Abdominal Area, Kidneys & Pelvis

Active celiac disease as promoter of cardiovascular morbidity: exploration of underlying mechanisms and effect of therapeutic intervention

Institution: Department for Cardiology, Cardiology I, University Medical Center Mainz
Applicant: PD Dr. Sebastian Steven
Funding line:
Else Kröner Excellence Fellowships

Celiac disease (CeD), induced by nutritional gluten proteins, is a frequent autoimmune disease with a prevalence of 1-2 % worlwide. In CeD, immunogenic gluten peptides are incompletely digested by gastrointestinal proteases, which then reach the lamina propria of the proximal small intestine, where they are bound on HLA-DQ2 or -DQ8 molecules of antigen-presenting cells that activate CD4 T cells and intraepithelial lymphocytes (IELs). This leads to chronic inflammation of the small intestine with atrophy of the resorptive villi, and frequently to malabsorption and extra-intestinal inflammation. Recent clinical studies show an increased cardiovascular risk in untreated celiac patients. A connection between inflammatory processes in the intestine and the vascular wall is obvious, but underlying mechanisms have not been investigated. Possible pathophysiological connections, and therefore also nutritional and pharmacological targets, are the migration of activated inflammatory cells from the intestine to the periphery or mediators and hormones induced by the inflammation. The latter could include the peptide hormone glucagon-like peptide-1 (GLP-1) whose bioavailability is regulated by IELs. Notably, a lack of native GLP-1 has a pro-atherosclerotic effect. GLP-1 itself is a peptide hormone secreted from intestinal enteroendocrine L cells that displays anti-inflammatory properties, increases insulin release from pancreatic beta cells, and whose analogs are used to treat type 2 diabetes mellitus (T2DM). Thus, cardiovascular outcome trials such as LEADER showed that GLP-1 analogs like liraglutide significantly reduced the risk of cardiovascular events in T2DM patients. In this proposal, we plan to use an optimized mouse model of CeD (non-obese diabetic (NOD) mice, transgenic for humane HLA-DQ8 on the mouse MHCII0/0 background; sensitized with gluten peptides and adjuvants). These mice develop all characteristics of human CeD when set on a gluten-containing diet. We plan to 1. dissect the pathophysiological relationships between CeD and cardiovascular disease, and 2. investigate new therapeutic approaches such as GLP 1 analogs for the treatment of CeD and its consequences on the cardiovascular system.

Here you can find further information.