Anti-Microbial Antibody Response is Associated With Future Onset of Crohn’s Disease Independent of Biomarkers of Altered Gut Barrier Function, Subclinical Inflammation, and Genetic Risk
Academic Article
Overview
Research
Identity
Additional Document Info
View All
Overview
abstract
BACKGROUND: /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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
