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Introduction: Antibodies to baker's yeast (mannan) have been widely used to aid in diagnosis of Crohn's disease. Recently, there has been interest in antibodies against a flagellin from Clostridium coccoides subphylum. We hypothesized that reactivity with these antigens is a surrogate marker for a generalized increased IgG response against intestinal microbiota in Crohn's disease., Methods: We compared the diagnostic utility of IgG antibodies against flagellin and mannan with two complex surface antigen preparations, one derived from B. vulgatus (Bv), the other from over 20 common mucosa-associated microbiota, a multibacterial membrane preparation (MBP). IgG antibodies were measured in sera from two age- and sex-matched populations: 120 Crohn's patients (CD) and 160 gastroenterology controls (CON) comprising 40 ulcerative colitis (UC) and 120 non-IBD patients., Results: IgG was elevated against all antigen preparations in Crohn's but statistical analysis of receiver operator characteristic (ROC) plots showed that IgG against the complex antigen preparations MBP and Bv had better diagnostic accuracy to distinguish the two populations (CD and CON) than IgG against mannan (P < or = 0.01) or flagellin (P < or = 0.04). Concentrations of antibody reactive with distinct individual antigens correlated weakly., Discussion: The findings support our hypothesis that measurement of IgG reactivity against individual antigens gives an indication of a generalized increased IgG response against individual intestinal microbiota in Crohn's, rather than measuring specific immune responses important for pathogenesis. The data are consistent with either a mucosal defect that facilitates increased exposure to microbial antigens or an altered immune response, both of which could occur due to known genetic and molecular defects in Crohn's disease.