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AbstractBackground & AimsElevated antimicrobial antibodies have been reported up to 6 years before diagnosis of Crohn’s disease (CD), but the specific antibody response is unclear. Here, we characterized the antimicrobial antibody responses before CD diagnosis in healthy first-degree relatives (FDRs) of patients with CD. MethodsThe CCC-GEM (Crohn’s and Colitis Canada – Genetic, Environmental, Microbial) Project nested case-control cohort consisted of FDRs who later developed CD (n = 77), matched 1:4 by age, sex, follow-up duration, and geographical location with healthy FDRs (n = 304). Sera at enrollment were probed for antimicrobial reactivity using a microbiota antigen microarray and a flagellin peptide cytometric bead array. Conditional logistic regression was used to assess association with CD onset, and partial Spearman was used to correlate serologic responses with lactulose-to-mannitol ratio (LMR), C-reactive protein (CRP), and fecal calprotectin (FCP). False discovery rate was controlled using the Benjamini-Hochberg method (q < 0.05).