Reversal of Endothelial Dysfunction and Vascular Inflammation in Celiac Disease: Recovery Study by Switching to Gluten-Free Diet.

Clin Res Cardiol (2024). DOI 10.1007/s00392-024-02406-5
K. Keppeler (Mainz)¹, A. Pesi (Mainz)², S. Lange (Mainz)¹, J. Helmstädter (Mainz)¹, L. Strohm (Mainz)¹, H. Ubbens (Mainz)¹, M. Kuntic (Mainz)¹, I. Kuntic (Mainz)¹, D. Mihalikova (Mainz)¹, K. Vujacic-Mirski (Mainz)¹, A. Rosenberger (Mainz)¹, L. Küster (Mainz)¹, C. Frank (Mainz)², M. Oelze (Mainz)¹, S. Finger (Mainz)³, A. Zakrzewska (Krakow)⁴, E. Verdu (Hamilton)⁵, J. Wild (Mainz)³, S. Karbach (Mainz)¹, P. Wenzel (Mainz)¹, P. S. Wild (Mainz)¹, D. Leistner (Frankfurt am Main)⁶, T. Münzel (Mainz)¹, A. Daiber (Mainz)¹, D. Schuppan (Mainz)², S. Steven (Frankfurt am Main)⁶
¹Universitätsmedizin der Johannes Gutenberg-Universität Mainz Kardiologie 1, Zentrum für Kardiologie Mainz, Deutschland; ²Universitätsmedizin der Johannes Gutenberg-Universität Mainz Institut für Translationale Immunologie Mainz, Deutschland; ³Universitätsmedizin der Johannes Gutenberg-Universität Mainz Centrum für Thrombose und Hämostase Mainz, Deutschland; ⁴Jagiellonian University Jagiellonian Centre for Experimental Therapeutics Krakow, Polen; ⁵McMaster University Farncombe Digestive Disease Center Hamilton, Kanada; ⁶Universitätsklinikum Frankfurt Med. Klinik III - Kardiologie, Angiologie Frankfurt am Main, Deutschland

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.

Reversal of Endothelial Dysfunction and Vascular Inflammation in Celiac Disease: Recovery Study by Switching to Gluten-Free Diet.

Starke Unterstützung*