Gender differences in a murine celiac disease model - effects on the cardiovascular system

Clin Res Cardiol (2024). DOI 10.1007/s00392-024-02406-5
S. Lange (Mainz)¹, K. Keppeler (Mainz)¹, A. Pesi (Mainz)², M. Neerukonda (Mainz)², H. Ubbens (Mainz)¹, L. Strohm (Mainz)¹, I. Kuntic (Mainz)¹, M. Kuntic (Mainz)¹, A. Rosenberger (Mainz)¹, E. Verdu (Hamilton)³, D. Schuppan (Mainz)², P. Lurz (Mainz)¹, A. Daiber (Mainz)¹, D. Leistner (Frankfurt am Main)⁴, S. Steven (Frankfurt am Main)^4
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; ³McMaster University Farncombe Digestive Disease Center Hamilton, Kanada; ⁴Universitätsklinikum Frankfurt Med. Klinik III - Kardiologie, Angiologie Frankfurt am Main, Deutschland

Objective: Celiac disease (CeD) is an auto-inflammation of the small intestine’s mucosa caused by wheat sensitivity. Celiac patients suffer from a variety of symptoms spanning from abdominal pain, diarrhoea, and malabsorption due to blunting of the microvilli. However, women have a higher prevalence for celiac disease with complex symptoms like infertility, early menopause and osteoporosis, experimental studies are still focussing on sex-specific effects in male animals. In this study females of the humanised celiac mouse line NOD-DQ8 were investigated for their cardiovascular complications when exposed to a gluten-containing diet and compared to their male littermates undergoing the same treatments.

Methods and results: Female and male mice of the NOD-DQ8 genotype were fed a gluten-free zein diet in the control group while CeD was triggered in the second group by feeding a gluten-containing diet and performing gavage with either zein or gliadin. Heart and aortic tissue were investigated for inflammatory markers. While the male mice expressed high RNA levels of Vcam1, Tnfa and Nox2 when exposed to gliadin, such inflammatory markers where either unaltered or showed lower expression levels in females undergoing the same treatment. Gliadin-fed female mice showed also unchanged vascular health, whereas male mice suffered from endothelium-dependent and endothelium-independent dysfunction. A similar outcome was found regarding blood pressure where male but not female mice developed hypertension under CeD conditions. 

Conclusion: The need for gender-adjusted research and therapy is gaining more and more interest across all clinical fields. This study presents the very first analysis of female and male mice of the humanised CeD mouse line NOD-DQ8. Although both sexes develop CeD, the intestinal inflammation has different effects on the cardiovascular system in male and female mice. All investigated cardiovascular parameters remained unaltered in gliadin-fed female mice, whereas male mice developed a cardiovascular disease phenotype. Further studies need to show whether the effect of celiac disease on the cardiovascular system is different in men and women. Analysing these mechanisms can help to find new therapeutic approaches and define risk groups.