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

Crohn's and Colitis Canada Genetics Environment Microbial Project Research Consortium

doi:10.1053/j.gastro.2021.07.009

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

Crohn's and Colitis Canada Genetics Environment Microbial Project Research Consortium

Faculty of Medicine

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

19 Scopus citations

Abstract

Background and Aims: 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 (FDRs) of CD patients is an independent risk factor for future CD development. Methods: We measured host serum antibody response to 6 microbial antigens at enrollment (Prometheus enzyme-linked immunosorbent assay test: anti-Saccharomyces cerevisiae antibodies immunoglobulin A/immunoglobulin G, 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 Crohn's and Colitis Canada Genetics Environment Microbial Project. Those who later developed CD (n = 77) were matched 1:4 by age, sex, follow-up duration, and geographic 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 odds ratio, 6.5; 95% confidence interval, 3.4–12.7; P < .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 predisease event in the development of CD.

Original language	American English
Pages (from-to)	1540-1551
Number of pages	12
Journal	Gastroenterology
Volume	161
Issue number	5
DOIs	https://doi.org/10.1053/j.gastro.2021.07.009
State	Published - Nov 2021

Bibliographical note

Funding Information:
Funding This study was supported by grants from Crohn's and Colitis Canada grant number Crohn's and Colitis Canada Genetics Environment Microbial (CCC-GEM) III, Canadian Institutes of Health Research (CIHR) grant number CMF108031, and The Leona M. and Harry B. Helmsley Charitable Trust. Williams Turpin is a former recipient of a Postdoctoral Fellowship Research Award from the CIHR Fellowship/Canadian Association of Gastroenterology (CAG)/Ferring Pharmaceuticals Inc. Sun-Ho Lee is a recipient of the Imagine/CIHR/CAG Fellowship Award. Sun-Ho Lee, Juan Antonio Raygoza Garay, and Williams Turpin are recipients of fellowship awards from the Department of Medicine, Mount Sinai Hospital, Toronto, Canada. Wei Xu was partially supported by the Natural Sciences and Engineering Research Council of Canada (NSERC; grant number RGPIN-2017-06672). We thank the members of the CCC GEM Global Project Office. Kenneth Croitoru is the recipient of the Canada Research Chair in Inflammatory Bowel Diseases. Of note, SciNet (Niagara supercomputer at the SciNet High-Performance Computing Consortium) is funded by the following: the Canada Foundation for Innovation; the Government of Ontario; Ontario Research Fund - Research Excellence; and the University of Toronto.

Funding Information:
Funding This study was supported by grants from Crohn’s and Colitis Canada grant number Crohn’s and Colitis Canada Genetics Environment Microbial (CCC-GEM) III, Canadian Institutes of Health Research (CIHR) grant number CMF108031, and The Leona M. and Harry B. Helmsley Charitable Trust. Williams Turpin is a former recipient of a Postdoctoral Fellowship Research Award from the CIHR Fellowship/ Canadian Association of Gastroenterology (CAG)/ Ferring Pharmaceuticals Inc. Sun-Ho Lee is a recipient of the Imagine/CIHR/CAG Fellowship Award. Sun-Ho Lee, Juan Antonio Raygoza Garay, and Williams Turpin are recipients of fellowship awards from the Department of Medicine, Mount Sinai Hospital, Toronto, Canada. Wei Xu was partially supported by the Natural Sciences and Engineering Research Council of Canada (NSERC; grant number RGPIN-2017-06672). We thank the members of the CCC GEM Global Project Office. Kenneth Croitoru is the recipient of the Canada Research Chair in Inflammatory Bowel Diseases. Of note, SciNet (Niagara supercomputer at the SciNet High-Performance Computing Consortium) is funded by the following: the Canada Foundation for Innovation; the Government of Ontario; Ontario Research Fund - Research Excellence; and the University of Toronto .

Publisher Copyright:
© 2021 AGA Institute

Keywords

Anti-Microbial Antibody
Crohn's Disease
Mediation
Serology

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10.1053/j.gastro.2021.07.009

Cite this

@article{32d8e84bfaa34c3dac395c0564f32df3,

title = "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",

abstract = "Background and Aims: 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 (FDRs) of CD patients is an independent risk factor for future CD development. Methods: We measured host serum antibody response to 6 microbial antigens at enrollment (Prometheus enzyme-linked immunosorbent assay test: anti-Saccharomyces cerevisiae antibodies immunoglobulin A/immunoglobulin G, 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 Crohn's and Colitis Canada Genetics Environment Microbial Project. Those who later developed CD (n = 77) were matched 1:4 by age, sex, follow-up duration, and geographic 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 odds ratio, 6.5; 95% confidence interval, 3.4–12.7; P < .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 predisease event in the development of CD.",

