Abstract
Background and Aims: 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 (FDRs) of CD patients is an independent risk factor for future CD development. Methods: We measured host serum antibody response to 6 microbial antigens at enrollment (Prometheus enzyme-linked immunosorbent assay test: anti-Saccharomyces cerevisiae antibodies immunoglobulin A/immunoglobulin G, 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 Crohn's and Colitis Canada Genetics Environment Microbial Project. Those who later developed CD (n = 77) were matched 1:4 by age, sex, follow-up duration, and geographic 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 odds ratio, 6.5; 95% confidence interval, 3.4–12.7; P < .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 predisease event in the development of CD.
Original language | American English |
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Pages (from-to) | 1540-1551 |
Number of pages | 12 |
Journal | Gastroenterology |
Volume | 161 |
Issue number | 5 |
DOIs | |
State | Published - Nov 2021 |
Bibliographical note
Funding Information:Funding This study was supported by grants from Crohn's and Colitis Canada grant number Crohn's and Colitis Canada Genetics Environment Microbial (CCC-GEM) III, Canadian Institutes of Health Research (CIHR) grant number CMF108031, and The Leona M. and Harry B. Helmsley Charitable Trust. Williams Turpin is a former recipient of a Postdoctoral Fellowship Research Award from the CIHR Fellowship/Canadian Association of Gastroenterology (CAG)/Ferring Pharmaceuticals Inc. Sun-Ho Lee is a recipient of the Imagine/CIHR/CAG Fellowship Award. Sun-Ho Lee, Juan Antonio Raygoza Garay, and Williams Turpin are recipients of fellowship awards from the Department of Medicine, Mount Sinai Hospital, Toronto, Canada. Wei Xu was partially supported by the Natural Sciences and Engineering Research Council of Canada (NSERC; grant number RGPIN-2017-06672). We thank the members of the CCC GEM Global Project Office. Kenneth Croitoru is the recipient of the Canada Research Chair in Inflammatory Bowel Diseases. Of note, SciNet (Niagara supercomputer at the SciNet High-Performance Computing Consortium) is funded by the following: the Canada Foundation for Innovation; the Government of Ontario; Ontario Research Fund - Research Excellence; and the University of Toronto.
Funding Information:
Funding This study was supported by grants from Crohn’s and Colitis Canada grant number Crohn’s and Colitis Canada Genetics Environment Microbial (CCC-GEM) III, Canadian Institutes of Health Research (CIHR) grant number CMF108031, and The Leona M. and Harry B. Helmsley Charitable Trust. Williams Turpin is a former recipient of a Postdoctoral Fellowship Research Award from the CIHR Fellowship/ Canadian Association of Gastroenterology (CAG)/ Ferring Pharmaceuticals Inc. Sun-Ho Lee is a recipient of the Imagine/CIHR/CAG Fellowship Award. Sun-Ho Lee, Juan Antonio Raygoza Garay, and Williams Turpin are recipients of fellowship awards from the Department of Medicine, Mount Sinai Hospital, Toronto, Canada. Wei Xu was partially supported by the Natural Sciences and Engineering Research Council of Canada (NSERC; grant number RGPIN-2017-06672). We thank the members of the CCC GEM Global Project Office. Kenneth Croitoru is the recipient of the Canada Research Chair in Inflammatory Bowel Diseases. Of note, SciNet (Niagara supercomputer at the SciNet High-Performance Computing Consortium) is funded by the following: the Canada Foundation for Innovation; the Government of Ontario; Ontario Research Fund - Research Excellence; and the University of Toronto .
Publisher Copyright:
© 2021 AGA Institute
Keywords
- Anti-Microbial Antibody
- Crohn's Disease
- Mediation
- Serology