A159 SERUM IGG RESPONSE TO THE D0-D1 HINGE PEPTIDE OF COMMENSAL FLAGELLIN PREDICTS THE FUTURE ONSET OF CROHN’S DISEASE IN HEALTHY FIRST-DEGREE RELATIVES

TL;DR

A specific antibody response to a bacterial protein in healthy relatives of Crohn's disease patients predicts future disease onset.

Contribution

Identifies a conserved flagellin epitope as an early immune marker for Crohn’s disease in asymptomatic relatives.

Findings

19 IgG antimicrobial antibody responses were significantly associated with future Crohn’s disease risk.

Elevated IgG reactivity to a conserved flagellin hinge peptide correlated with gut inflammation and permeability markers.

Pre-CD participants showed shared seroreactivity to a conserved bacterial flagellin epitope.

Abstract

Elevated antimicrobial antibody levels have been reported up to 6 years before diagnosis of Crohn’s disease (CD), but the specific antibody response is poorly defined.

Here, we characterized the nature of the antimicrobial antibody responses before the diagnosis of CD in healthy first-degree relatives (FDR) of CD patients.

The CCC-GEM 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 FDRs who remained healthy (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 the serologic responses with gut permeability (fractional urinary excretion of lactulose-to-mannitol ratio (LMR)) and fecal calprotectin (FCP).

19 (out 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 (q<0.02); 5 antibodies positively correlated with FCP (q<0.046), whereas 3 antibodies positively correlated with LMR (q<0.049). These IgG-seroreactive flagellins shared significant amino acid sequence homology, characterized by a conserved “hinge peptide” within D0-D1 domains of the amino-terminus. Elevated IgG seroreactivity to this hinge peptide (determined by cytometric bead array) was associated with multi-flagellin reactivity and future risk of CD.

Increased antibody response in healthy asymptomatic FDRs towards Lachnospiraceae flagellins is associated with future risk of CD, and markers of gut inflammation and altered intestinal permeability. Importantly, pre-CD participants shared seroreactivity towards a conserved bacterial flagellin epitope, suggesting a possible role in the early immunopathogenesis of CD.

CCC, CIHRThe Leona M. and Harry B. Helmsley Charitable Trust