Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

Cardiovascular damage in experimental celiac disease is mediated by gut-derived vascular inflammation and oxidative stress
S. Steven1, K. Keppeler1, J. Helmstädter1, L. Küster1, L. Strohm1, H. Ubbens1, M. T. Bayo Jimenez1, M. Kuntic1, I. Djordjevic1, S. Finger1, M. Oelze1, E. Verdu2, S. Kahl3, D. Schuppan3, P. Wenzel1, P. S. Wild1, T. Münzel1, A. Daiber1
1Kardiologie 1, Zentrum für Kardiologie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz; 2Farncombe Digestive Diseases Center, McMaster University, Hamilton, CA; 3Institut für Translationale Immunologie, Universitätsmedizin Mainz, Mainz;

Objective: Celiac disease (CeD) is an autoimmune enteropathy triggered by dietary gluten, with a worldwide prevalence of up to 2%. Since many patients only show mild or extraintestinalsymptoms, CeD is grossly underdiagnosed. Vascular function testing indicated that untreated CeD may be a a cardiovascular risk factor. With the present study we aimed to explore the cardiovascular effects of active CeD in a humanized HLA-DQ8-transgenic  mouse model of CeD, with special emphasis on endothelial dysfunction, vascular/intestinal inflammation and oxidative stress, all known major contributors to cardiovascular disease.

Methods: 8-week old NOD.DQ8-transgenic mice were raised on a zein (corn prolamine) -based, gluten-free diet. At day 0, 7 and 14, animals received an oral gavage with a peptic-tryptic digest of gliadin and switched to a gluten-containing diet (25% of Zein) for 15 days (Gluten group). Controls (Zein group) were continued on the gluten-free diet and received pepsin-trypsin digested zein via gavage. Another Gluten group was switched back to the gluten-free diet for 14 days to test reversibility. Small animal echocardiography and non-invasive blood pressure measurements were performed. Vascular function was tested by isometric tension recording. Aortic, cardiac, perivascular adipose (pVAT) and small intestinal tissue were used for western blotting, qRT-PCR and IHC to determine the extent of vascular and intestinal inflammation and oxidative stress. Plasma proteomics was performed using Olink. 

Results: Gliadin group developed arterial hypertension with reduced heart rate and stroke volume resulting in significantly reduced cardiac output. Endothelium-dependent relaxation (acetylcholine) was impaired in the Gliadin group compared to Zein group, whereas no change in endothelium-independent (nitroglycerine) was observed. Pro-inflammatory genes (Il6, Tnfa, Nos2, Vcam1 and Nox2) were upregulated in aortic and intestinal tissue of the Gliadin group compared to control. Infiltration by intraepithelial T-Lymphocytes into the epithelium of the small intestine was shown by IHC. In pVAT, mRNA transcripts of proinflammatory markers (IL6, CD11b), leptin and adiponectin were elevated. In cardiac tissue, gliadin-treatment increased the oxidative stress parameters 3-nitrotyrosine (3NT), 4‑hydroxynonenal (4HNE). To investigate the inflammatory link between gut and the cardiovascular system plasma proteomics were performed and revealed elevated levels of IL17a, IL17f, TNFrsf12a, CXCL9 and CCL20. A switch to gluten-free diet resulted in normalization of selected parameters such as endothelial dysfunction or vascular inflammation.

Conclusion: Using our humanized mouse model, we demonstrated that CeD, a common autoimmune disease triggered by dietary gluten, is a cardiovascular risk factor. We demonstrated that in this model dietary gluten clearly elevates blood pressure and impairs cardiovascular function. Therefore, intestinal inflammation due to CeD is conveyed to the cardiovascular system, leading to oxidative stress and thereby impaired endothelial function and cardiac output. A potential mediator might be IL17a since its role in other autoimmunity-based cardiovascular risk factors (e.g. psoriasis) has already been demonstrated.With the present study we demonstrate a mechanistic link to explain the role of celiac disease as a cardiovascular risk factor and provide evidence for a gut-to-cardiovascular inflammatory axis.


https://dgk.org/kongress_programme/jt2022/aV594.html