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 Aumais; Charles N. Bernstein; Remo Panaccione; Batia Weiss; Jonas Halfvarson; Wei Xu; Williams Turpin; Kenneth Croitoru

doi:10.1136/gutjnl-2022-328421

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

Faculty of Medicine

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

Abstract

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 language	English
Pages (from-to)	1462–1471
Number of pages	10
Journal	Gut
Volume	72
Issue number	8
DOIs	https://doi.org/10.1136/gutjnl-2022-328421
State	Published - 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.

Keywords

CHEMOKINES
CROHN'S DISEASE
GUT INFLAMMATION
IMMUNE RESPONSE
INTESTINAL BARRIER FUNCTION

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Leibovitzh, H., Lee, S. H., Raygoza Garay, J. A., Espin-Garcia, O., Xue, M., Neustaeter, A., Goethel, A., Huynh, H. Q., Griffiths, A. M., Turner, D., Madsen, K. L., Moayyedi, P., Steinhart, A. H., Silverberg, M. S., Deslandres, C., Bitton, A., Mack, D. R., Jacobson, K., Cino, M., ... Croitoru, K. (2023). Immune response and barrier dysfunction-related proteomic signatures in preclinical phase of Crohn's disease highlight earliest events of pathogenesis. Gut, 72(8), 1462–1471. https://doi.org/10.1136/gutjnl-2022-328421

@article{7a8bcb698abd444fb15638a27340463b,

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

abstract = "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.",

keywords = "CHEMOKINES, CROHN'S DISEASE, GUT INFLAMMATION, IMMUNE RESPONSE, INTESTINAL BARRIER FUNCTION",

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

note = "Publisher Copyright: {\textcopyright} Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.",

year = "2023",

month = feb,

doi = "10.1136/gutjnl-2022-328421",

language = "אנגלית",

volume = "72",

pages = "1462–1471",

journal = "Gut",

issn = "0017-5749",

publisher = "BMJ Publishing Group",

number = "8",

}

Leibovitzh, H, Lee, SH, Raygoza Garay, JA, Espin-Garcia, O, Xue, M, Neustaeter, A, Goethel, A, Huynh, HQ, Griffiths, AM, Turner, D, Madsen, KL, Moayyedi, P, Steinhart, AH, Silverberg, MS, Deslandres, C, Bitton, A, Mack, DR, Jacobson, K, Cino, M, Aumais, G, Bernstein, CN, Panaccione, R, Weiss, B, Halfvarson, J, Xu, W, Turpin, W & Croitoru, K 2023, 'Immune response and barrier dysfunction-related proteomic signatures in preclinical phase of Crohn's disease highlight earliest events of pathogenesis', Gut, vol. 72, no. 8, pp. 1462–1471. https://doi.org/10.1136/gutjnl-2022-328421

TY - JOUR

T1 - Immune response and barrier dysfunction-related proteomic signatures in preclinical phase of Crohn's disease highlight earliest events of pathogenesis

AU - Leibovitzh, Haim

AU - Lee, Sun Ho

AU - Raygoza Garay, Juan Antonio

AU - Espin-Garcia, Osvaldo

AU - Xue, Mingyue

AU - Neustaeter, Anna

AU - Goethel, Ashleigh

AU - Huynh, Hien Q.

AU - Griffiths, Anne M.

AU - Turner, Dan

AU - Madsen, Karen L.

AU - Moayyedi, Paul

AU - Steinhart, A. Hillary

AU - Silverberg, Mark S.

AU - Deslandres, Colette

AU - Bitton, Alain

AU - Mack, David R.

AU - Jacobson, Kevan

AU - Cino, Maria

AU - Aumais, Guy

AU - Bernstein, Charles N.

AU - Panaccione, Remo

AU - Weiss, Batia

AU - Halfvarson, Jonas

AU - Xu, Wei

AU - Turpin, Williams

AU - Croitoru, Kenneth

PY - 2023/2

Y1 - 2023/2

N2 - 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.

AB - 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.

KW - CHEMOKINES

KW - CROHN'S DISEASE

KW - GUT INFLAMMATION

KW - IMMUNE RESPONSE

KW - INTESTINAL BARRIER FUNCTION

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SN - 0017-5749

VL - 72

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JO - Gut

JF - Gut

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

Abstract

Bibliographical note

Keywords

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