Serum IgG Response to a Conserved Domain of...

Serum IgG Response to a Conserved Domain of Commensal Flagellins Predicts Future Risk of Crohn’s Disease in First-Degree Relatives

Abstract

BACKGROUND & AIMS: Elevated antimicrobial antibodies have been reported up to 6 years before diagnosis of Crohn's disease (CD), but the specific antibody response is unclear. Here, we characterized the antimicrobial antibody responses before CD diagnosis in healthy first-degree relatives (FDRs) of patients with CD. METHODS: The CCC-GEM (Crohn's and Colitis Canada - Genetic, Environmental, Microbial) Project nested case-control cohort consisted of FDRs who later developed CD (N = 77), matched 1:4 by age, sex, follow-up duration, and geographical location with healthy FDRs (N = 304). Sera at enrollment were probed for antimicrobial reactivity using a microbiota antigen microarray and a flagellin peptide cytometric bead array. Conditional logistic regression was used to assess association with CD onset, and partial Spearman was used to correlate serologic responses with lactulose-to-mannitol ratio (LMR), C-reactive protein (CRP), and fecal calprotectin (FCP). False discovery rate was controlled using the Benjamini-Hochberg method (q < 0.05). RESULTS: Nineteen of 49 IgG antimicrobial antibody responses were significantly associated with the risk of CD; these antibodies were reactive to Lachnospiraceae family, particularly Roseburia-derived flagellins; 5 antibodies positively correlated with FCP, whereas 3 positively correlated with LMR. These IgG-seroreactive flagellins shared significant amino acid sequence homology, characterized by a conserved "hinge peptide" within D0-D1 domains of the amino-terminus. The cytometric bead array confirmed that elevated IgG seroreactivity to the hinge peptide is associated with future risk of CD independent of LMR and FCP. CONCLUSIONS: Increased antibody response in healthy FDRs towards Lachnospiraceae flagellins is associated with future risk of CD. Importantly, pre-CD subjects shared seroreactivity toward a conserved bacterial flagellin epitope, which may represent an early preclinical biomarker of CD.

Authors

Wu RY; Xue M; Zhao Q; Jeong S; Griffiths AM; Dieleman LA; Steinhart AH; Aumais G; Bressler B; Panaccione R

Journal

Clinical Gastroenterology and Hepatology, Vol. 24, No. 8, pp. 2226–2236

Publisher

Elsevier

Publication Date

August 1, 2026

DOI

10.1016/j.cgh.2025.12.006

ISSN

1542-3565

Associated Experts

John Kenneth Marshall

Professor, Medicine

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