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.
Highlights
To improve our understanding of celiac pathogenesis, we applied a standardized high throughput mRNA sequencing (RNAseq) approach on formalin-fixed paraffin-embedded (FFPE) archived duodenum biopsies used for clinical diagnosis of active pre-treatment celiac disease and controls subjects (n = 54)
Using archived clinical FFPE duodenal biopsies and high-throughput transcriptome sequencing of celiac and control subjects we captured many of the previously described pathogenic pathways associated with celiac disease[9,10,11,12], suggesting that our analysis is robust, and that using FFPE clinical samples is a valid approach
We provide evidence for host gene expression profiles driving lymphocyte activation and cytokine signaling in treatment naïve pediatric celiac disease
Summary
To improve our understanding of celiac pathogenesis, we applied a standardized high throughput mRNA sequencing (RNAseq) approach on FFPE archived duodenum biopsies used for clinical diagnosis of active pre-treatment celiac disease and controls subjects (n = 54). Our cohort represent the largest celiac disease mucosal transcriptomic cohort to date[9,10,11,12] (Table S1). We capture robust gene expression and pathways that are linked to celiac pathogenesis, which were validated independently in other cohorts[9,10]. Comparison of the celiac disease signature with our previously published Crohn disease signature showed similar and divergent pathways that can shed light on those intestinal inflammatory diseases, emphasizing the more unique signal for the increase in epithelial cell cycle and proliferation coupled with reduced epithelial mature metabolic function associated with epithelial de-differentiation in celiac disease
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
