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 Journal Articles uri icon

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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.


  • Lee, Sun-Ho
  • Turpin, Williams
  • Espin-Garcia, Osvaldo
  • Raygoza Garay, Juan Antonio
  • Smith, Michelle I
  • Leibovitzh, Haim
  • Goethel, Ashleigh
  • Turner, Dan
  • Mack, David
  • Deslandres, Colette
  • Cino, Maria
  • Aumais, Guy
  • Panaccione, Remo
  • Jacobson, Kevan
  • Bitton, Alain
  • Steinhart, A Hillary
  • Huynh, Hien Q
  • Princen, Fred
  • Moayyedi, Paul
  • Griffiths, Anne M
  • Silverberg, Mark S
  • Paterson, Andrew D
  • Xu, Wei
  • Croitoru, Kenneth

publication date

  • November 2021

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