Vitamin D receptor and STAT6 interactome governs oesophageal epithelial barrier responses to IL-13 signalling

Abstract

ObjectiveThe contribution of vitamin D (VD) deficiency to the pathogenesis of allergic diseases remains elusive. We aimed to define the impact of VD on oesophageal allergic inflammation.DesignWe assessed the genomic distribution and function of VD receptor (VDR) and STAT6 using histology, molecular imaging, motif discovery and metagenomic analysis. We examined the role of VD supplementation in oesophageal epithelial cells, in a preclinical model of IL-13-induced oesophageal allergic inflammation and in human subjects with eosinophilic oesophagitis (EoE).ResultsVDR response elements were enriched in oesophageal epithelium, suggesting enhanced VDR binding to functional gene enhancer and promoter regions. Metagenomic analysis showed that VD supplementation reversed dysregulation of up to 70% of the transcriptome and epigenetic modifications (H3K27Ac) induced by IL-13 in VD-deficient cells, including genes encoding the transcription factors HIF1A and SMAD3, endopeptidases (SERPINB3) and epithelial-mesenchymal transition mediators (TGFBR1, TIAM1, SRC, ROBO1, CDH1). Molecular imaging and chromatin immunoprecipitation showed VDR and STAT6 colocalisation within the regulatory regions of the affected genes, suggesting that VDR and STAT6 interactome governs epithelial tissue responses to IL-13 signalling. Indeed, VD supplementation reversed IL-13-induced epithelial hyperproliferation, reduced dilated intercellular spaces and barrier permeability, and improved differentiation marker expression (filaggrin, involucrin). In a preclinical model of IL-13-mediated oesophageal allergic inflammation and in human EoE, VD levels inversely associated with severity of oesophageal eosinophilia and epithelial histopathology.ConclusionsCollectively, these findings identify VD as a natural IL-13 antagonist with capacity to regulate the oesophageal epithelial barrier functions, providing a novel therapeutic entry point for type 2 immunity-related diseases.

Assessment of local and systemic signature of eosinophilic esophagitis (EoE) in children through multi-omics approaches

“…Transcriptomic analysis and network visualization of DE genes further highlighted the dysregulation of major immune processes, both innate and adaptive. It also identified other dysregulated pathways, notably major downregulation of genes involved in epithelial cell and barrier functions (SPINK6/7/8, SFTA2, EPGN, TGM3, SLURP1, ENDOU, MUC22, MUC21), in line with previous studies ( 35 – 37 ). The involvement of IL-20 subfamily in this epithelial barrier impairment was less evident than that observed recently in adults ( 37 ).…”

“…The role of environmental chemicals in the initiation / perpetuation of EoE in children thus clearly warrant further investigations. Conversely, and considering the critical role of vitamin D in EoE pathogenesis ( 35 ), VDR gene was rather increased in biopsies from our EoE patients (log 2 [FC] = 1.557, p=0.003).…”

EGIDExpress: An Interactive Shiny Web App to Visualize and Share Large Biological Datasets

“…Since its inception in 2019, it has demonstrated its utility at the local laboratory level and beyond such as by generating interest from collaborators in academia and industry. At least 12 publications have already been facilitated by EGIDExpress 15, 16, 17, 18, 19,20, 21, 14, 22, 23, 24, 25 . Datasets will continue to be added to EGIDExpress as they are generated, and we remain flexible to adding new data formats or modes of visualization as new dataset types arise, and we are open to developing new functionalities within the app.…”

Eosinophilic esophagitis and the promise of vitamin D

“…Vitamin D serum levels are inversely associated with severity of eosinophilic inflammation. The new, important mechanistic data presented in this issue in Gut put that it is likely that vitamin D supplementation will be effective in EoE 1. However, the learnings from trials in the other extraskeletal conditions described above reduce the enthusiasm and show that both associations between low vitamin D levels and disease prevalence and severity as well as in vitro effects of supplementation do not necessarily lead to clinically relevant improvements in clinical trials in patients.…”

“…Vitamin D plays an essential role in the calcium and bone metabolism, but it has become clear that subclinical vitamin D deficiency is a risk factor for several other extraskeletal diseases as well. In this issue of Gut , new evidence is published on the role of vitamin D in the pathophysiology of Th2 inflammation and eosinophilic esophagitis (EoE) in particular 1. Brusilovsky et al show that vitamin D has important interleukin (IL)-13 antagonistic properties and was shown to regulate epithelial barrier and immune functions.…”