Deciphering the prodrome of inflammatory bowel disease up to 10 years before disease onset by massively parallel serology

Background Defining immune dysregulation during the asymptomatic prodrome of immune-mediated diseases offers opportunities for early disease detection and interception. In inflammatory bowel disease (IBD), prodromal immune changes remain poorly characterised. Objective To define preclinical immunological alterations by characterising longitudinal serum antibody repertoires using high-throughput phage-display immunoprecipitation sequencing (PhIP-Seq). Design We applied PhIP-Seq to profile antibody responses in 2000 longitudinal serum samples from 200 individuals who developed Crohn’s disease (CD), 200 who developed ulcerative colitis (UC) and 100 matched healthy controls within the US military Proteomic Evaluation and Discovery in an IBD Cohort of Tri-service Subjects cohort, collected up to 10 years before diagnosis. Antibody repertoires were profiled against 357 000 microbial-associated, viral-associated, food-associated and immune-associated peptides. Results Antibody repertoire variability was increased up to ~4 years prediagnosis in pre-CD and pre-UC individuals. Differential analyses revealed elevated herpesvirus-directed responses (notably Epstein-Barr virus) and anti-flagellin antibodies up to 10 years prediagnosis in CD, particularly in individuals who later developed complicated or ileal disease. In contrast, responses to encapsulated bacteria (eg, Streptococcus pneumoniae , Haemophilus , Neisseria ) progressively declined towards diagnosis. Pre-UC was characterised by combined antimicrobial, antiviral and autoantibody signatures, including antibodies against the MAP kinase-activating death domain protein. Conclusions Large-scale serological profiling of archived prediagnostic samples identified disease-specific immune trajectories years before IBD onset, providing novel insights into disease pathogenesis in its prodromal phase.