/Aim: Altered host immune reactivity to microbial antigens is hypothesized to trigger the onset of Crohn’s disease (CD). We aimed to assess whether increased serum anti-microbial antibody response in asymptomatic first-degree relatives (FDR) of CD patients is an independent risk factor for future CD development.
We measured host serum antibody response to six microbial antigens at enrollment (Prometheus ELISA test: ASCA IgA/IgG, anti-OmpC, anti-A4-Fla2, anti-FlaX, anti-CBir1) and derived the sum of positive antibodies (AS). We used samples at enrollment of prospectively followed healthy FDRs from a nested case-control cohort of the CCC-GEM Project. Those who later developed CD (n=77) were matched 1:4 by age, sex, follow-up duration, and geographical location with control FDRs remaining healthy (n=307). To address our research aims, we fitted a multivariable conditional logistic regression model and performed causal mediation analysis.
High baseline AS (≥2) (43% of cases, 11% of controls) was associated with higher risk of developing CD (adjusted OR 6.5, 95% CI 3.4-12.7; p<0.001). Importantly, this association remained significant when adjusted for markers of gut barrier function, fecal calprotectin, C-reactive protein, and CD-polygenic risk score, and in subjects recruited more than 3 years before diagnosis. Causal mediation analysis showed that the effect of high AS on future CD development is partially mediated (42%) via preclinical gut inflammation.
Our results suggest that increased anti-microbial antibody responses are associated with risk of future development of CD, independent of biomarkers of abnormal gut barrier function, subclinical inflammation, and CD-related genetic risks. This suggests that anti-microbial antibody responses are an early pre-disease event in the development of CD.

Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.

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