TY - JOUR

T1 - Butyrate ameliorates allergic airway inflammation by limiting eosinophil trafficking and survival

AU - Theiler, Anna

AU - Bärnthaler, Thomas

AU - Platzer, Wolfgang

AU - Richtig, Georg

AU - Peinhaupt, Miriam

AU - Rittchen, Sonja

AU - Kargl, Julia

AU - Ulven, Trond

AU - Marsh, Leigh M

AU - Marsche, Gunther

AU - Schuligoi, Rufina

AU - Sturm, Eva M

AU - Heinemann, Akos

N1 - Copyright © 2019. Published by Elsevier Inc.

PY - 2019

Y1 - 2019

N2 - 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 (SCFA), e.g. acetate, propionate and butyrate are produced in high amounts in the gastro-intestinal tract by commensal bacteria and can be absorbed into the blood stream. Although, there is recent evidence that SCFA are beneficial in allergic asthma models, the effect on eosinophils has remained elusive.OBJECTIVE: The role of SCFA 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 endothelium and survival of eosinophils was studied in vitro. Ca2+ flux, apoptosis, mitochondrial membrane potential and expression of surface markers was determined by flow cytometry and in part by real time PCR. Allergic airway inflammation was assessed in vivo in an ovalbumin-induced asthma model using invasive spirometry.RESULTS: We observed for the first time that SCFA were able to attenuate human eosinophils at several functional levels including (i) adhesion to the endothelium, (ii) migration and (iii) survival. These effects were independent from GPR41 and GPR43, but were accompanied by histone acetylation and mimicked by TSA, a pan-HDAC inhibitor. In vivo, butyrate ameliorated allergen-induced airway and lung eosinophilia, reduced type 2 cytokines in the bronchial fluid and improved airway hyperresponsiveness in mice.CONCLUSION: These in vitro and in vivo findings highlight the importance of SCFA, especially butyrate as a promising therapeutic agent in allergic inflammatory diseases.

AB - 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 (SCFA), e.g. acetate, propionate and butyrate are produced in high amounts in the gastro-intestinal tract by commensal bacteria and can be absorbed into the blood stream. Although, there is recent evidence that SCFA are beneficial in allergic asthma models, the effect on eosinophils has remained elusive.OBJECTIVE: The role of SCFA 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 endothelium and survival of eosinophils was studied in vitro. Ca2+ flux, apoptosis, mitochondrial membrane potential and expression of surface markers was determined by flow cytometry and in part by real time PCR. Allergic airway inflammation was assessed in vivo in an ovalbumin-induced asthma model using invasive spirometry.RESULTS: We observed for the first time that SCFA were able to attenuate human eosinophils at several functional levels including (i) adhesion to the endothelium, (ii) migration and (iii) survival. These effects were independent from GPR41 and GPR43, but were accompanied by histone acetylation and mimicked by TSA, a pan-HDAC inhibitor. In vivo, butyrate ameliorated allergen-induced airway and lung eosinophilia, reduced type 2 cytokines in the bronchial fluid and improved airway hyperresponsiveness in mice.CONCLUSION: These in vitro and in vivo findings highlight the importance of SCFA, especially butyrate as a promising therapeutic agent in allergic inflammatory diseases.

U2 - 10.1016/j.jaci.2019.05.002

DO - 10.1016/j.jaci.2019.05.002

M3 - Journal article

C2 - 31082458

VL - 144

SP - 764

EP - 776

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

IS - 3

ER -