Identification of Gene Expression Profiles Associated with an Increased Risk of Post-Operative Recurrence in Crohn's Disease

REMIND Study Group Investigators

doi:10.1093/ecco-jcc/jjac021

Identification of Gene Expression Profiles Associated with an Increased Risk of Post-Operative Recurrence in Crohn's Disease

REMIND Study Group Investigators

Population Health Sciences

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

16 Citations (Scopus)

Abstract

BACKGROUND AND AIMS: Ileocolonic resection is frequently needed in the course of Crohn's disease [CD] treatment and post-operative recurrence is extremely common. Our main objective was to analyse gene expression in the mucosa of CD patients at the time of surgery and at post-operative endoscopy, in order to identify predictors and mechanisms of early endoscopic recurrence.

METHODS: We conducted transcriptome analyses on ileal mucosa samples collected from inflamed sections of the surgical specimens [n = 200], from ileal resection margins [n = 149] and in the neo-terminal ileum 6 months after surgery [n = 122]; these were compared with non-inflammatory bowel disease controls [n = 25]. The primary endpoint was post-operative endoscopic recurrence at 6 months. We applied regression models to identify gene signatures predicting endoscopic recurrence.

RESULTS: Chronic inflammation was associated with strong expression of inflammatory genes [IL-6, IL-8, IL-1B] and decreased expression of genes involved in metabolic processes, but with a high inter-individual heterogeneity. Gene signatures associated with early endoscopic recurrence were mainly characterized by upregulation of TNFα, IFNγ, IL23A and IL17A. Pathway analyses showed that upregulation of mitochondrial dysfunction within the inflamed sections and JAK/STAT at the ileal margin were predictive of post-operative recurrence. A combined model integrating these top pathway signatures improved the prediction of endoscopic recurrence [area under the curve of 0.79]. STAT3 phosphorylation at the surgical ileal margin was associated with severe recurrence at 6 months.

CONCLUSION: We identified several biological pathways in surgical ileal mucosa specimens associated with an increased risk of disease recurrence. Integration of the JAK/STAT and mitochondrial dysfunction pathways in the clinical model improved the prediction of post-operative recurrence.

Original language	English
Pages (from-to)	1269-1280
Number of pages	12
Journal	Journal of Crohn's & colitis
Volume	16
Issue number	8
Early online date	10 Feb 2022
DOIs	https://doi.org/10.1093/ecco-jcc/jjac021
Publication status	Published - 30 Aug 2022

Keywords

Anastomosis, Surgical
Crohn Disease/drug therapy
Endoscopy, Gastrointestinal
Humans
Ileum/surgery
Recurrence
Transcriptome

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10.1093/ecco-jcc/jjac021

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@article{9abe65de945a4403af539af448896ad0,

title = "Identification of Gene Expression Profiles Associated with an Increased Risk of Post-Operative Recurrence in Crohn's Disease",

abstract = "BACKGROUND AND AIMS: Ileocolonic resection is frequently needed in the course of Crohn's disease [CD] treatment and post-operative recurrence is extremely common. Our main objective was to analyse gene expression in the mucosa of CD patients at the time of surgery and at post-operative endoscopy, in order to identify predictors and mechanisms of early endoscopic recurrence.METHODS: We conducted transcriptome analyses on ileal mucosa samples collected from inflamed sections of the surgical specimens [n = 200], from ileal resection margins [n = 149] and in the neo-terminal ileum 6 months after surgery [n = 122]; these were compared with non-inflammatory bowel disease controls [n = 25]. The primary endpoint was post-operative endoscopic recurrence at 6 months. We applied regression models to identify gene signatures predicting endoscopic recurrence.RESULTS: Chronic inflammation was associated with strong expression of inflammatory genes [IL-6, IL-8, IL-1B] and decreased expression of genes involved in metabolic processes, but with a high inter-individual heterogeneity. Gene signatures associated with early endoscopic recurrence were mainly characterized by upregulation of TNFα, IFNγ, IL23A and IL17A. Pathway analyses showed that upregulation of mitochondrial dysfunction within the inflamed sections and JAK/STAT at the ileal margin were predictive of post-operative recurrence. A combined model integrating these top pathway signatures improved the prediction of endoscopic recurrence [area under the curve of 0.79]. STAT3 phosphorylation at the surgical ileal margin was associated with severe recurrence at 6 months.CONCLUSION: We identified several biological pathways in surgical ileal mucosa specimens associated with an increased risk of disease recurrence. Integration of the JAK/STAT and mitochondrial dysfunction pathways in the clinical model improved the prediction of post-operative recurrence.",

keywords = "Anastomosis, Surgical, Crohn Disease/drug therapy, Endoscopy, Gastrointestinal, Humans, Ileum/surgery, Recurrence, Transcriptome",

author = "{REMIND Study Group Investigators} and Marjolaine Ngollo and Kevin Perez and Nassim Hammoudi and Yuri Gorelik and Marc Delord and Claire Auzolle and Hugo Bottois and Dominique Cazals-Hatem and Madeleine Bezault and St{\'e}phane Nancey and Maria Nachury and Xavier Treton and Mathurin Fumery and Anthony Buisson and Nicolas Barnich and Philippe Seksik and Shen-Orr, {Shai S} and {Le Bourhis}, Lionel and Matthieu Allez",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn{\textquoteright}s and Colitis Organisation. All rights reserved. For permissions, please email: [email protected].",

year = "2022",

month = aug,

day = "30",

doi = "10.1093/ecco-jcc/jjac021",

language = "English",

volume = "16",

pages = "1269--1280",

journal = "Journal of Crohn's & colitis",

issn = "1873-9946",

publisher = "Oxford University Press (OUP)",

number = "8",

}

TY - JOUR

T1 - Identification of Gene Expression Profiles Associated with an Increased Risk of Post-Operative Recurrence in Crohn's Disease

