title: Lipopolysaccharide exposure is linked to activation of the acute phase response and growth failure in pediatric Crohn's disease and murine colitis.
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-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.
authors.affiliation: Department of Pediatric Gastroenterology, Phoenix Children's Hospital, Phoenix, Arizona, USA.
authors.forename: Brad A
authors.initials: BA
authors.lastname: Pasternak
authors.forename: Sharon
authors.initials: S
authors.lastname: D'Mello
authors.forename: Ingrid I
authors.initials: II
authors.lastname: Jurickova
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Han
authors.forename: Tara
authors.initials: T
authors.lastname: Willson
authors.forename: Leah
authors.initials: L
authors.lastname: Flick
authors.forename: Lisa
authors.initials: L
authors.lastname: Petiniot
authors.forename: Naonori
authors.initials: N
authors.lastname: Uozumi
authors.forename: Senad
authors.initials: S
authors.lastname: Divanovic
authors.forename: Anna
authors.initials: A
authors.lastname: Traurnicht
authors.forename: Erin
authors.initials: E
authors.lastname: Bonkowski
authors.forename: Subra
authors.initials: S
authors.lastname: Kugathasan
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Karp
authors.forename: Lee A
authors.initials: LA
authors.lastname: Denson
mesh_terms: 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
chemical_list: 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