131 Discussion In this study, we demonstrate that patients with IBD exhibit distinct antibody epitope repertoires compared to individuals derived from the general population. In particular, patients with CD show strong and diverse antibody responses against flagellin-coated bacteria, which were dominated by bacteria belonging to the Lachnospiraceae family. This anti-flagellin antibody signature was particularly present in patients with ileal disease involvement and more complicated disease (e.g. fibrostenotic disease or surgical history). Consequently, antibody epitope repertoires were able to accurately discriminate patients with CD from healthy controls with high discriminative performance, which was not clearly observed for patients with UC. In addition, we examined the concordance between antibody epitope repertoires and gut microbiota composition, but saw no clear associations with individual microbial taxa or microbial dysbiosis. Collectively, our study presents a large-scale, comprehensive characterization of antibody epitope repertoires of patients with IBD, showing a multitude of unique associations with disease phenotypes and representing a valuable information resource to query for systemic immune-based biomarkers for IBD. Patients with IBD demonstrated selective patterns of antimicrobial antibody reactivity, particularly responses in patients with CD directed against microbiota flagellins. Flagellins are dominant antigens and elicit strong IgG immune responses in CD.34,35 However, the exact nature of the antigens to which these responses are directed to is now gradually being uncovered, although not yet so comprehensively within a large cohort of patients with IBD.36 More specifically, we found many antibody responses against Lachnospiraceae flagellins (e.g. flagellins of Roseburia, Clostridium, Eubacterium and Agathobacter species), particularly in patients with (ileal) CD. These findings corroborate those from previous studies that profiled adaptive immune responses in IBD.37 Many Lachnospiraceae bacteria (belonging to the order Clostridiales, phylum Firmicutes) are typically reduced in patients with CD, similar to what has been observed for Faecalibacterium prausnitzii, a member of the Ruminococcaceae family in the Clostridiales order that is closely related to Lachnospiraceae.5,38 These bacteria are usually strict anaerobes and well-known butyrate producers, and butyrate has anti-inflammatory and barrier-protective effects on the intestinal epithelium.39 As such, most flagellated Lachnospiraceae members are commensal symbionts, which makes their strong immunogenicity rather unexpected. However, flagellins are highly immunogenic proteins, and bacterial flagellae are able to facilitate transport across the intestinal epithelial mucus barrier. This cross-barrier transport may, in turn, be particularly enhanced when intestinal barrier integrity is disrupted, which may translate into an increased propensity to be exposed to the adaptive immune system.40 In addition, the intestinal distribution pattern of Lachnospiraceae bacteria largely overlaps with the classical ileocolonic disease localization of CD. The specificity of this anti-flagellin antibody signature for CD but not UC emphasizes that the two diseases have a different pathophysiology, which may be explained by CD-specific immunity (e.g. aberrant Th1-driven immunity) or genetic susceptibility.37 In addition, one may envision potential therapeutic modulation of this anti-flagellin antibody response, as such specific anti-flagellin ‘immunotherapy’ has previously been shown to prevent colitis in mice by selective ablation of flagellin-reactive CD4+ T-lymphocytes.41 This principle could be followed to design and test flagellin-directed immunotherapy in patients with IBD. The antibody epitope repertoire in IBD
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