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

Celiac disease (CeD) is an autoimmune condition characterized by an aberrant immune response triggered by the ingestion of gluten, which damages epithelial cells lining the small intestine. Small intestinal epithelial cells (sIECs) play key roles in the enzymatic digestion and absorption of nutrients, maintaining gut barrier integrity, and regulating immune response. Chronic inflammation and tissue damage associated with CeD disrupt the intricate network of metabolic processes in sIECs that support these functions, impairing their ability to perform their essential roles. However, the specific disrupted metabolic processes underlying sIECs dysfunction in CeD remain largely undefined.

To address this knowledge gap, personalized, sex-specific genome-scale models of sIECs metabolism were constructed using transcriptional data from intestinal biopsies of 42 subjects with active CeD, CeD in remission (on a gluten-free diet), and non-CeD controls. These models were computationally simulated under relevant dietary conditions for each group of subjects to assess the activity of several metabolic tasks essential for sIECs function and to profile metabolite secretion into the bloodstream and intestinal lumen.

Significant alterations in the activity of 28 essential metabolic tasks were observed in active CeD and remission CeD, impacting critical processes integral to sIECs function such as oxidative stress regulation, nucleotide synthesis and DNA repair, energy production, and polyamine and amino acid metabolism. Additionally, altered secretion profiles of several metabolites, encompassing amino acids, vitamins, polyamines, lipids, and fatty acids, into the bloodstream were detected in active CeD and remission CeD patients. These findings were partially supported by comparisons with independent external datasets and further corroborated through extensive review of existing literature. Furthermore, a drug target analysis was performed, identifying 22 FDA-approved drugs that target genes encoding impaired sIECs metabolic functions in CeD, potentially helping to restore their normal activity.

This study unveils new insights into the metabolic reprogramming of sIECs in CeD, highlighting specific dysregulated metabolic processes that compromise cellular functions essential for gut health. These findings offer a foundation for developing therapeutic interventions targeting impaired metabolic processes in CeD.