105 Introduction Inflammatory bowel diseases (IBDs), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), are chronic inflammatory diseases of the gastrointestinal tract that are characterized by an inappropriate and uncontrolled immune response triggered by the gut microbiota in genetically susceptible individuals.1 A complex interplay between inherited and environmental factors, the gut microbiota and the host immune system is considered causative in the pathogenesis of IBD.2,3 The gut microbiota of patients with IBD show alterations in their composition and functionality, in particular a decrease in microbial diversity and the abundance of commensal, butyrate-producing bacteria and increased proportions of potentially pathogenic bacteria.4-6 An immense traffic of luminal antigens occurs across the human intestinal epithelium, representing an interface between the mucosal immune system and the luminal microenvironment, where antigens are continuously sampled as an immune surveillance mechanism.7 In the context of IBD, intestinal barrier function is compromised, resulting in excessive passage of luminal antigens (e.g. bacterial translocation) that elicits mucosal and systemic immune activation, which may in turn trigger and aggravate intestinal inflammation.8,9 The human gut microbiota contains a variety of genes and species that represent a tremendous amount of potential antigens.10,11 However, it is challenging to fully capture the complete set of antigens recognized by the human antibody repertoire because conventional technologies (e.g. enzyme-linked immunosorbent assays [ELISAs] or peptide arrays) do not allow for such large-scale measurements and are usually limited to parallel measurements of only a few hundreds to thousands of antigens. Moreover, although B-cell receptor sequencing (BCRseq) methods report on the clonal diversity of the BCR DNA sequences that underlie antibody specificity, the exact nature of the antigens bound and their associations with IBD remain incompletely addressed.12-14 Phage-display immunoprecipitation sequencing (PhIP-Seq) is a highthroughput technology that now allows for systematic investigation of hundreds of thousands of antigens simultaneously, and it has been successfully applied in both healthy populations and in the context of viral infections, although there is little data available on immune-mediated diseases.12,15-19 PhIP-Seq is based on antigen libraries encoded by synthetic DNA oligonucleotides that are displayed on bacteriophages. These phages are incubated with human blood to initiate antigen–antibody pairingwith the reactive antibodies present in the sample, and these antibodies are subsequently extracted by immunoprecipitation and sequenced for identification, resulting in an in-depth characterization of the blood antibody epitope profile.12,15 In this study, we aimed to characterize the serum antibody epitope repertoire in patients with IBD versus healthy controls representing the general population and to associate these antibody epitope repertoires to relevant patient phenotypes, including clinical data and IBDspecific parameters, and to their fecal metagenomes. Using PhIP-Seq technology, we established specific immune-based biomarker signatures in patients with IBD and identified distinct profiles for specific disease phenotypes. The antibody epitope repertoire in IBD
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