; Han, Xiaonan PhD2; Willson, Tara BS2; Flick, Leah MS3; Petiniot, Lisa MD3; Uozumi, Naonori MD, PhD3; Divanovic, Senad PhD3; Traurnicht, Anna MD2; Bonkowski, Erin BS2; Kugathasan, Subra MD4; Karp, Christopher L. MD3; Denson, Lee A. MD2,*

Inflammatory Bowel Diseases:
doi: 10.1002/ibd.21132
Original Clinical Articles
Abstract

Background:: Systemic exposure to lipopolysaccharide (LPS) has been linked to clinical disease activity in adults with inflammatory bowel disease (IBD). We hypothesized that markers of LPS exposure and the acute phase response (APR) would be increased in pediatric IBD patients with growth failure, and that LPS signaling would be required for induction of the APR in murine colitis.

Methods:: Serum markers of LPS exposure, endotoxin core IgA antibody (EndoCAb), and the APR, LPS binding protein (LBP) were quantified in pediatric IBD patients and controls. LBP and cytokine production were determined after administration of trinitrobenzene sulfonic acid (TNBS) enemas to mice with genetic deletion of Toll‐Like receptor 4 (TLR4), and wildtype (WT) controls.

Results:: Serum EndoCAb and LBP were significantly elevated in patients with Crohn's disease (CD), compared to disease controls with ulcerative colitis (UC) and healthy controls (P < 0.001). This was independent of disease activity or location. CD patients with elevated serum EndoCAb and LBP exhibited linear growth failure which persisted during therapy. Serum LBP increased in WT mice following TNBS administration, in conjunction with increased serum TNF‐α, IL‐6, and IL‐10, and expansion of regulatory T‐cell numbers. Both the APR and expansion of foxp3+ T cells were abrogated in TLR4‐deficient mice, in conjunction with a reduction in acute weight loss.

Conclusions:: LPS exposure and a persistent APR are associated with growth failure in pediatric CD. LPS signaling is required for the APR in murine colitis. Therapies targeting this pathway may benefit the subset of patients with refractory growth failure. (Inflamm Bowel Dis 2010)

Author Information

1Department of Pediatric Gastroenterology, Phoenix Children's Hospital, Phoenix, Arizona

2Division of Pediatric Gastroenterology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio

3Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio

4Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia

*Reprints: MLC 2010, 3333 Burnet Ave., Cincinnati, OH 45229. e‐mail: lee.denson@cchmc.org

Received 2 July 2009; Accepted 9 September 2009

Conflict of Interest Disclosure: The authors do not have any conflict of interest to declare; they do not have any financial interests or affiliations with institutions, organizations, or companies that are mentioned in the article or whose products or services are discussed.

Supported by NICHD, K12‐HD00850; NIH, R01 AI075159 and R01 DK058259; Crohn's and Colitis Foundation of America; Cincinnati Children's Hospital Research Foundation Digestive Health Center Integrative Morphology Core, P30 DK0789392.

Published online 18 November 2009 in Wiley InterScience (www.interscience.wiley.com).

© Crohn's & Colitis Foundation of America, Inc.

You currently do not have access to this article.

You may need to:

Note: If your society membership provides for full-access to this article, you may need to login on your society’s web site first.