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Quantitative proteomics of coeliac gut during 14-day gluten challenge: low-level baseline inflammation despite clinical and histological normality predicts subsequent response

ABSTRACT: Coeliac disease is a small intestinal disorder caused by an abarrent immune response towards dietary gluten due to activation of pro-inflammatory gluten specific CD4+ T cells. Histological evaluation and classification of gluten induced musosal changes is part of the diagnostic work up. of adults. The kinetics of mucosal recovery following commencesment of a gluten free diet (disease remission) and the degree of mucosal changes induced by gluten reintroduction (gluten challenge) varies between patients. Also, patients classified with similar clinical and histological disease remission, can develop different degree of mucosal damage following the same gluten challenge regime. This variation poses a challenge for the interpretation of gluten induced mucosal changes both in a diagnostic and clinical trial settings. In this study, we have analysed material from small intestinal biopsies collected from 19 treated coeliac disease patients before and after completion of a 14-day oral gluten challenge. These patients are part of a previoslpreviouslyu described study where all patients were in clinical and mucosal remission at baseline but only some patients developed histological changes in the mucosa in response to gluten. We have performed shotgun LC-MSMS analysis and label-free quantification of total gut tissue and from laser capture microdissected epithelial cell layer samples. We found that differences in tissue proteome expression could separate patients as responders and non-responders to the gluten challenge. Patients whoich responded strongly to gluten , had signs of gut inflammation already at baseline, supported by presence of low-level blood inflammatory parameters and a slight increase in numbers of gluten-specific CD4+ T cells at baseline. Our proteomics analysis demonstrated baseline differences in gut tissue state between patients that were not evident from routine clinical and histological evaluation. These baseline differences likely explains why some patients respond more strongly to gluten challenge than others.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Tuula Nyman

LAB HEAD: Tuula Nyman

PROVIDER: PXD018977 | Pride | 2021-03-03

REPOSITORIES: Pride

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In Well-Treated Celiac Patients Low-Level Mucosal Inflammation Predicts Response to 14-day Gluten Challenge.

Stamnaes Jorunn J Stray Daniel D Stensland Maria M Sarna Vikas K VK Nyman Tuula A TA Lundin Knut E A KEA Sollid Ludvig M LM

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20210104 4

In celiac disease (CeD), gluten activates adaptive immune cells that cause damage to the small intestinal mucosa. Histological evaluation of intestinal biopsies allows for grading of disease severity. CeD can effectively be treated with a life-long gluten-free diet. Gluten challenge of treated CeD patients is used to confirm diagnosis and to test drug efficacy in clinical trials, but patients respond with different magnitudes to the same gluten challenge. In this study of 19 well-treated CeD pat ...[more]

PMID: 33643806

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Project description:Background & Aims: Traditional celiac disease diagnostics based on histomorphometric evaluations are liable to misinterpretations due to the common technical flaws e.g. wrong orientation of the biopsy and subjective errors are relatively common e.g. interobserver errors. We envisioned that there is a need for molecular histomorphometric tool that obviates these error sources yielding an objective ratio instead. Gene expression determine the state of a tissue, so the changes in expression may be associated with the severity of lesions during CD and can be used to classify it. Methods: 15 CD patients, who have been at least one year on gluten-free diet, were enrolled. All participants were biopsied before and after the gluten challenge (10 weeks, 4 grams of gluten daily). 6 healthy non-CD individuals were included as controls. Biopsies were taken on PAXgene biological fixative and embedded in paraffin and Vh/Cd ratio was assessed. RNA was extracted from the same sections and subjected to genome-wide 3’RNA-sequencing. Sequencing data was used to determine differentially expressed genes and regression model, that successfully describes the mucosal damage, was created and tested in independent material. Results: 167 differentially expressed genes were identified in healthy vs. treated CD comparisons with 117 genes downregulated and 50 genes upregulated. 415 differentially expressed genes were identified in Post gluten challenge to Treated CD comparisons with 195 genes downregulated and 220 genes upregulated. 119 genes whose expression highly correlates to Vh/Cd ratio (Spearman’s rank correlation coefficient, |rho|>0.7) were identified. Gene ontology analyses show that genes involved in cellular response to cytokines, including interferons, were over-represented. Stepwise regression allowed us computationally cut down the number of genes, that describe Vh/Cd ratio changes, to 7 and IELs number to 5. Created models describe 98.9% of observed Vh/Cd and 97.5% of IELs number variabilities; there is a strong correlation between the model’s predicted and observed ratios. Conclusions: Adoption of molecular histomorphometry, with our selected set of target genes, is quantitative and reliable way of estimating gluten-induced mucosal injury and inflammation. By including this technology one can overcome the typical shortcomings common in celiac disease diagnostics based on traditional histomorphometry analyses alone. Likewise, molecular histomorphometry is a promising instrument when incorporated in clinical trials where assessing drug efficacy on mucosal health is paramount. In addition, despite deemed healthy, based on traditional histomorphometric analyses, celiac patients on gluten free diet have significantly distinctive molecular histomorphometric pattern when compared to healthy controls.

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