Objective: Celiac disease (CeD) is increasingly recognized for its extraintestinal manifestations, particularly its cardiovascular implications. Although an association between CeD and heightened cardiovascular risk is known, a comprehensive characterization of the ensuing vascular inflammation and endothelial dysfunction is lacking. This study advances the understanding of these cardiovascular anomalies and examines their reversibility in a humanized mouse model of CeD following the reintroduction of a gluten-free diet.
Methods: Utilizing the NOD.DQ8 mouse model predisposed to CeD, we initiated CeD characteristics through a gluten-containing diet following gliadin and cholera toxin sensitization. To assess reversibility, a subsequent 14-day gluten-free diet was introduced (OFF-study treatment scheme). Comprehensive evaluations included duodenal histology, cardiovascular functional assessments through echocardiography and blood pressure measurements, vascular reactivity, and molecular assessments of systemic inflammation and oxidative stress.
Results: Gluten administration led to the successful induction of CeD, as confirmed by intestinal histopathology and vascular profiles indicative of inflammation. The gluten-free diet recovery phase resulted in a normalization of cardiovascular parameters, including both systolic and diastolic blood pressures and body weight metrics. A significant amelioration in vascular function was documented, with a reinstatement of endothelium-dependent and endothelium-independent vascular relaxations. This functional recovery was corroborated by a return to baseline levels of plasma nitrate and nitrite, and a pronounced decrease in oxidative stress markers, such as 3-nitrotyrosine and 4-hydroxynonenal, within the vascular endothelium, also supported by dihydroethidium (DHE) staining for reactive oxygen species formation.
Conclusion: This study provides the first concrete evidence of vascular inflammation and endothelial dysfunction in a CeD context and their subsequent remission through dietary intervention. Our findings not only chart unexplored territories in CeD-related cardiovascular pathology but also affirm the reversibility of such disturbances, promoting a gluten-free diet as a cornerstone in managing the vascular complications of CeD. These insights could pave the way for novel therapeutic perspectives in reducing cardiovascular risks for CeD patients.
