Sex-related differences in cardiovascular inflammation and metabolomics in a humanized transgenic mouse model of celiac disease

Celiac disease (CeD) is an immune-mediated disorder driven by dietary gluten, characterized by intestinal, such as diarrhoea and malabsorption, and many extraintestinal manifestations. Epidemiological studies have linked untreated CeD to an elevated risk of cardiovascular complications. In this study, CeD induced in humanized transgenic male NOD.DQ8 mice resulted in vascular dysfunction, cardiovascular oxidative stress, and systemic as well as vascular inflammation. In contrast, female NOD-DQ8 mice developed comparable CeD-specific small intestinal pathology upon gluten exposure but were protected from vascular dysfunction and cardiovascular inflammation. Compared with females, male CeD mice displayed pronounced dysregulation of cholesterol metabolism, activation of the kynurenine pathway, and mast cell activation in perivascular tissues. Pharmacological reduction of estrogen with the aromatase inhibitor letrozole partly impaired vascular dilatation in female CeD mice. These findings underscore the importance of considering sex-specific manifestations of CeD with its associated systemic inflammation in preclinical and clinical research.