Effects of In Vivo Gluten Challenge on PBMC Gene Expression Profiles in Diet Treated Celiac Disease
Open Access
- 11 December 2020
- journal article
- research article
- Published by Frontiers Media SA in Frontiers in Immunology
Abstract
The pathological mechanisms that lead to the onset and reactivation of celiac disease (CD) remain largely unknown. While gluten free diet (GFD) improves the intestinal damage and associated clinical symptoms in majority of cases, it falls short of providing full recovery. Additionally, late or misdiagnosis is also common as CD presents with a wide range of symptoms. Clear understanding of CD pathogenesis is thus critical to address both diagnostic and treatment concerns. We aimed to study the molecular impact of short gluten exposure in GFD treated CD patients, as well as identify biological pathways that remain altered constitutively in CD regardless of treatment. Using RNAseq profiling of PBMC samples collected from treated CD patients and gluten challenged patient and healthy controls, we explored the peripheral transcriptome in CD patients following a short gluten exposure. Short gluten exposure of just three days was enough to alter the genome-wide PBMC transcriptome of patients. Pathway analysis revealed gluten-induced upregulation of mainly immune response related pathways, both innate and adaptive, in CD patients. We evaluated the perturbation of biological pathways in sample-specific manner. Compared to gluten exposed healthy controls, pathways related to tight junction, olfactory transduction, metabolism of unsaturated fatty acids (such as arachidonic acid), metabolism of amino acids (such as cysteine and glutamate), and microbial infection were constitutively altered in CD patients regardless of treatment, while GFD treatment appears to mostly normalize immune response pathways to “healthy” state. Upstream regulator prediction analysis using differentially expressed genes identified constitutively activated regulators relatively proximal to previously reported CD associated loci, particularly SMARCA4 on 19p13.2 and CSF2 on 5q31. We also found constitutively upregulated genes in CD that are in CD associated genetic loci such as MEF2BNB-MEF2B (BORCS8-MEF2B) on 19p13.11 and CSTB on 21q22.3. RNAseq revealed strong effects of short oral gluten challenge on whole PBMC fraction and constitutively altered pathways in CD PBMC suggesting important factors other than gluten in CD pathogenesis.This publication has 69 references indexed in Scilit:
- Neurologic Deficits in Patients With Newly Diagnosed Celiac Disease Are Frequent and Linked With Autoimmunity to Transglutaminase 6Clinical Gastroenterology and Hepatology, 2019
- Global Prevalence of Celiac Disease: Systematic Review and Meta-analysisClinical Gastroenterology and Hepatology, 2018
- Delayed celiac disease diagnosis predisposes to reduced quality of life and incremental use of health care services and medicines: A prospective nationwide studyUnited European Gastroenterology Journal, 2018
- Profiling Celiac Disease-Related Transcriptional ChangesInternational Review of Cell and Molecular Biology, 2018
- Transcriptome Analysis of CD4+ T Cells in Coeliac Disease Reveals Imprint of BACH2 and IFNγ RegulationPLOS ONE, 2015
- Persistence of elevated deamidated gliadin peptide antibodies on a gluten‐free diet indicates nonresponsive coeliac diseaseAlimentary Pharmacology & Therapeutics, 2014
- Celiac Disease—A Complex DisorderPublished by Elsevier BV ,2014
- Long-term and acute effects of gliadin on small intestine of patients on potentially pathogenic networks in celiac diseaseAutoimmunity, 2009
- A microarray screen for novel candidate genes in coeliac disease pathogenesisGut, 2004
- cDNA microarray analysis of gene expression in coeliac disease jejunal biopsy samplesJournal of Autoimmunity, 2004