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

TL;DR

This study shows that male and female mice with celiac disease have different cardiovascular effects, highlighting the need to consider sex in disease research.

Contribution

The study reveals sex-specific differences in cardiovascular inflammation and metabolism in a humanized mouse model of celiac disease.

Findings

Male mice with celiac disease showed vascular dysfunction and inflammation, while females were protected.

Males exhibited cholesterol metabolism dysregulation and kynurenine pathway activation not seen in females.

Estrogen reduction in females partially impaired vascular dilatation, suggesting hormonal influence.

Abstract

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.

The online version contains supplementary material available at 10.1038/s41598-026-45481-6.

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