Host Antibody Response to Microbial Antigens May Be Early Marker of Crohn Disease

Investigators assessed whether increased antibody responses to microbial antigens is an independent risk factor for future development of Crohn disease.

Study data published in Gastroenterology suggest that increased antimicrobial antibody response is associated with future risk for Crohn disease (CD). This association persists after adjusting for biomarkers of abnormal gut barrier function and genetic risk for CD.

Prior research has suggested that abnormal immune response to microbial antigens may trigger the onset of CD. To investigate this hypothesis, investigators conducted a multicenter, prospective study of asymptomatic first-degree relatives (FDR) of patients with CD. FDRs aged 6-35 years were recruited between 2008 and 2017 as part of the Crohn’s and Colitis Canada Genetics Environment Microbial (CCC-GEM) Project.

Baseline serum samples were tested for host serum antibody response to 6 microbial antigens: anti-Saccharomyces cerevisiae antibodies (ASCA) immunoglobulin A (IgA)/IgG, anti-Escherichia coli outer membrane porin C (anti-OmpC), anti-A4-Fla2, anti-FlaX, and anti-CBir1. The cumulative number of positive antibodies (antibody sum [AS]) was computed for each patient, ranging from 0 to 6. The main exposure of interest was high AS, defined as having an AS of ≥2.

Patients were prospectively followed; those who later developed CD were matched 1:4 by age, sex, follow-up duration, and geographic location with control individuals who did not develop CD. Multivariable conditional logistic regression was used to assess the relationship between high AS and future development of CD.

The study cohort consisted of 77 FDRs who developed CD over follow-up and 307 matched control individuals. In the total cohort, median age at enrollment was 16.1 (interquartile range, 12.2-22.3) years; 57.0% were women; 85.0% were recruited in Canada. The remaining participants were recruited in Israel (11.7%) and the United States (3.3%).

High AS was significantly more common among FDRs who developed CD compared with control individuals who remained healthy (42.9% vs 11.1%; P <.001). In conditional regression models, the risk for CD was significantly higher in patients with high baseline AS (adjusted odds ratio [aOR], 6.5; 95% CI, 3.4-12.7). This association remained significant after adjusting for levels of fecal calprotectin and C-reactive protein, markers of abnormal gut barrier function, and polygenic risk score for CD.

Time between baseline visit and CD diagnosis also did not affect the impact of AS on CD risk. However, in causal mediation analyses, preclinical gut inflammation was found to partially mediate (42%) the effect of high AS on future CD. These data suggest that greater antimicrobial antibody response may be a “pre-disease event” in the development of CD.

As far as study limitations, investigators noted that the use of healthy FDRs as study participants limits the generalizability of findings. Further, given the mediating effect of gut inflammation on CD risk, detailed studies exploring the immunopathogenesis of CD are warranted.

“[G]iven the early and robust signals preceding the onset of CD, we anticipate that stratifying the risk for future CD by antibody response to microbial antigens at an early preclinical phase could be an efficient approach for identifying individuals at higher risk of developing CD,” investigators wrote. “This may help lead to future intervention

studies aiming for primary prevention of CD as in other chronic immune-mediated diseases,” they concluded.

Disclosure: One study author declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Lee SH, Turpin W, Espin-Garcia O, et al. 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. Gastroenterol. Published online July 19, 2021. doi: 10.1053/j.gastro.2021.07.009