Serological profiling of Crohn’s disease and ulcerative colitis patients reveals anti-microbial antibody signatures

Abstract

BACKGROUND

The healthcare burden of inflammatory bowel disease (IBD) is rising globally and there are limited non-invasive biomarkers for accurate and early diagnosis.

AIM

To understand the important role that intestinal microbiota play in IBD pathogenesis and identify anti-microbial antibody signatures that benefit clinical management of IBD patients.

METHODS

We performed serological profiling of 100 Crohn’s disease (CD) patients, 100 ulcerative colitis (UC) patients and 100 healthy controls against 1173 bacterial and 397 viral proteins from 50 bacteria and 33 viruses on protein microarrays. The study subjects were randomly divided into discovery (n = 150) and validation (n = 150) sets. Statistical analysis was performed using R packages.

RESULTS

Anti-bacterial antibody responses showed greater differential prevalence among the three subject groups than anti-viral antibody responses. We identified novel antibodies against the antigens of Bacteroidetes vulgatus (BVU_0562) and Streptococcus pneumoniae (SP_1992) showing higher prevalence in CD patients relative to healthy controls. We also identified antibodies against the antigen of Streptococcus pyogenes (SPy_2009) showing higher prevalence in healthy controls relative to UC patients. Using these novel antibodies, we built biomarker panels with area under the curve (AUC) of 0.81, 0.87, and 0.82 distinguishing CD vs control, UC vs control, and CD vs UC, respectively. Subgroup analysis revealed that penetrating CD behavior, colonic CD location, CD patients with a history of surgery, and extensive UC exhibited highest antibody prevalence among all patients. We demonstrated that autoantibodies and anti-microbial antibodies in CD patients had minimal correlation.

CONCLUSION

We have identified antibody signatures for CD and UC using a comprehensive analysis of anti-microbial antibody response in IBD. These antibodies and the source microorganisms of their target antigens improve our understanding of the role of specific microorganisms in IBD pathogenesis and, after future validation, should aid early and accurate diagnosis of IBD.

Keywords: Inflammatory bowel disease; Anti-microbial antibody; Protein microarray; Crohn’s disease; Ulcerative colitis; Gut microbiome

Core Tip: We performed the largest serological profiling of anti-microbial antibodies to date in using 100 Crohn’s disease (CD) and 100 ulcerative colitis (UC) patients. We identified novel anti-microbial antibodies with differential prevalence in inflammatory bowel disease (IBD) patients compared with healthy controls. There was minimal correlation between anti-microbial antibodies and our previously reported autoantibodies in CD patients. We combined novel anti-microbial antibodies to build biomarker panels distinguishing CD vs control, UC vs control and CD vs UC with an area under the curve of 0.81, 0.87, and 0.82, respectively. Subgroup analysis revealed that IBD patients with severe disease had the highest antibody prevalence.