BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is a chronic manifestation of dysregulated immune response to the gut microbiota in genetically predisposed hosts. Nearly half of patients with Crohn's disease (CD) develop selective serum immunoglobulin (Ig)G response to fl agellin proteins expressed by bacteria in the Lachnospiraceae family. This study aimed to identify the binding epitopes of these IgG antibodies and assess their relevance in CD and in homeostasis. METHODS: Sera from an adult CD cohort, a treatment-na & iuml;ve pediatric CD cohort, and 3 independent non-IBD infant cohorts were analyzed using novel techniques including a fl agellin peptide microarray and a fl agellin peptide cytometric bead array. RESULTS: A dominant B cell peptide epitope in patients with CD was identified, located in the highly conserved " hinge region" between the D0 and D1 domains at the amino-terminus of Lachnospiraceae fl agellins. Elevated serum IgG reactivity to the hinge peptide was strongly associated with incidence of CD and the development of disease complications in children with CD up to 5 years in advance. Notably, high levels of serum IgG to the hinge epitope were also found in most infants from 3 different geographic regions (Uganda, Sweden, and the United States) at 1 year of age, which decrements rapidly afterward. CONCLUSIONS: These fi ndings identified a distinct subset of patients with CD, united by a shared reactivity to a dominant commensal bacterial fl agellin epitope, that may represent failure of a homeostatic response to the gut microbiota beginning in infancy.