Identification of Gene Expression Profiles Associated with an Increased Risk of Post-Operative Recurrence in Crohn’s Disease
Authors: Ngollo Marjolaine , Perez Kevin , Hammoudi Nassim , Gorelik Yuri , Delord Marc , Auzolle Claire , Bottois Hugo , Cazals-Hatem Dominique , Bezault Madeleine , Nancey Stéphane , Nachury Maria , Treton Xavier , Fumery Mathurin , Buisson Anthony , Barnich Nicolas , Seksik Philippe ,   REMIND Study Group Investigators, Corte Hélène , Cattan Pierre , Chirica Mircea , Munoz-Bongrand Nicolas , Gornet Jean-Marc , Baudry Clotilde , Lourenco Nelson , Maillet Marianne , Tran-Minh My-Linh , Nisard Andrée , Bonnet Joelle , Chedouba Leila , Sokol Harry , Beaugerie Laurent , Bourrier Anne , Nion-Larmurier Isabelle , Marteau Philippe , Landman Cecilia , Rajca Sylvie , Quevrain Elodie , Brot Loic , Chafai Najim , Lefevre Jeremie H , Tiret Emmanuel , Svrcek Magali , Hoyau-Idrissi Nadia , François Flejou Jean , Bouhnik Yoram , Stefanescu Carmen , Guedj Nathalie , Panis Yves , Maggiori Leon , Corcos Olivier , Bommelaer Gilles , Goutte Marion , Vazeille Emilie , Rodrigues Michael , Sauvanet Pierre , Desreumaux Pierre , Nachury Maria , Sommeville Coralie , Dupas Jean-Louis , Brazier Franck , Chatelain Denis , Attencourt Christophe , Sabbagh Charles , Leconte Martine , Boschetti Gilles , Flourié Bernard , François Yves , Cotte Eddy , Charlois Anne-Laure , Falgon Peggy , Moussata Driffa , Chauvenet Marion , Boyer Sarah , Hebuterne Xavier , Filippi Jérome , Hofman Paul , Bezault Madeleine , Shen-Orr Shai S , Le Bourhis Lionel , Allez Matthieu 
Published: February 2022

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.