keywords = "Anti-Microbial Antibody, Crohn's Disease, Mediation, Serology",

author = "{Crohn's and Colitis Canada Genetics Environment Microbial Project Research Consortium} and Lee, {Sun Ho} and Williams Turpin and Osvaldo Espin-Garcia and {Raygoza Garay}, {Juan Antonio} and Smith, {Michelle I.} and Haim Leibovitzh and Ashleigh Goethel and Dan Turner and David Mack and Colette Deslandres and Maria Cino and Guy Aumais and Remo Panaccione and Kevan Jacobson and Alain Bitton and Steinhart, {A. Hillary} and Huynh, {Hien Q.} and Fred Princen and Paul Moayyedi and Griffiths, {Anne M.} and Silverberg, {Mark S.} and Paterson, {Andrew D.} and Wei Xu and Kenneth Croitoru",

note = "Funding Information: Funding This study was supported by grants from Crohn's and Colitis Canada grant number Crohn's and Colitis Canada Genetics Environment Microbial (CCC-GEM) III, Canadian Institutes of Health Research (CIHR) grant number CMF108031, and The Leona M. and Harry B. Helmsley Charitable Trust. Williams Turpin is a former recipient of a Postdoctoral Fellowship Research Award from the CIHR Fellowship/Canadian Association of Gastroenterology (CAG)/Ferring Pharmaceuticals Inc. Sun-Ho Lee is a recipient of the Imagine/CIHR/CAG Fellowship Award. Sun-Ho Lee, Juan Antonio Raygoza Garay, and Williams Turpin are recipients of fellowship awards from the Department of Medicine, Mount Sinai Hospital, Toronto, Canada. Wei Xu was partially supported by the Natural Sciences and Engineering Research Council of Canada (NSERC; grant number RGPIN-2017-06672). We thank the members of the CCC GEM Global Project Office. Kenneth Croitoru is the recipient of the Canada Research Chair in Inflammatory Bowel Diseases. Of note, SciNet (Niagara supercomputer at the SciNet High-Performance Computing Consortium) is funded by the following: the Canada Foundation for Innovation; the Government of Ontario; Ontario Research Fund - Research Excellence; and the University of Toronto. Funding Information: Funding This study was supported by grants from Crohn{\textquoteright}s and Colitis Canada grant number Crohn{\textquoteright}s and Colitis Canada Genetics Environment Microbial (CCC-GEM) III, Canadian Institutes of Health Research (CIHR) grant number CMF108031, and The Leona M. and Harry B. Helmsley Charitable Trust. Williams Turpin is a former recipient of a Postdoctoral Fellowship Research Award from the CIHR Fellowship/ Canadian Association of Gastroenterology (CAG)/ Ferring Pharmaceuticals Inc. Sun-Ho Lee is a recipient of the Imagine/CIHR/CAG Fellowship Award. Sun-Ho Lee, Juan Antonio Raygoza Garay, and Williams Turpin are recipients of fellowship awards from the Department of Medicine, Mount Sinai Hospital, Toronto, Canada. Wei Xu was partially supported by the Natural Sciences and Engineering Research Council of Canada (NSERC; grant number RGPIN-2017-06672). We thank the members of the CCC GEM Global Project Office. Kenneth Croitoru is the recipient of the Canada Research Chair in Inflammatory Bowel Diseases. Of note, SciNet (Niagara supercomputer at the SciNet High-Performance Computing Consortium) is funded by the following: the Canada Foundation for Innovation; the Government of Ontario; Ontario Research Fund - Research Excellence; and the University of Toronto . Publisher Copyright: {\textcopyright} 2021 AGA Institute",

year = "2021",

month = nov,

doi = "10.1053/j.gastro.2021.07.009",

language = "American English",

volume = "161",

pages = "1540--1551",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders Ltd",

number = "5",

}

Crohn's and Colitis Canada Genetics Environment Microbial Project Research Consortium 2021, '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', Gastroenterology, vol. 161, no. 5, pp. 1540-1551. https://doi.org/10.1053/j.gastro.2021.07.009

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. / Crohn's and Colitis Canada Genetics Environment Microbial Project Research Consortium.
In: Gastroenterology, Vol. 161, No. 5, 11.2021, p. 1540-1551.

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

TY - JOUR

T1 - 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

AU - Crohn's and Colitis Canada Genetics Environment Microbial Project Research Consortium

AU - Lee, Sun Ho

AU - Turpin, Williams

AU - Espin-Garcia, Osvaldo

AU - Raygoza Garay, Juan Antonio

AU - Smith, Michelle I.

AU - Leibovitzh, Haim

AU - Goethel, Ashleigh

AU - Turner, Dan

AU - Mack, David

AU - Deslandres, Colette

AU - Cino, Maria

AU - Aumais, Guy

AU - Panaccione, Remo

AU - Jacobson, Kevan

AU - Bitton, Alain

AU - Steinhart, A. Hillary

AU - Huynh, Hien Q.

