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

• Applicants: Professor Dr. Detlef Schuppan; Dr. Sebastian Steven
• Subject Area: Cardiology, Angiology ; Gastroenterology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 467458564

Celiac disease (CeD) that is induced by nutritional gluten proteins is a frequent autoimmune disease with a prevalence of 1-2% in most countries in the world. In CeD immunogenic gluten peptides are incompletely digested by gastrointestinal proteases reach the lamina propria of the proximal small intestine, where they are bound on HLA-DQ2 or -DQ8 molecules of antigen presenting cells and activate CD4+ T cells and intraepithelial lymphocytes. This leads to a 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, changes in the intestinal microbiome and immune-active metabolites generated by the respective microbiome, or mediators and hormones induced by the inflammation or the altered microbiome. The latter could include the peptide hormone glucagon-like peptide-1 (GLP-1) whose bioavailability is regulated by IEL. Notably, a lack of native GLP-1 has a pro-atherosclerotic effect. GLP-1 itself is a peptide hormone formed in the small intestinal epithelium that displays anti-inflammatory properties, that increases insulin release from pancreatic beta cells, and whose analogs are used to treat type 2 diabetes mellitus (T2DM). Thus, the LEADER study showed that GLP-1 analogs 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 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 and intestinal microbial metabolites for the treatment of CeD and its consequences on the cardiovascular system.

• DFG Programme: Research Grants
• International Connection: Poland
• Cooperation Partner: Professor Stefan Chlopicki, Ph.D.