AU - REMIND Study Group Investigators

AU - Ngollo, Marjolaine

AU - Perez, Kevin

AU - Hammoudi, Nassim

AU - Gorelik, Yuri

AU - Delord, Marc

AU - Auzolle, Claire

AU - Bottois, Hugo

AU - Cazals-Hatem, Dominique

AU - Bezault, Madeleine

AU - Nancey, Stéphane

AU - Nachury, Maria

AU - Treton, Xavier

AU - Fumery, Mathurin

AU - Buisson, Anthony

AU - Barnich, Nicolas

AU - Seksik, Philippe

AU - Shen-Orr, Shai S

AU - Le Bourhis, Lionel

AU - Allez, Matthieu

N1 - Publisher Copyright: © The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: [email protected].

PY - 2022/8/30

Y1 - 2022/8/30

N2 - BACKGROUND AND AIMS: Ileocolonic resection is frequently needed in the course of Crohn's disease [CD] treatment and post-operative recurrence is extremely common. Our main objective was to analyse gene expression in the mucosa of CD patients at the time of surgery and at post-operative endoscopy, in order to identify predictors and mechanisms of early endoscopic recurrence.METHODS: We conducted transcriptome analyses on ileal mucosa samples collected from inflamed sections of the surgical specimens [n = 200], from ileal resection margins [n = 149] and in the neo-terminal ileum 6 months after surgery [n = 122]; these were compared with non-inflammatory bowel disease controls [n = 25]. The primary endpoint was post-operative endoscopic recurrence at 6 months. We applied regression models to identify gene signatures predicting endoscopic recurrence.RESULTS: Chronic inflammation was associated with strong expression of inflammatory genes [IL-6, IL-8, IL-1B] and decreased expression of genes involved in metabolic processes, but with a high inter-individual heterogeneity. Gene signatures associated with early endoscopic recurrence were mainly characterized by upregulation of TNFα, IFNγ, IL23A and IL17A. Pathway analyses showed that upregulation of mitochondrial dysfunction within the inflamed sections and JAK/STAT at the ileal margin were predictive of post-operative recurrence. A combined model integrating these top pathway signatures improved the prediction of endoscopic recurrence [area under the curve of 0.79]. STAT3 phosphorylation at the surgical ileal margin was associated with severe recurrence at 6 months.CONCLUSION: We identified several biological pathways in surgical ileal mucosa specimens associated with an increased risk of disease recurrence. Integration of the JAK/STAT and mitochondrial dysfunction pathways in the clinical model improved the prediction of post-operative recurrence.

AB - BACKGROUND AND AIMS: Ileocolonic resection is frequently needed in the course of Crohn's disease [CD] treatment and post-operative recurrence is extremely common. Our main objective was to analyse gene expression in the mucosa of CD patients at the time of surgery and at post-operative endoscopy, in order to identify predictors and mechanisms of early endoscopic recurrence.METHODS: We conducted transcriptome analyses on ileal mucosa samples collected from inflamed sections of the surgical specimens [n = 200], from ileal resection margins [n = 149] and in the neo-terminal ileum 6 months after surgery [n = 122]; these were compared with non-inflammatory bowel disease controls [n = 25]. The primary endpoint was post-operative endoscopic recurrence at 6 months. We applied regression models to identify gene signatures predicting endoscopic recurrence.RESULTS: Chronic inflammation was associated with strong expression of inflammatory genes [IL-6, IL-8, IL-1B] and decreased expression of genes involved in metabolic processes, but with a high inter-individual heterogeneity. Gene signatures associated with early endoscopic recurrence were mainly characterized by upregulation of TNFα, IFNγ, IL23A and IL17A. Pathway analyses showed that upregulation of mitochondrial dysfunction within the inflamed sections and JAK/STAT at the ileal margin were predictive of post-operative recurrence. A combined model integrating these top pathway signatures improved the prediction of endoscopic recurrence [area under the curve of 0.79]. STAT3 phosphorylation at the surgical ileal margin was associated with severe recurrence at 6 months.CONCLUSION: We identified several biological pathways in surgical ileal mucosa specimens associated with an increased risk of disease recurrence. Integration of the JAK/STAT and mitochondrial dysfunction pathways in the clinical model improved the prediction of post-operative recurrence.

KW - Anastomosis, Surgical

KW - Crohn Disease/drug therapy

KW - Endoscopy, Gastrointestinal

KW - Humans

KW - Ileum/surgery

KW - Recurrence

KW - Transcriptome

UR - http://www.scopus.com/inward/record.url?scp=85135853884&partnerID=8YFLogxK

U2 - 10.1093/ecco-jcc/jjac021

DO - 10.1093/ecco-jcc/jjac021

M3 - Article

C2 - 35143619

SN - 1873-9946

VL - 16

SP - 1269

EP - 1280

JO - Journal of Crohn's & colitis

JF - Journal of Crohn's & colitis

IS - 8

ER -

Identification of Gene Expression Profiles Associated with an Increased Risk of Post-Operative Recurrence in Crohn's Disease

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