Exposure to dietary alpha-amylase-trypsin inhibitors (ATI) induces vascular inflammation and endothelial dysfunction

S. Lange (Mainz)¹, K. Keppeler (Mainz)¹, A. Pesi (Mainz)², M. Neerukonda (Mainz)², H. Ubbens (Mainz)³, L. Strohm (Mainz)³, I. Kuntic (Mainz)³, M. Kuntic (Mainz)³, A. Rosenberger (Mainz)¹, D. Schuppan (Mainz)², P. Lurz (Mainz)¹, A. Daiber (Mainz)³, D. Leistner (Frankfurt am Main)⁴, S. Steven (Frankfurt am Main)^4
1Universitätsmedizin der Johannes Gutenberg-Universität Mainz Kardiologie 1, Zentrum für Kardiologie Mainz, Deutschland; ²Universitätsmedizin der Johannes Gutenberg-Universität Mainz Institut für Translationale Immunologie Mainz, Deutschland; ³Universitätsmedizin der Johannes Gutenberg-Universität Mainz Labor für Molekulare Kardiologie Mainz, Deutschland; ⁴Universitätsklinikum Frankfurt Med. Klinik III - Kardiologie, Angiologie Frankfurt am Main, Deutschland

Objective: Cereals are an essential part of the human diet and alpha-amylase-trypsin inhibitors (ATI) are a group of 19 heat-stable peptides present in all gluten-containing cereals. Since ATIs activate auto-inflammatory pathways via the Toll-like receptor 4 (TLR4) in the gut, they are suspected to promote inflammation in remote organ systems as it has been shown for non-alcoholic liver disease, multiple sclerosis and Morbus Alzheimer. This study aims to investigate the cardiovascular effects of an ATI-containing diet regarding vascular function and inflammatory hallmarks in a murine model.

Methods and results: Male C57BL/6J mice were fed an ATI-free, gluten-free diet for two weeks in advance to the experiment. Animals were divided in two groups. The control group received ATI-free, gluten-free diet for further four weeks while the ATI group was changed to a diet containing an ATI isolate (0,5 % w/w) from wheat flour. Blood pressure and body weight was monitored during the treatment. Vascular function (endothelium-dependent and -independent relaxation) was measured upon stimulation with acetylcholine and nitroglycerine. While blood pressure and weight gain remained unaltered by the ATI diet, a mild endothelial-dependent dysfunction occurred in the ATI‑fed mice. qPCR results revealed that CD11b and CD68 were significantly elevated in aortic tissue and perivascular adipose tissue indicating infiltration of inflammatory cells.

Conclusion: As human diets are mainly based on cereals, almost all humans are exposed to significant amounts of ATIs. This study revealed for the first time that ATIs have inflammatory properties on the cardiovascular system. The measured endothelial dysfunction in combination with increased leukocyte markers indicates an inflammatory response to ATI exposure in remote organs. Further studies are necessary to explore the cardiovascular effects of ATI-containing diets in patients with cardiovascular disease or relevant cardiovascular risk factors.