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

Objectives: Phenotype characteristics of inflammatory bowel disease (IBD) may differ significantly among ethnic subpopulations. The aim of this study was to characterize the IBD phenotype in French Canadians, the most prominent founder population in North America., Methods: Using well-characterized phenotype data in the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)-IBD Genetics Consortium repository on patients with IBD, we compared phenotypic characteristics of 202 French Canadians with those of 1,287 other Caucasian patients. These included diagnosis, anatomical location, disease behavior, extraintestinal manifestations, surgical history, and family history of IBD., Results: French-Canadian patients with Crohn's disease (CD) were less likely to have stricturing disease (11 vs. 21%, P=0.005; odds ratio (OR): 0.45, 95% confidence interval (95% CI): 0.24-0.85). Using a stringent definition of ethnicity (three out of four grandparents being French Canadians, as opposed to self-report, n=148), French Canadians had a tendency toward developing fistulizing CD (37 vs. 28%, P=0.07), and there was an increased prevalence of sacroiliitis among those with IBD (4 vs. 2%, P=0.045). Among French Canadians, the numbers of current smokers in CD (40 vs. 25%, P=0.006) and former smokers in ulcerative colitis (UC) (35 vs. 20%, P=0.03) were significantly higher. The prevalence of one of the three main variants of nucleotide-binding oligomerization domain containing 2 (NOD2) single-nucleotide polymorphisms (SNPs) among French-Canadian CD patients was 43.2%. The 3020insC SNP correlated with small bowel disease in French Canadians (25 [corrected] vs. 0%, P=0.006)., Conclusions: French Canadians show an IBD phenotype profile distinct from other Caucasian IBD populations, with an accentuated association between smoking status and IBD. This unique profile may have implications regarding the need for a different approach to the management of IBD in this population.