Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Theiler, A.
Role of Short Chain Fatty Acids (SCFA) in Allergic Inflammation
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2019. pp. 137
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Böhm Eva
- Gorkiewicz Gregor
- Heinemann Akos
- Altmetrics:
- Abstract:
- Eosinophils are forceful effector cells in allergic asthma and have been implicated in tissue damage and the inhibition of resolution of inflammation. Blood and sputum eosinophilia is an indicator for disease severity and was linked to airway hyperresponsiveness. As the prevalence of asthma and other allergic inflammatory diseases have been increasing in western countries over the last decades and is accompanied with a change of life style, the hygiene hypothesis has emerged. Additionally, the composition of commensal gut microbiota and the presence of SCFA, as their major metabolic product have been demonstrated to be crucial in the prevention of allergic asthma and other inflammatory eosinophilic disorders. Acetate, propionate and butyrate are the major components in the group of SCFA, which are produced in the gut, but can enter circulation and thereby act on peripheral tissues, especially on leukocytes. However, the effect on eosinophils is not known until now. Therefore, this thesis aimed to elucidate the effect of SCFA on eosinophil effector function of human peripheral blood eosinophils and in a mouse model acute allergic asthma. Eosinophils express GPR43 and GPR41 on mRNA level. Propionate and butyrate strongly induced apoptosis in human eosinophils, whereas this was not mimicked by acetate. This effect was independent of the SCFA receptors GPR43 and GPR41 but was accompanied by histone acetylation and mimicked by the pan-HDAC inhibitor TSA. Additionally, propionate and butyrate hampered the adhesion of eosinophils to the endothelium and TSA mimicked this, whereas acetate was again ineffective. Accordingly, butyrate and TSA inhibited eosinophil migration. These finding proved to be relevant in vivo as systemic butyrate application, blunted lung eosinophilia, reduced the secretion of type 2 cytokines into the airways and improved airway hyperreactivity as determined by invasive spirometry. Strikingly, these effects were specific for eosinophils as other cell types remained unaffected. This thesis clearly demonstrates for the first time that SCFA, especially butyrate, hamper eosinophil function at multiple stages including (1) adhesion to the endothelium, (2) migration, and (3) survival. These effects were confirmed to have in vivo relevance as butyrate alleviated allergic airway inflammation in mice. Collectively, these data suggest that SCFA, especially butyrate directly target eosinophils and could represent a novel strategy in the therapy of already established forms of allergic asthma and other eosinophil-driven disorders.