Introduction

Inflammatory bowel diseases (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is a chronic debilitating. Current clinical practice is focused on managing disease flares and complications, requiring lifelong medical treatment and/or surgery. However, a paradigm shift in IBD care is needed, moving from treatment of established disease towards creating opportunities for prevention of disease development. Such strategies recently proved successful in rheumatoid arthritis and type 1 diabetes. Before being able to achieve this, however, preclinical disease biomarkers are urgently needed. IBD is characterized by unique immunological changes early in development. Although >300 IBD-specific antibody responses have been identified¹, systemic antibody epitope repertoires of preclinical IBD remain elusive. This study aimed to profile systemic antibody responses at unprecedented depth in individuals before and after the onset of IBD, aiming to identify preclinical disease biomarkers.

Aims & Methods

This study included individuals participating in the Lifelines Cohort Study, a large prospective population-based cohort study in the Netherlands including 167,000 individuals with longitudinal follow-up. Participants without IBD at baseline were screened for any reported IBD diagnosis during follow-up (2006-2021). Individuals who reported IBD during follow-up and with available serum samples were included. Samples at baseline (pre-diagnosis) and during follow-up (post-diagnosis) were used to profile antibody repertoires against 344,000 rationally selected microbial-, food-, and immune antigens using phage-display immunoprecipitation sequencing (PhIP-Seq).

Results

A total of 178 new-onset cases with IBD were identified. Median follow-up time until diagnosis was 3.9 (IQR: 3.4-4.3) years. Most individuals newly developed UC (n=123, 69.1%), followed by CD (n=44, 24.7%), and undetermined IBD (IBD-U, n=11, 6.2%). A total of 5,174 antibody responses were observed in 5-95% of participants. Fifty-nine antibodies were differentially abundant (FDR<0.05) pre-diagnosis vs. post-diagnosis, 14 of which (24%) were previously reported in established IBD¹. Thirteen were more (22%) and 46 less (78%) frequently observed post-diagnosis. Individuals developing IBD exhibited reduced frequencies of antibody responses against EBV-associated peptides post-diagnosis, e.g. Epstein-Barr nuclear antigen-1 (EBNA-1) and capsid protein V26, and other herpesviruses including varicella-zoster virus (VZV), herpes simplex virus type 1 (HSV-1), and noroviruses. Conversely, significantly increased antibody responses were observed against bacterial flagellins (notably from Lachnospiraceae and pathogenic (e.g. Legionella) bacteria) in individuals developing CD, already before disease onset. Individuals developing UC showed elevated antibody responses mainly against viruses (e.g. human adenovirus C, enteroviruses B/C) and particular pathogenic bacterial species (e.g. pneumococcal histidine triad proteins) post-diagnosis compared to pre-diagnosis.

Conclusion

This study represents the first comprehensive and high-resolution analysis of the exact antigenic nature of systemic antibody responses changing during the transition from preclinical to established IBD. Distinct antibody responses appear years before IBD diagnosis, indicating potential involvement in pre-clinical disease development. Furthermore, post-diagnosis, lower frequencies of antibody responses against EBV may suggest reduced immunogenicity against this virus in early disease pathogenesis.

References

1. Bourgonje et al. Immunity. 2023.