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Metabolic network analysis of Crohn's disease reveals sex- and age-specific cellular phenotypes
Connor J Moore1, Mariska Batavia1, William Shao1
1Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA.
Insights
Genome-scale metabolic models reveal altered cholesterol metabolism in pediatric Crohn's disease (CD). Inhibiting cholesterol synthesis reduced inflammation, suggesting a new therapeutic target for this inflammatory gastrointestinal disease.
Area of Science:
- Gastroenterology
- Metabolomics
- Systems Biology
Background:
- Crohn's disease (CD) is a rising inflammatory gastrointestinal disorder, particularly impacting pediatric populations with higher risks of severe outcomes.
- Genome-scale metabolic models (GEMs) offer a powerful approach to study metabolic alterations in diseases like pediatric CD.
- Understanding systems-level metabolic changes is crucial for developing targeted therapies.
Purpose of the Study:
- To develop an ileum-specific GEM (Ileum1) using pediatric and adult omics data.
- To investigate broad metabolic differences across clinical cohorts using reaction inclusion analysis (RIA).
- To identify metabolic alterations associated with Crohn's disease, especially in pediatric and adult populations.
Main Methods:
- Construction of an ileum-specific genome-scale metabolic model (Ileum1) integrating pediatric and adult omics data.
- Development and application of reaction inclusion analysis (RIA) to compare hundreds of subject-specific GEMs.
- In vitro experiments to validate metabolic findings, including cholesterol synthesis inhibition.
Main Results:
- RIA identified altered cholesterol metabolism in males with CD.
- In vitro studies demonstrated that inhibiting cholesterol synthesis reduced inflammatory cytokine levels.
- Transcriptomics analysis revealed unique metabolic alterations in adult CD patients.
Conclusions:
- Metabolic modeling and RIA are effective tools for dissecting disease-specific metabolic perturbations.
- Altered cholesterol metabolism is a key feature in CD, particularly in males, and presents a potential therapeutic target.
- Metabolic dysregulation in CD is context-dependent, varying between pediatric and adult patients.
Abstract:
Crohn's disease (CD) is an inflammatory gastrointestinal disease affecting approximately 1 in 1,000 people in North America. Incidence of pediatric CD has been rising in recent decades, and this group is especially at risk of more severe disease development because of the association of CD with developmental deficits. Genome-scale metabolic models (GEMs) present an opportunity to investigate systems-level changes in metabolism in specific contexts, such as pediatric CD. In this work, we utilized pediatric and adult omics data to create an ileum-specific GEM, Ileum1. We also developed reaction inclusion analysis (RIA) to quantify broad metabolic differences of several clinical cohorts and used this method to compare hundreds of subject-specific GEMs. RIA predicted altered cholesterol metabolism in males with CD, and in vitro testing found that cholesterol synthesis inhibition prevented an increase of inflammatory cytokines. We used transcriptomics from adult subjects and found that metabolism is uniquely altered in adult CD. A record of this paper's transparent peer review process is included in the supplemental information.
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