AU - Princen, Fred

AU - Moayyedi, Paul

AU - Griffiths, Anne M.

AU - Silverberg, Mark S.

AU - Paterson, Andrew D.

AU - Xu, Wei

AU - Croitoru, Kenneth

N1 - Funding Information: Funding This study was supported by grants from Crohn's and Colitis Canada grant number Crohn's and Colitis Canada Genetics Environment Microbial (CCC-GEM) III, Canadian Institutes of Health Research (CIHR) grant number CMF108031, and The Leona M. and Harry B. Helmsley Charitable Trust. Williams Turpin is a former recipient of a Postdoctoral Fellowship Research Award from the CIHR Fellowship/Canadian Association of Gastroenterology (CAG)/Ferring Pharmaceuticals Inc. Sun-Ho Lee is a recipient of the Imagine/CIHR/CAG Fellowship Award. Sun-Ho Lee, Juan Antonio Raygoza Garay, and Williams Turpin are recipients of fellowship awards from the Department of Medicine, Mount Sinai Hospital, Toronto, Canada. Wei Xu was partially supported by the Natural Sciences and Engineering Research Council of Canada (NSERC; grant number RGPIN-2017-06672). We thank the members of the CCC GEM Global Project Office. Kenneth Croitoru is the recipient of the Canada Research Chair in Inflammatory Bowel Diseases. Of note, SciNet (Niagara supercomputer at the SciNet High-Performance Computing Consortium) is funded by the following: the Canada Foundation for Innovation; the Government of Ontario; Ontario Research Fund - Research Excellence; and the University of Toronto. Funding Information: Funding This study was supported by grants from Crohn’s and Colitis Canada grant number Crohn’s and Colitis Canada Genetics Environment Microbial (CCC-GEM) III, Canadian Institutes of Health Research (CIHR) grant number CMF108031, and The Leona M. and Harry B. Helmsley Charitable Trust. Williams Turpin is a former recipient of a Postdoctoral Fellowship Research Award from the CIHR Fellowship/ Canadian Association of Gastroenterology (CAG)/ Ferring Pharmaceuticals Inc. Sun-Ho Lee is a recipient of the Imagine/CIHR/CAG Fellowship Award. Sun-Ho Lee, Juan Antonio Raygoza Garay, and Williams Turpin are recipients of fellowship awards from the Department of Medicine, Mount Sinai Hospital, Toronto, Canada. Wei Xu was partially supported by the Natural Sciences and Engineering Research Council of Canada (NSERC; grant number RGPIN-2017-06672). We thank the members of the CCC GEM Global Project Office. Kenneth Croitoru is the recipient of the Canada Research Chair in Inflammatory Bowel Diseases. Of note, SciNet (Niagara supercomputer at the SciNet High-Performance Computing Consortium) is funded by the following: the Canada Foundation for Innovation; the Government of Ontario; Ontario Research Fund - Research Excellence; and the University of Toronto . Publisher Copyright: © 2021 AGA Institute

PY - 2021/11

Y1 - 2021/11

N2 - Background and Aims: 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 (FDRs) of CD patients is an independent risk factor for future CD development. Methods: We measured host serum antibody response to 6 microbial antigens at enrollment (Prometheus enzyme-linked immunosorbent assay test: anti-Saccharomyces cerevisiae antibodies immunoglobulin A/immunoglobulin G, 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 Crohn's and Colitis Canada Genetics Environment Microbial Project. Those who later developed CD (n = 77) were matched 1:4 by age, sex, follow-up duration, and geographic 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 odds ratio, 6.5; 95% confidence interval, 3.4–12.7; P < .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 predisease event in the development of CD.

AB - Background and Aims: 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 (FDRs) of CD patients is an independent risk factor for future CD development. Methods: We measured host serum antibody response to 6 microbial antigens at enrollment (Prometheus enzyme-linked immunosorbent assay test: anti-Saccharomyces cerevisiae antibodies immunoglobulin A/immunoglobulin G, 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 Crohn's and Colitis Canada Genetics Environment Microbial Project. Those who later developed CD (n = 77) were matched 1:4 by age, sex, follow-up duration, and geographic 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 odds ratio, 6.5; 95% confidence interval, 3.4–12.7; P < .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 predisease event in the development of CD.

KW - Anti-Microbial Antibody

KW - Crohn's Disease

KW - Mediation

KW - Serology

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U2 - 10.1053/j.gastro.2021.07.009

DO - 10.1053/j.gastro.2021.07.009

M3 - Article

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AN - SCOPUS:85114997240

SN - 0016-5085

VL - 161

SP - 1540

EP - 1551

JO - Gastroenterology

JF - Gastroenterology

IS - 5

ER -

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

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Keywords

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