Abstract
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.
| Original language | English |
|---|---|
| Article number | 334362 |
| Pages (from-to) | 1977-1988 |
| Number of pages | 12 |
| Journal | Gut |
| Volume | 74 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published Online - 2 Jul 2025 |
Funding
The corresponding authors confirm on behalf of all authors that there have been no involvements that might raise the question of bias in the work reported or in the conclusions, implications or opinions stated. ARB reports receiving research grants from Janssen Pharmaceuticals and received speaker’s fees from AbbVie. RKW acted as consultant for Takeda Pharmaceuticals; received unrestricted research grants from Takeda, Johnson & Johnson, Tramedico and Ferring; and received speaker’s fees from MSD, Abbvie and Janssen Pharmaceuticals. BvdV reports honoraria received by UMCG for expertise or scientific advisory board/consultancy (on request): Visiopharm, Philips, MSD/Merck, Daiichi-Sankyo/AstraZenica; speaker’s fees from Visiopharm, Diaceutics, MSD/Merck; unrestricted research grants from Owkin and GE Healthcare; personal fees from DEKRA: all unrelated to the current manuscript. All other authors have no conflicts of interest to declare. ARB is supported by a Rubicon fellowship from the Dutch Science Foundation (NWO) (452022317), the EU Horizon Health consortium grant ID-DarkMatter-NCD (101136582) and the Innovation Health Initiative Joint Undertaking (IHI JU) grant INTERCEPT (101194780). AW is the Louis H Sackin Research Fellow Chair in Computer Science. ES is supported by grants from the European Research Council (ERC) and the Israel Science Foundation and by the Seerave Foundation. AZ is supported by the EU Horizon Health consortium grant ID-DarkMatter-NCD (101136582). TV is supported by an ERC Starting Grant (EarlyMicroAbs) and coordinates the EU Horizon Health consortium grant ID-DarkMatter-NCD (101136582). RKW is supported by the Seerave Foundation, NWO, the Innovation Health Initiative Joint Undertaking (IHI JU) grant INTERCEPT (101194780) and the EU Horizon Health consortium grant ID-DarkMatter-NCD (101136582). JF is supported by the Dutch Heart Foundation IN-CONTROL (CVON2018-27), an ERC Consolidator grant (grant agreement No. 101001678), NWO-VICI grant VI.C.202.022, the AMMODO Science Award 2023 for Biomedical Sciences from Stichting Ammodo and the Netherlands Organ-on-Chip Initiative, an NWO Gravitation project (024.003.001) funded by the Ministry of Education, Culture and Science of the government of the Netherlands. Views and opinions expressed are, however, those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible for them. The funders had no role in study design, data collection and analysis, preparation of the manuscript or decision to publish. The Lifelines initiative has been made possible by subsidy from the Dutch Ministry of Health, Welfare and Sport; the Dutch Ministry of Economic Affairs; the University Medical Center Groningen (UMCG); the University of Groningen and the Northern Provinces of the Netherlands (Drenthe, Friesland, Groningen). The authors wish to acknowledge the services of the Lifelines Cohort Study, the contributing research centres delivering data to Lifelines and all the study participants. The authors also acknowledge affiliation with the Innovative Health Initiative (IHI) Joint Undertaking INTERCEPT consortium (101194780) , although this study was not funded by IHI. The authors would like to thank Kate McIntyre (Scientific Editor, Department of Genetics, University Medical Center Groningen) for language editing.
All Science Journal Classification (ASJC) codes
- Gastroenterology