Lipopolysaccharide exposure is linked to activation of the acute phase response and growth failure in pediatric Crohn's disease and murine colitis.
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-alpha, 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.
Pasternak
Brad A
BA
Department of Pediatric Gastroenterology, Phoenix Children's Hospital, Phoenix, Arizona, USA.
D'Mello
Sharon
S
Jurickova
Ingrid I
II
Han
Xiaonan
X
Willson
Tara
T
Flick
Leah
L
Petiniot
Lisa
L
Uozumi
Naonori
N
Divanovic
Senad
S
Traurnicht
Anna
A
Bonkowski
Erin
E
Kugathasan
Subra
S
Karp
Christopher L
CL
Denson
Lee A
LA
D000209:Acute-Phase Proteins / Q000378:metabolism; D000210:Acute-Phase Reaction / Q000209:etiology* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000150:complications* / Q000188:drug therapy; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D003424:Crohn Disease / Q000150:complications* / Q000188:drug therapy; D016207:Cytokines / Q000378:metabolism; D004733:Enema; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006130:Growth Disorders / Q000209:etiology* / Q000473:pathology; D006801:Humans; D007223:Infant; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D051197:Toll-Like Receptor 4 / Q000502:physiology; D014302:Trinitrobenzenesulfonic Acid / Q000494:pharmacology; D055815:Young Adult; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D015415:Biomarkers; D002352:Carrier Proteins; D016207:Cytokines; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D051197:Toll-Like Receptor 4; D014302:Trinitrobenzenesulfonic Acid; D000099231:Lipopolysaccharide-Binding Protein; C493487:Tlr4 protein, mouse