Crohn’s disease and ulcerative colitis exhibit prediagnostic antibody signatures with shared and divergent changes towards disease onset

BACKGROUND: The development of IBD is known to involve early immunological alterations, but our understanding of the changes in antibody epitope repertoires moving from the prediagnostic phase towards disease onset remains incomplete. OBJECTIVE: In this study, we comprehensively characterised systemic antibody responses in patients with IBD before and after disease onset, aiming to identify prediagnostic disease biomarkers. DESIGN: Within Lifelines, a population-based cohort study collecting and storing longitudinal samples from 167 000 individuals over∼15 years, we identified 178 individuals with blood samples taken both before and after IBD-onset. In these prediagnosis and postdiagnosis serum samples (median time span 3.9 years), we profiled antibody epitope repertoires against 344 000 rationally selected microbial, food and immune antigens using phage-display immunoprecipitation sequencing. RESULTS: Postdiagnosis, we observe reduced antibody frequencies against herpesviruses, particularly for Epstein-Barr virus and varicella zoster virus, and elevated antibody frequencies against specific enteroviruses, including adenovirus C and enterovirus types B and C. Even before diagnosis, individuals who ultimately developed Crohn's disease (CD) displayed elevated antibody reactivity against flagellins of both commensal and pathogenic bacteria. This CD-specific profile became even more pronounced postdiagnosis, suggesting the formation of IBD-specific antibody responses years before disease onset. CONCLUSION: This study is the first comprehensive high-resolution analysis of the exact antigenic nature of systemic antibody responses during the transition from prediagnostic to established IBD. The antibody signatures we found may represent a route to developing biomarkers that identify individuals at high risk of developing disease.