ORIGINAL ARTICLE Serum Lipopolysaccharide-Binding Protein in Endotoxemic Patients with Inflammatory Bowel Disease O ´ scar Pastor Rojo,* Antonio Lo ´pez San Roma ´n, † Eduardo Albe ´niz Arbizu, † Antonio de la Hera Martı ´nez, ‡ Eduardo Ripoll Sevillano,* and Agustı ´n Albillos Martı ´nez †‡ Background: In inflammatory bowel disease (IBD), enhanced inflammatory activity in the gut is thought to increase the risk of bacterial translocation and endotoxemia. By searching for signs of endotoxin-signaling cascade activation, including augmented levels of endotoxin, lipopolysaccharide-binding protein (LBP), and soluble CD14 receptor (sCD14), this prospective study sought to establish whether endotoxemia could contribute to greater clinical activity of disease. Methods: Concentrations of plasma endotoxin, LBP, sCD14, sev- eral cytokines, acute phase proteins and clinical activity indices were determined in 104 patients with Crohn’s disease (CD) and 52 patients with ulcerative colitis (UC). Results: Endotoxemia was present in 48% of the patients with CD and in 28% of the patients with UC. The mean LBP was higher in patients with active CD (23.1  13.7 g/mL) and UC (21.4  10.9 g/mL) than in healthy controls (7.2  1.8 g/mL; P  0.01). Elevated serum concentrations of endotoxin and LBP were even detected in patients with inactive CD. Among the patients with active IBD, those with higher endotoxin levels had the worst clinical activity scores and the highest LBP levels. Treatment normalized LBP concentrations, from 29.1  13.0 to 15.2  7.3 g/mL; (P  0.05) in active CD and from 21.7  9.8 to 13.6  5.7 g/mL; (P  0.01) in active UC, along with normalizing endotoxin and sCD14 plasma concentrations. Conclusions: Patients with IBD show increased serum levels of endotoxin, LBP and sCD14. This alteration correlates with disease activity, with normal levels recovered after treatment, although less completely in Crohn’s disease, and parallels a rise in proinflamma- tory cytokines, suggesting a contribution of bacterial products to the inflammatory cascade in these patients. (Inflamm Bowel Dis 2007;13:269 –277) Key Words: inflammatory bowel disease; Crohn’s disease; ulcer- ative colitis, bacterial translocation, endotoxemia; lipopolysaccha- ride-binding protein T he exaggerated intestinal inflammatory response ob- served in ulcerative colitis (UC) and Crohn’s disease (CD), collectively termed inflammatory bowel disease (IBD), is thought to result from a combination of genetic, immuno- logical, and bacterial factors. 1 In turn, intestinal inflammation is suspected to lead to enhanced intestinal permeability with an increased risk of bacterial translocation and endotox- emia. 2,3 Indeed, the administration of endotoxin [Gram-neg- ative bacterial lipopolysaccharide (LPS)] to human volun- teers induces many of the systemic signs (fever, tachycardia, proinflammatory cytokine release, hypercoagulable state, etc. 4 ) frequently observed in IBD. Several studies have pro- vided evidence that circulating endotoxins are detectable in IBD, 5–8 but it is not yet known whether endotoxemia con- tributes to disease activity in these patients. This is partly because there is no marker that reliably identifies individuals who suffer the frequent passage of bacteria or their products into circulation because measurement of endotoxin in biolog- ical fluids is notoriously difficult 9 and because the endotox- emia that follows bacterial translocation is episodic and short- lived. 4 Once in the bloodstream, endotoxin or endotoxin-con- taining particles (including intact Gram-negative bacteria) form complexes with lipopolysaccharide-binding protein (LBP) and activate monocytes and macrophages through toll-like receptors, probably involving the nucleotide-binding oligomerization domain 2 protein (NOD2) pathway. 10 This leads to cytokine production (tumor necrosis factor alpha [TNF-], interleukin-6 [IL-6], and interleukin-8 [IL-8]), shedding of the extracellular domain of the soluble CD14 receptor (sCD14), and further LBP production. Studies of other disease states commonly associated with endotoxemia, such as sepsis or cirrhosis, have detected elevated levels of sCD14 and LBP. 11,12 Indeed, given the long half-lives of sCD14 and LBP (24-48 hours) compared to endotoxin (1–3 Received for publication July 19, 2006; accepted September 25, 2006. From the *Servicio de Bioquı ´mica Clı ´nica, Hospital Universitario Ramo ´n y Cajal, Madrid, Spain; † Servicio de Gastroenterologı ´a, Hospital Universi- tario Ramo ´n y Cajal, Madrid, Spain; ‡ Laboratorio de Enfermedades del Sistema Inmune, Unidad I+D Asociada al Centro Nacional de Biotecnologı ´a (CSIC), Departamento de Medicina, Universidad de Alcala ´, Alcala ´ de Henares, Madrid, Spain. Reprints: Agustı ´n Albillos, Departamento de Medicina, Facultad de Me- dicina—Campus Universitario, Universidad de Alcala ´, Carretera Madrid- Barcelona km. 33.600, 28871 Alcala ´ de Henares, Madrid, Spain (e-mail: aalbillosm@meditex.es) Copyright © 2006 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1002/ibd.20019 Published online 19 December 2006 in Wiley InterScience (www. interscience.wiley.com). Inflamm Bowel Dis ● Volume 13, Number 3, March 2007 269