Co-expression of fibrotic genes in inflammatory bowel disease; A localized event?

Nikolas Dovrolis; Eirini Filidou; Gesthimani Tarapatzi; Georgios Kokkotis; Michail Spathakis; Leonidas Kandilogiannakis; Ioannis Drygiannakis; Vassilis Valatas; Konstantinos Arvanitidis; Ioannis Karakasiliotis; Stergios Vradelis; Vangelis G Manolopoulos; Vasilis Paspaliaris; Giorgos Bamias; George Kolios

doi:10.3389/fimmu.2022.1058237

Co-expression of fibrotic genes in inflammatory bowel disease; A localized event?

Front Immunol. 2022 Dec 23:13:1058237. doi: 10.3389/fimmu.2022.1058237. eCollection 2022.

Authors

Nikolas Dovrolis^{1

2

3}, Eirini Filidou^{1

3}, Gesthimani Tarapatzi^{1

3}, Georgios Kokkotis⁴, Michail Spathakis^{1

3}, Leonidas Kandilogiannakis^{1

3}, Ioannis Drygiannakis⁵, Vassilis Valatas^{1

5}, Konstantinos Arvanitidis^{1

3}, Ioannis Karakasiliotis², Stergios Vradelis⁶, Vangelis G Manolopoulos^{1

3}, Vasilis Paspaliaris⁷, Giorgos Bamias⁴, George Kolios^{1

3}

Affiliations

¹ Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece.
² Laboratory of Biology, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece.
³ Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), Alexandroupolis, Greece.
⁴ Gastrointestinal (GI) Unit, 3 Department of Internal Medicine, Sotiria Hospital, National and Kapodistrian University of Athens, Athens, Greece.
⁵ Gastroenterology and Hepatology Research Laboratory, Medical School, University of Crete, Heraklion, Greece.
⁶ Second Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece.
⁷ Tithon Biotech Inc., San Diego, CA, United States.

Abstract

Introduction: Extracellular matrix turnover, a ubiquitous dynamic biological process, can be diverted to fibrosis. The latter can affect the intestine as a serious complication of Inflammatory Bowel Diseases (IBD) and is resistant to current pharmacological interventions. It embosses the need for out-of-the-box approaches to identify and target molecular mechanisms of fibrosis.

Methods and results: In this study, a novel mRNA sequencing dataset of 22 pairs of intestinal biopsies from the terminal ileum (TI) and the sigmoid of 7 patients with Crohn's disease, 6 with ulcerative colitis and 9 control individuals (CI) served as a validation cohort of a core fibrotic transcriptomic signature (FIBSig), This signature, which was identified in publicly available data (839 samples from patients and healthy individuals) of 5 fibrotic disorders affecting different organs (GI tract, lung, skin, liver, kidney), encompasses 241 genes and the functional pathways which derive from their interactome. These genes were used in further bioinformatics co-expression analyses to elucidate the site-specific molecular background of intestinal fibrosis highlighting their involvement, particularly in the terminal ileum. We also confirmed different transcriptomic profiles of the sigmoid and terminal ileum in our validation cohort. Combining the results of these analyses we highlight 21 core hub genes within a larger single co-expression module, highly enriched in the terminal ileum of CD patients. Further pathway analysis revealed known and novel inflammation-regulated, fibrogenic pathways operating in the TI, such as IL-13 signaling and pyroptosis, respectively.

Discussion: These findings provide a rationale for the increased incidence of fibrosis at the terminal ileum of CD patients and highlight operating pathways in intestinal fibrosis for future evaluation with mechanistic and translational studies.

Keywords: IBD; co-expression; fibrosis; tissue localization; transcriptomics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Colitis, Ulcerative* / pathology
Colon, Sigmoid / pathology
Crohn Disease* / metabolism
Fibrosis
Humans
Inflammatory Bowel Diseases* / genetics
Inflammatory Bowel Diseases* / pathology