Serum IgG Response to a Conserved Domain of Commensal Flagellins Predicts Future Risk of Crohn’s Disease in First-degree Relatives

Background & Aims Elevated 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. Methods The 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). Results Nineteen of 49 IgG antimicrobial antibody responses were significantly associated with the risk of CD; these antibodies were reactive to Lachnospiraceae family, particularly Roseburia -derived flagellins; 5 antibodies positively correlated with FCP, whereas 3 positively correlated with LMR. These IgG-seroreactive flagellins shared significant amino acid sequence homology, characterized by a conserved “hinge peptide” within D0–D1 domains of the amino-terminus. The cytometric bead array confirmed that elevated IgG seroreactivity to the hinge peptide is associated with future risk of CD independent of LMR and FCP. Conclusions Increased antibody response in healthy FDRs towards Lachnospiraceae flagellins is associated with future risk of CD. Importantly, pre-CD subjects shared seroreactivity towards a conserved bacterial flagellin epitope, which may represent an early preclinical biomarker of CD.