Celiac disease (CeD) is a chronic autoimmune disorder triggered by dietary gluten in genetically predisposed individuals, affecting approximately 0.7% to 1.4% of the global population. The only current treatment is a strict gluten-free diet (GFD), which can be challenging to maintain and does not completely prevent accidental gluten exposure. This can lead to persistent symptoms, ongoing intestinal damage, and a reduced quality of life. Additionally, the economic burden of CeD is significant due to the higher cost of gluten-free foods and increased medical expenses.
To address these challenges, recent advancements, such as the transglutaminase inhibitor ZED1227, show promise in reducing gluten-induced intestinal damage. In her doctoral dissertation, Valeriia Dotsenko investigates the molecular changes in CeD patients' intestines following gluten exposure simultaneously with drug or placebo. This study aims to evaluate the effects of a novel pharmacological intervention on intestinal transcriptomics and systemic plasma lipid composition and to improve diagnostic molecular measures for CeD.
“The main strength of this dissertation was the opportunity to study well-defined cohorts of patients with previously detected CeD who adhered well to GFD and underwent a gluten challenge, receiving a defined amount of gluten for a specified duration,” says Valeriia Dotsenko.
This approach enabled the identification of gluten-induced transcriptomic changes in the mucosa, confirming that despite adherence to a strict GFD, patients continue to show signs of active disease through differential gene expression.
The study showed that ZED1227 treatment maintained gene expression patterns related to mucosal structure, inflammation, cell differentiation, and nutrient absorption at levels comparable to those in the GFD group. The protective effect of ZED1227 on mucosal architecture was influenced by specific genetic variations related to CeD, specifically the presence of either the HLA-DQ2 or HLA-DQ8 genes. The overall impact of ZED1227 on the entire body was also examined through a detailed analysis of lipid molecules in the blood plasma of patients.
Overall, Valeriia Dotsenko’s dissertation provides comprehensive insights into the molecular mechanisms within the intestinal mucosa and systemic plasma of CeD patients. The dissertation highlights that a daily 100 mg dose of ZED1227 can block nearly all gluten-induced transcriptomic alterations. It advocates for HLA-DQ2/8 genetic testing to support a personalized medicine approach for CeD patients and better preventing gluten-induced mucosal damage. The protective effect of ZED1227 is also confirmed on the entire body level, showing its potential to mitigate gluten-induced mucosal damage and enhance CeD diagnosis and patient care.
Public defence on Friday 16 August
M.Sc. Valeriia Dotsenko's dissertation in the field of molecular biology titled Unraveling Celiac Disease from Pathogenesis to Precision Medicine: A Multiomics Approach will be publicly examined at the Faculty of Medicine and Health Technology at Tampere University at 12 o’clock on Friday 16 August 2024. The venue is the Jarmo Visakorpi auditorium in the Arvo building on the Kauppi campus (address: Arvo Ylpön katu 34, Tampere). The Opponent will be Associate professor Iris H. Jonkers from University Medical Center Groningen, Netherlands. The Custos will be Docent Keijo Viiri from the Faculty of Medicine and Health Technology, Tampere University.