Immune response and barrier dysfunction-related proteomic signatures in preclinical phase of Crohn's disease highlight earliest events of pathogenesis

Haim Leibovitzh, Sun Ho Lee, Juan Antonio Raygoza Garay, Osvaldo Espin-Garcia, Mingyue Xue, Anna Neustaeter, Ashleigh Goethel, Hien Q. Huynh, Anne M. Griffiths, Dan Turner, Karen L. Madsen, Paul Moayyedi, A. Hillary Steinhart, Mark S. Silverberg, Colette Deslandres, Alain Bitton, David R. Mack, Kevan Jacobson, Maria Cino, Guy AumaisCharles N. Bernstein, Remo Panaccione, Batia Weiss, Jonas Halfvarson, Wei Xu, Williams Turpin, Kenneth Croitoru*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


Objective The measure of serum proteome in the preclinical state of Crohn's disease (CD) may provide insight into biological pathways involved in CD pathogenesis. We aimed to assess associations of serum proteins with future CD onset and with other biomarkers predicting CD risk in a healthy at-risk cohort. Design In a nested case-control study within the Crohn's and Colitis Canada Genetics Environment Microbial Project (CCC-GEM) cohort, which prospectively follows healthy first-degree relatives (FDRs), subjects who developed CD (n=71) were matched with four FDRs remaining healthy (n=284). Using samples at recruitment, serum protein profiles using the Olink Proximity Extension Assay platform was assessed for association with future development of CD and with other baseline biomarkers as follows: serum antimicrobial antibodies (AS: positive antibody sum) (Prometheus); faecal calprotectin (FCP); gut barrier function using the fractional excretion of lactulose-to-mannitol ratio (LMR) assay. Results We identified 25 of 446 serum proteins significantly associated with future development of CD. C-X-C motif chemokine 9 (CXCL9) had the highest OR with future risk of CD (OR=2.07 per SD, 95% CI 1.58 to 2.73, q=7.9e-5), whereas matrix extracellular phosphoglycoprotein had the lowest OR (OR 0.44, 95% CI 0.29 to 0.66, q=0.02). Notably, CXCL9 was the only analyte significantly associated with all other CD-risk biomarkers with consistent direction of effect (FCP: OR=2.21; LMR: OR=1.67; AS: OR=1.59) (q<0.05 for all). Conclusion We identified serum proteomic signatures associated with future CD development, reflecting potential early biological processes of immune and barrier dysfunction.

Original languageAmerican English
Pages (from-to)1462–1471
Number of pages10
Issue number8
StatePublished - Feb 2023

Bibliographical note

Funding Information:
This study was supported by grants from Crohn's and Colitis Canada Grant #CCC-GEMIII, Canadian Institutes of Health Research (CIHR) Grant #CMF108031 and The Leona M. and Harry B. Helmsley Charitable Trust. WT is a former recipient of a Postdoctoral Fellowship Research Award from the CIHR Fellowship/ Canadian Association of Gastroenterology (CAG)/ Ferring Pharmaceuticals. SHL is a recipient of the Imagine/CAG/CIHR Fellowship Award. HL is a former recipient of a fellowship award from the Israeli Association of Gastroenterology. SHL, JARG and WT are former recipients of a fellowship award from the Department of Medicine, Mount Sinai Hospital, Toronto. We thank the members of the CCC-GEM Global Project Office. KC is recipient of the Canada Research Chair in Inflammatory Bowel Diseases.

Publisher Copyright:
© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.




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