Investigating intestinal epithelium metabolic dysfunction in celiac disease using personalized genome-scale models

Area of Science:

• Gastroenterology
• Metabolic Engineering
• Immunology

Background:

• Celiac disease (CeD) is an autoimmune disorder triggered by gluten, causing small intestinal epithelial cell (sIEC) damage.
• sIECs are crucial for nutrient absorption, gut barrier integrity, and immune regulation.
• CeD-induced inflammation disrupts sIEC metabolic processes, but specific dysfunctions remain unclear.

Purpose of the Study:

• To define the specific metabolic processes dysregulated in sIECs in Celiac disease.
• To investigate sex-specific metabolic alterations in sIECs.
• To identify potential therapeutic targets for CeD.

Main Methods:

• Construction of personalized, sex-specific genome-scale models of sIEC metabolism.
• Utilized transcriptional data from intestinal biopsies of 42 subjects (active CeD, remission CeD, controls).
• Computational simulations under dietary conditions to assess metabolic tasks and metabolite secretion.

Main Results:

• Identified significant alterations in 28 essential metabolic tasks in active and remission CeD.
• Observed dysregulated oxidative stress, nucleotide synthesis, energy production, and amino acid/polyamine metabolism.
• Detected altered secretion of amino acids, vitamins, polyamines, lipids, and fatty acids in CeD patients.
• Identified 22 FDA-approved drugs targeting impaired sIEC metabolic functions.

Conclusions:

• CeD causes significant metabolic reprogramming in sIECs, compromising essential cellular functions.
• Specific dysregulated metabolic pathways in sIECs are identified, offering insights into CeD pathogenesis.
• Findings provide a basis for developing novel therapeutic strategies targeting metabolic pathways in CeD.