Defining the Celiac Disease Transcriptome using Clinical Pathology Specimens Reveals Biologic Pathways and Supports Diagnosis

Nurit Loberman-Nachum, Katya Sosnovski, Ayelet Di Segni, Gilat Efroni, Tzipi Braun, Marina BenShoshan, Lait Anafi, Camila Avivi, Iris Barshack, Dror S. Shouval, Lee A. Denson, Amnon Amir, Ron Unger, Batia Weiss, Yael Haberman

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Celiac disease is provoked by gluten exposure, but the complete pathogenic process in the duodenum and the loss of tolerance to gluten is not well understood. We aimed to define the core celiac transcriptomic signature and pathologic pathways in pre-treatment formalin-fixed paraffin-embedded (FFPE) duodenum biopsies used for clinical diagnosis. We use mRNAseq to define pre-treatment diagnostic duodenum gene expression in 54 pediatric celiac patients and non-celiac controls, and we validate our key findings in two independent cohorts of 67 adults and pediatric participants that used fresh frozen biopsies. We further define similar and divergent genes and pathways in 177 small bowel Crohn disease patients and controls. We observe a marked suppression of mature epithelial metabolic functions in celiac patients, overlapping substantially with the Crohn disease signature. A marked adaptive immune response was noted for the up-regulated signature including interferon response, alpha-beta, and gamma-delta T-cells that overlapped to some extent with the Crohn disease signature. However, we also identified a celiac disease specific signature linked to increased cell proliferation, nuclear division, and cell cycle activity that was localized primarily to the epithelia as noted by CCNB1 and Ki67 staining. Lastly, we demonstrate the utility of the transcriptomic date to correctly classify disease or healthy states in the discovery and validation cohorts. Our data supplement recently published datasets providing insights into celiac pathogenesis using clinical pathology FFPE samples, and can stimulate new approaches to address this highly prevalent condition.

Original languageEnglish
Article number16163
JournalScientific Reports
Volume9
Issue number1
DOIs
StatePublished - 7 Nov 2019

Bibliographical note

Publisher Copyright:
© 2019, The Author(s).

Funding

All authors have no financial and non-financial conflict of interests or competing interests associated with this work. Funding for this work was in part from the Israel Science Foundation, European Research Council, and Crohn's & Colitis Foundation. The authors thank the patients who participated in this important study, the CCF funded RISK Crohn Disease study, and the RISK steering committee and investigators. The authors greatly appreciate the funding sources including the Israel Science Foundation (YH, grant No. 908/15), and the I-CORE program (YH, grants No. 41/11), and ERC starting grant (YH, grant No. 758313) for support for this work.

FundersFunder number
ERC starting758313
National Institute of Diabetes and Digestive and Kidney DiseasesP30DK078392
Crohn's and Colitis Foundation
European Commission
Israel Science Foundation908/15
Israeli Centers for Research Excellence41/11

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