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. 2022 Feb 11:15:5-25.
doi: 10.2147/CEG.S343468. eCollection 2022.

Mucosal Gene Transcript Signatures in Treatment Naïve Inflammatory Bowel Disease: A Comparative Analysis of Disease to Symptomatic and Healthy Controls in the European IBD-Character Cohort

Simen Svendsen Vatn #  1   2 , Jonas Christoffer Lindstrøm #  3   4 , Aina E F Moen  1   4   5 , Stephan Brackmann  1   2 , Tone M Tannæs  1   5 , Christine Olbjørn  1   6 , Daniel Bergemalm  7 , Åsa V Keita  8 , Fernando Gomollon  9 , Trond Espen Detlie  1   2 , Torben Lüders  5 , Rahul Kalla  10 , Alex Adams  10   11 , Jack Satsangi  10   11 , Jørgen Jahnsen  1   2 , Morten H Vatn  1 , Jonas Halfvarson  7 , Petr Ricanek  2 , Hilde Nilsen  1   5 ; IBD-CHARACTER consortium
Affiliations

Mucosal Gene Transcript Signatures in Treatment Naïve Inflammatory Bowel Disease: A Comparative Analysis of Disease to Symptomatic and Healthy Controls in the European IBD-Character Cohort

Simen Svendsen Vatn et al. Clin Exp Gastroenterol. .

Abstract

Background: Studies of the mucosal transcriptomic landscape have given new insight into the pathogenesis of inflammatory bowel disease (IBD). Recently, the predictive biomarker potential of gene expression signatures has been explored. To further investigate the mucosal gene expression in IBD, we recruited a cohort of treatment naïve patients and compared them to both symptomatic and healthy controls.

Methods: Altogether, 323 subjects were included: Crohn's disease (N = 75), ulcerative colitis (N = 87) and IBD unclassified (N = 3). Additionally, there were two control groups: symptomatic controls (N = 131) and healthy controls (N = 27). Mucosal biopsies were collected during ileocolonoscopy and gene expression in inflamed and non-inflamed mucosa was explored. Gene expression profiling was performed using Agilent G3 Human Gene Expression 860K v3 One-Color microarray. We recorded information about treatment escalation to anti-TNF agents or surgery, and anti-TNF response, to explore predictive opportunities of the mucosal transcriptome.

Results: Gene expression profiles in symptomatic controls in whom IBD had been excluded resembled that of IBD patients and diverged from that of healthy controls. In non-inflamed Crohn's disease and ulcerative colitis, gene set enrichment analysis revealed dysregulation of pathways involved in basic cellular biological processes. Mitochondria-associated pathways were dysregulated both in non-inflamed and inflamed Crohn's disease and ulcerative colitis (>2.6 normalized enrichment scores <-1.8). Gene expression signatures of Crohn's disease and ulcerative colitis did not predict time for treatment escalation (p = 0.175). No significant association was found between gene expression signatures and anti-TNF response.

Conclusion: Non-inflamed samples are probably superior to inflamed samples when exploring gene expression signatures in IBD and might reveal underlying mechanisms central for disease initiation. The gene expression signatures of the control groups were related to if they were symptomatic or not, which may have important implications for future study designs.

Keywords: Crohn’s disease; healthy controls; mitochondria; mucosal transcriptome; non-inflamed; prediction; symptomatic controls; ulcerative colitis.

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Conflict of interest statement

Prof. Dr. Stephan Brackmann reports personal fees from Athna/Pharmanovia, personal fees from Augere medical, outside the submitted work. Dr Daniel Bergemalm reports grants from EU FP7 grant, during the conduct of the study; personal fees from Pfizer, personal fees from Janssen, personal fees from Ferring, outside the submitted work. Professor Fernando Gomollon reports grants, personal fees from TAKEDA, grants and personal fees from JANSSEN, grants, personal fees from ABBVIE, personal fees from PFIZER, outside the submitted work. Dr Trond Espen Detlie reports personal fees from Ferring, personal fees from Tillotts, personal fees from Pharmacosmos, personal fees from Vifor Pharma, outside the submitted work. Prof. Dr. Jonas Halfvarson reports grants from EU, during the conduct of the study; grants, personal fees from Janssen, grants, personal fees from Takeda, grants, personal fees from MSD, personal fees from AbbVie, personal fees from Aqilion, personal fees from Celgene, personal fees from Celltrion, personal fees from Ferring, personal fees from Gilead, personal fees from Index Pharma, personal fees from Lincs, personal fees from Novartis, non-financial support from Olink Proteomics, personal fees from Pfizer, personal fees from Prometheus Laboratories Inc., personal fees from Sandoz, personal fees from Shire, personal fees from Thermo Fisher Scientific, personal fees from Tillotts Pharma, personal fees from Vifor Pharma, outside the submitted work. The authors declare no other conflicts of interest to this work.

Figures

Figure 1
Figure 1
Principal Component Analysis plots, demonstrating separation of samples based on (A) diagnostic group, (B) gut segments and (C) inflammation status separated by color (inflamed samples in red, vs non-inflamed samples in blue) and gut segment separated by shape (samples from colon demonstrated with circles, vs samples from ileum demonstrated with triangles.
Figure 2
Figure 2
Continued.
Figure 2
Figure 2
Continued.
Figure 2
Figure 2
Crohn's disease. (A) Hierarchical clustering of differentially regulated genes. (B) Volcano plot comparing inflamed (CDi) and non-inflamed (CDni) samples in CD. (C) Volcano plot of inflamed biopsies from CD (CDi) compared to healthy controls. (D) Volcano plot of non-inflamed biopsies from CD (CDni) compared to healthy controls. (E) Gene set enrichment analyses given as Normalised Enrichment Scores (NES) in CDi (top panel) and CDni (bottom panel) versus healthy controls. “Orange” represents overrepresented GO terms, with positive NES. “Green” represents underrepresented GO terms, with negative NES.
Figure 3
Figure 3
Continued.
Figure 3
Figure 3
Continued.
Figure 3
Figure 3
Ulcerative colitis. (A) Hierarchical clustering of differentially regulated genes. (B) Volcano plot comparing inflamed (UCi) and non-inflamed (UCni) samples in UC. (C) Volcano plot of inflamed biopsies from UC (UCi) compared to healthy controls. (D) Volcano plot of non-inflamed biopsies from UC (UCni) compared to healthy controls. (E) Gene set enrichment analyses given as Normalised Enrichment Scores (NES) in UCi (top panel) and UCni (bottom panel) versus healthy controls. “Orange” represents overrepresented GO terms, with positive NES. “Green” represents underrepresented GO terms, with negative NES.
Figure 4
Figure 4
Gene set enrichment analyses. Ranking of the biological processes that are among the top 30 enriched in at least two datasets based on Normalized Enrichment Scores (NES). NES scores span from −2 to 3, where negative scores define underrepresented GO terms (green) and positive scores define overrepresented GO terms (Orange). Color intensity correlates with NES score. Significantly regulated biological processes are labelled with an asterisk (*).
See this image and copyright information in PMC

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