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

Gastroenterology. 2021 Nov;161(5):1540-1551. doi: 10.1053/j.gastro.2021.07.009. Epub 2021 Jul 20.


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.

Keywords: Anti-Microbial Antibody; Crohn’s Disease; Mediation; Serology.

Publication types

  • Multicenter Study
  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antibodies, Bacterial / blood*
  • Antigens, Bacterial / immunology*
  • Asymptomatic Diseases
  • Biomarkers / blood
  • C-Reactive Protein / analysis*
  • Case-Control Studies
  • Child
  • Crohn Disease / blood
  • Crohn Disease / genetics
  • Crohn Disease / immunology*
  • Crohn Disease / microbiology
  • Female
  • Genetic Predisposition to Disease
  • Host-Pathogen Interactions
  • Humans
  • Inflammation Mediators / blood
  • Intestinal Mucosa / metabolism*
  • Israel
  • Male
  • Mediation Analysis
  • North America
  • Permeability
  • Prospective Studies
  • Risk Assessment
  • Risk Factors
  • Young Adult


  • Antibodies, Bacterial
  • Antigens, Bacterial
  • Biomarkers
  • Inflammation Mediators
  • C-Reactive Protein