Unraveling Celiac Disease from Pathogenesis to Precision Medicine : A Multiomics Approach
Dotsenko, Valeriia (2024)
Dotsenko, Valeriia
Tampere University
2024
Lääketieteen ja biotieteiden tohtoriohjelma - Doctoral Programme in Medicine and Life Sciences
Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology
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Väitöspäivä
2024-08-16
Julkaisun pysyvä osoite on
https://urn.fi/URN:ISBN:978-952-03-3544-1
https://urn.fi/URN:ISBN:978-952-03-3544-1
Tiivistelmä
Celiac disease (CeD) is an autoimmune disorder triggered by dietary gluten in genetically predisposed individuals, affecting approximately 0.7% to 1.4% of the global population, depending on the assessment methods used. The only current treatment is a gluten-free diet (GFD), which, while generally effective, poses significant challenges due to accidental gluten ingestion. This can lead to ongoing symptoms, intestinal damage, and reduced quality of life. CeD also imposes economic burdens on individuals and communities, as gluten-free foods are more expensive and medical care costs increase, especially for those with poor disease control.
To address these challenges, there is a pursuit of effective pharmacological treatments. Recent advances, such as the development of the transglutaminase inhibitor ZED1227, show promise in mitigating gluten-induced intestinal damage.
This dissertation aims to better characterize molecular changes in the intestines of CeD patients in response to gluten exposure in a controlled environment, establish more accurate molecular measures for diagnosing CeD, and test the effects of a novel pharmacological intervention on intestinal transcriptomics and systemic plasma lipid composition. High-throughput multi-omics methods, including RNA sequencing and mass spectrometry, were applied to patient samples obtained during drug trials. The results are organized into four scientific articles manuscripts.
Our findings demonstrate that, despite adherence to a strict GFD, patients continue to exhibit patterns indicative of ongoing disease, as shown by differential gene expression. This indicates that a GFD might not completely restore intestinal mucosa to a healthy state. Furthermore, a gluten challenge activated immune response genes and induced hyperactive intestinal WNT signaling. The gene expression changes correlated with histological damage observed in biopsies, suggesting that transcriptomic changes could serve as biomarkers for the extent of intestinal damage.
ZED1227 treatment effectively maintained transcriptome profiles related to mucosal morphology, inflammation, cell differentiation, and nutrient absorption at levels comparable to the GFD group. Nearly half of the gene expression changes induced by gluten in CeD were linked to an epithelial IFN-γ response. The effectiveness of ZED1227 in protecting mucosal architecture and shielding the epithelium from the IFN-γ response was influenced by the HLA-DQ2 or -DQ8 genetic background.
We also describe a transcriptomic regression model based on four gene transcripts, accurately describing 97.2% of mucosal morphology and 86% of the histological changes. Intestinal organoids proved useful in studying pathogenic agents and mechanisms associated with CeD.
Lipidomic analysis identified significant differences in gluten-induced serum lipid profiles. Kidney function, as measured by the glomerular filtration rate and plasma creatinine levels, significantly decreased following the gluten challenge in the placebo group, correlating with changes in medium-chain fatty acylcarnitines (CARs), which were reversed by ZED1227 treatment. This suggests that specific carnitines, namely CAR 10:1 and CAR 9:0, could serve as early biomarkers for the systemic effects of gluten ingestion in CeD patients.
Overall, this dissertation provides insights into the molecular mechanisms within the intestinal mucosa and systemic plasma of CeD patients using high-throughput omics methodologies. It maps the transcriptomic landscape of mucosa in patients both challenged by gluten and maintained on a GFD, demonstrating that a daily 100 mg dose of ZED1227 can block nearly all gluten-induced transcriptomic alterations. The findings support a personalized medicine approach for CeD patients, advocating for HLA-DQ2/8 stratification to prevent IFN-γ-induced mucosal damage triggered by gluten. Additionally, ZED1227's protective effect is also evidenced on a systemic level, confirming its potential to attenuate gluten-induced mucosal damage and improve CeD diagnosis and patient care.
To address these challenges, there is a pursuit of effective pharmacological treatments. Recent advances, such as the development of the transglutaminase inhibitor ZED1227, show promise in mitigating gluten-induced intestinal damage.
This dissertation aims to better characterize molecular changes in the intestines of CeD patients in response to gluten exposure in a controlled environment, establish more accurate molecular measures for diagnosing CeD, and test the effects of a novel pharmacological intervention on intestinal transcriptomics and systemic plasma lipid composition. High-throughput multi-omics methods, including RNA sequencing and mass spectrometry, were applied to patient samples obtained during drug trials. The results are organized into four scientific articles manuscripts.
Our findings demonstrate that, despite adherence to a strict GFD, patients continue to exhibit patterns indicative of ongoing disease, as shown by differential gene expression. This indicates that a GFD might not completely restore intestinal mucosa to a healthy state. Furthermore, a gluten challenge activated immune response genes and induced hyperactive intestinal WNT signaling. The gene expression changes correlated with histological damage observed in biopsies, suggesting that transcriptomic changes could serve as biomarkers for the extent of intestinal damage.
ZED1227 treatment effectively maintained transcriptome profiles related to mucosal morphology, inflammation, cell differentiation, and nutrient absorption at levels comparable to the GFD group. Nearly half of the gene expression changes induced by gluten in CeD were linked to an epithelial IFN-γ response. The effectiveness of ZED1227 in protecting mucosal architecture and shielding the epithelium from the IFN-γ response was influenced by the HLA-DQ2 or -DQ8 genetic background.
We also describe a transcriptomic regression model based on four gene transcripts, accurately describing 97.2% of mucosal morphology and 86% of the histological changes. Intestinal organoids proved useful in studying pathogenic agents and mechanisms associated with CeD.
Lipidomic analysis identified significant differences in gluten-induced serum lipid profiles. Kidney function, as measured by the glomerular filtration rate and plasma creatinine levels, significantly decreased following the gluten challenge in the placebo group, correlating with changes in medium-chain fatty acylcarnitines (CARs), which were reversed by ZED1227 treatment. This suggests that specific carnitines, namely CAR 10:1 and CAR 9:0, could serve as early biomarkers for the systemic effects of gluten ingestion in CeD patients.
Overall, this dissertation provides insights into the molecular mechanisms within the intestinal mucosa and systemic plasma of CeD patients using high-throughput omics methodologies. It maps the transcriptomic landscape of mucosa in patients both challenged by gluten and maintained on a GFD, demonstrating that a daily 100 mg dose of ZED1227 can block nearly all gluten-induced transcriptomic alterations. The findings support a personalized medicine approach for CeD patients, advocating for HLA-DQ2/8 stratification to prevent IFN-γ-induced mucosal damage triggered by gluten. Additionally, ZED1227's protective effect is also evidenced on a systemic level, confirming its potential to attenuate gluten-induced mucosal damage and improve CeD diagnosis and patient care.
Kokoelmat
- Väitöskirjat [4891]