Anna Theiler1, Thomas Bärnthaler2, Wolfgang Platzer2, Georg Richtig2, Miriam Peinhaupt2, Sonja Rittchen2, Julia Kargl2, Trond Ulven3, Leigh M Marsh4, Gunther Marsche5, Rufina Schuligoi2, Eva M Sturm2, Akos Heinemann6. 1. Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria. 2. Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria. 3. Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark. 4. Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria. 5. Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria; BioTechMed-Graz, Graz, Austria. 6. Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria; BioTechMed-Graz, Graz, Austria. Electronic address: akos.heinemann@medunigraz.at.
Abstract
BACKGROUND: Lung eosinophilia is a hallmark of asthma, and eosinophils are believed to play a crucial role in the pathogenesis of allergic inflammatory diseases. Short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, are produced in high amounts in the gastrointestinal tract by commensal bacteria and can be absorbed into the bloodstream. Although there is recent evidence that SCFAs are beneficial in allergic asthma models, the effect on eosinophils has remained elusive. OBJECTIVE: The role of SCFAs was investigated in human eosinophil function and a mouse model of allergic asthma. METHODS: Eosinophils were purified from self-reported allergic or healthy donors. Migration, adhesion to the endothelium, and eosinophil survival were studied in vitro. Ca2+ flux, apoptosis, mitochondrial membrane potential, and expression of surface markers were determined by using flow cytometry and in part by using real-time PCR. Allergic airway inflammation was assessed in vivo in an ovalbumin-induced asthma model by using invasive spirometry. RESULTS: For the first time, we observed that SCFAs were able to attenuate human eosinophils at several functional levels, including (1) adhesion to the endothelium, (2) migration, and (3) survival. These effects were independent from GPR41 and GPR43 but were accompanied by histone acetylation and mimicked by trichostatin A, a pan-histone deacetylase inhibitor. In vivo butyrate ameliorated allergen-induced airway and lung eosinophilia, reduced type 2 cytokine levels in bronchial fluid, and improved airway hyperresponsiveness in mice. CONCLUSION: These in vitro and in vivo findings highlight the importance of SCFAs, especially butyrate as a promising therapeutic agent in allergic inflammatory diseases.
BACKGROUND:Lung eosinophilia is a hallmark of asthma, and eosinophils are believed to play a crucial role in the pathogenesis of allergic inflammatory diseases. Short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, are produced in high amounts in the gastrointestinal tract by commensal bacteria and can be absorbed into the bloodstream. Although there is recent evidence that SCFAs are beneficial in allergic asthma models, the effect on eosinophils has remained elusive. OBJECTIVE: The role of SCFAs was investigated in human eosinophil function and a mouse model of allergic asthma. METHODS: Eosinophils were purified from self-reported allergic or healthy donors. Migration, adhesion to the endothelium, and eosinophil survival were studied in vitro. Ca2+ flux, apoptosis, mitochondrial membrane potential, and expression of surface markers were determined by using flow cytometry and in part by using real-time PCR. Allergic airway inflammation was assessed in vivo in an ovalbumin-induced asthma model by using invasive spirometry. RESULTS: For the first time, we observed that SCFAs were able to attenuate human eosinophils at several functional levels, including (1) adhesion to the endothelium, (2) migration, and (3) survival. These effects were independent from GPR41 and GPR43 but were accompanied by histone acetylation and mimicked by trichostatin A, a pan-histone deacetylase inhibitor. In vivo butyrate ameliorated allergen-induced airway and lung eosinophilia, reduced type 2 cytokine levels in bronchial fluid, and improved airway hyperresponsiveness in mice. CONCLUSION: These in vitro and in vivo findings highlight the importance of SCFAs, especially butyrate as a promising therapeutic agent in allergic inflammatory diseases.
Authors: Martin Depner; Diana Hazard Taft; Pirkka V Kirjavainen; Karen M Kalanetra; Anne M Karvonen; Stefanie Peschel; Elisabeth Schmausser-Hechfellner; Caroline Roduit; Remo Frei; Roger Lauener; Amandine Divaret-Chauveau; Jean-Charles Dalphin; Josef Riedler; Marjut Roponen; Michael Kabesch; Harald Renz; Juha Pekkanen; Freda M Farquharson; Petra Louis; David A Mills; Erika von Mutius; Markus J Ege Journal: Nat Med Date: 2020-11-02 Impact factor: 53.440