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.

BACKGROUND /Aim: 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 (FDR) of CD patients is an independent risk factor for future CD development. METHODS We measured host serum antibody response to six microbial antigens at enrollment (Prometheus ELISA test: ASCA IgA/IgG, 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 CCC-GEM Project. Those who later developed CD (n=77) were matched 1:4 by age, sex, follow-up duration, and geographical 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 OR 6.5, 95% CI 3.4-12.7; p<0.001). 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 pre-disease event in the development of CD.

[1]  P. Mannon,et al.  Human microbiota flagellins drive adaptive immune responses in Crohn's disease. , 2021, Gastroenterology.

[2]  A. Paterson,et al.  Increased Intestinal Permeability is Associated with Later Development of Crohn's Disease. , 2020, Gastroenterology.

[3]  T. Lange,et al.  Causal mediation analysis in nested case‐control studies using conditional logistic regression , 2020, Biometrical journal. Biometrische Zeitschrift.

[4]  C. Lewis,et al.  Genetic and Inflammatory Biomarkers Classify Small Intestine Inflammation in Asymptomatic First-degree Relatives of Patients With Crohn's Disease. , 2020, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[5]  J. Murray,et al.  Serum Biomarkers Identify Patients Who Will Develop Inflammatory Bowel Diseases Up to 5 y Before Diagnosis. , 2020, Gastroenterology.

[6]  J. Krischer,et al.  An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes. , 2019, The New England journal of medicine.

[7]  A. Paterson,et al.  Sa1816 – Elevated Fecal Calprotectin in Healthy First Degree Relatives of Patients with Crohn's Disease is Associated with Future Diagnosis of Crohn's Disease , 2019, Gastroenterology.

[8]  G. Moran,et al.  Does fecal calprotectin equally and accurately measure disease activity in small bowel and large bowel Crohn’s disease?: a systematic review , 2019, Intestinal research.

[9]  I. Bruce,et al.  Arthritis prevention in the pre-clinical phase of RA with abatacept (the APIPPRA study): a multi-centre, randomised, double-blind, parallel-group, placebo-controlled clinical trial protocol , 2019, Trials.

[10]  Stephen R. Williams,et al.  Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders. , 2018, American journal of human genetics.

[11]  M. Silverberg,et al.  Fecal calprotectin correlates with active colonic inflammatory bowel disease but not with small intestinal Crohn's disease activity , 2018, JGH open : an open access journal of gastroenterology and hepatology.

[12]  Mary E. Haas,et al.  Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations , 2018, Nature Genetics.

[13]  Nima Hamidi,et al.  Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies , 2017, The Lancet.

[14]  D. Kao,et al.  Increased Intestinal Permeability in Relatives of Patients With Crohn’s Disease Is Not Associated With Small Bowel Ulcerations , 2017, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[15]  A. Paterson,et al.  Association of host genome with intestinal microbial composition in a large healthy cohort , 2016, Nature Genetics.

[16]  I. Ordás,et al.  Commensal-Specific CD4(+) Cells From Patients With Crohn's Disease Have a T-Helper 17 Inflammatory Profile. , 2016, Gastroenterology.

[17]  Alan M. Kwong,et al.  Next-generation genotype imputation service and methods , 2016, Nature Genetics.

[18]  J. Murray,et al.  Serologic microbial associated markers can predict Crohn's disease behaviour years before disease diagnosis , 2016, Alimentary pharmacology & therapeutics.

[19]  A. Ananthakrishnan,et al.  Association Between Circulating Levels of C-Reactive Protein and Interleukin-6 and Risk of Inflammatory Bowel Disease. , 2016, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[20]  P. Visscher,et al.  Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores , 2015, bioRxiv.

[21]  Judy H. Cho,et al.  Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations , 2015, Nature Genetics.

[22]  C. Ponsioen,et al.  Impact of disease location on fecal calprotectin levels in Crohn’s disease , 2015, Scandinavian Journal of Gastroenterology.

[23]  W. Sandborn,et al.  Crohn's disease , 2012, The Lancet.

[24]  A. Tjønneland,et al.  Serological markers predict inflammatory bowel disease years before the diagnosis , 2012, Gut.

[25]  W. Reinisch,et al.  The impact of intestinal resection on serum levels of anti‐Saccharomyces cerevisiae antibodies (ASCA) in patients with Crohn’s disease , 2012, Alimentary pharmacology & therapeutics.

[26]  S. Targan,et al.  Increased immune reactivity predicts aggressive complicating Crohn's disease in children. , 2008, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[27]  R. Balicer,et al.  Anti-Saccharomyces cerevisiae and antineutrophil cytoplasmic antibodies as predictors of inflammatory bowel disease , 2005, Gut.

[28]  S. Targan,et al.  Antibodies to CBir1 flagellin define a unique response that is associated independently with complicated Crohn's disease. , 2005, Gastroenterology.

[29]  W. Mow,et al.  Association of antibody responses to microbial antigens and complications of small bowel Crohn's disease. , 2004, Gastroenterology.

[30]  W. Reinisch,et al.  Anti-Saccharomyces cerevisiae antibodies: a stable marker for Crohn's disease during steroid and 5-aminosalicylic acid treatment , 2003, American Journal of Gastroenterology.

[31]  Jonathan Braun,et al.  Selected loss of tolerance evidenced by Crohn's disease-associated immune responses to auto- and microbial antigens. , 2002, Gastroenterology.

[32]  P. Rutgeerts,et al.  Anti-Saccharomyces Cerevisiae Antibodies (ASCA), Phenotypes of IBD, and Intestinal Permeability: A Study in IBD Families , 2001, Inflammatory bowel diseases.

[33]  J. Main,et al.  Antibody to selected strains of Saccharomyces cerevisiae (baker's and brewer's yeast) and Candida albicans in Crohn's disease. , 1990, Gut.

[34]  C. Fiocchi,et al.  Immunopathogenesis of IBD: current state of the art , 2016, Nature Reviews Gastroenterology &Hepatology.

[35]  S. Targan,et al.  Bacterial flagellin is a dominant antigen in Crohn disease. , 2004, The Journal of clinical investigation.