PMID- 32112426 OWN - NLM STAT- MEDLINE DCOM- 20210514 LR - 20210802 IS - 1398-9995 (Electronic) IS - 0105-4538 (Print) IS - 0105-4538 (Linking) VI - 75 IP - 8 DP - 2020 Aug TI - Butyrate inhibits human mast cell activation via epigenetic regulation of FcepsilonRI-mediated signaling. PG - 1966-1978 LID - 10.1111/all.14254 [doi] AB - BACKGROUND: Short-chain fatty acids (SCFAs) are fermented dietary components that regulate immune responses, promote colonic health, and suppress mast cell-mediated diseases. However, the effects of SCFAs on human mast cell function, including the underlying mechanisms, remain unclear. Here, we investigated the effects of the SCFAs (acetate, propionate, and butyrate) on mast cell-mediated pathology and human mast cell activation, including the molecular mechanisms involved. METHOD: Precision-cut lung slices (PCLS) of allergen-exposed guinea pigs were used to assess the effects of butyrate on allergic airway contraction. Human and mouse mast cells were co-cultured with SCFAs and assessed for degranulation after IgE- or non-IgE-mediated stimulation. The underlying mechanisms involved were investigated using knockout mice, small molecule inhibitors/agonists, and genomics assays. RESULTS: Butyrate treatment inhibited allergen-induced histamine release and airway contraction in guinea pig PCLS. Propionate and butyrate, but not acetate, inhibited IgE- and non-IgE-mediated human or mouse mast cell degranulation in a concentration-dependent manner. Notably, these effects were independent of the stimulation of SCFA receptors GPR41, GPR43, or PPAR, but instead were associated with inhibition of histone deacetylases. Transcriptome analyses revealed butyrate-induced downregulation of the tyrosine kinases BTK, SYK, and LAT, critical transducers of FcepsilonRI-mediated signals that are essential for mast cell activation. Epigenome analyses indicated that butyrate redistributed global histone acetylation in human mast cells, including significantly decreased acetylation at the BTK, SYK, and LAT promoter regions. CONCLUSION: Known health benefits of SCFAs in allergic disease can, at least in part, be explained by epigenetic suppression of human mast cell activation. CI - (c) 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd. FAU - Folkerts, Jelle AU - Folkerts J AUID- ORCID: 0000-0002-1014-330X AD - Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands. AD - Department of Pulmonary Medicine, Erasmus MC Rotterdam, Rotterdam, The Netherlands. AD - Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. AD - Dermatological Allergology, Dermatology and Allergy, Charite - Universitatsmedizin Berlin, Berlin, Germany. FAU - Redegeld, Frank AU - Redegeld F AD - Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands. FAU - Folkerts, Gert AU - Folkerts G AD - Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands. FAU - Blokhuis, Bart AU - Blokhuis B AD - Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands. FAU - van den Berg, Mariska P M AU - van den Berg MPM AD - Department of Molecular Pharmacology, Faculty of Science and Engineering, University of Groningen, Groningen, The Netherlands. FAU - de Bruijn, Marjolein J W AU - de Bruijn MJW AD - Department of Pulmonary Medicine, Erasmus MC Rotterdam, Rotterdam, The Netherlands. FAU - van IJcken, Wilfred F J AU - van IJcken WFJ AUID- ORCID: 0000-0002-0421-8301 AD - Center for Biomics, Erasmus MC Rotterdam, Rotterdam, The Netherlands. FAU - Junt, Tobias AU - Junt T AD - Department of Autoimmunity, Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Basel, Switzerland. FAU - Tam, See-Ying AU - Tam SY AD - Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. FAU - Galli, Stephen J AU - Galli SJ AD - Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. AD - Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA, USA. FAU - Hendriks, Rudi W AU - Hendriks RW AD - Department of Pulmonary Medicine, Erasmus MC Rotterdam, Rotterdam, The Netherlands. FAU - Stadhouders, Ralph AU - Stadhouders R AD - Department of Pulmonary Medicine, Erasmus MC Rotterdam, Rotterdam, The Netherlands. AD - Department of Cell Biology, Erasmus MC Rotterdam, Rotterdam, The Netherlands. FAU - Maurer, Marcus AU - Maurer M AUID- ORCID: 0000-0002-4121-481X AD - Dermatological Allergology, Dermatology and Allergy, Charite - Universitatsmedizin Berlin, Berlin, Germany. LA - eng GR - R01 AI132494/AI/NIAID NIH HHS/United States GR - R01 AR067145/AR/NIAMS NIH HHS/United States GR - R01 AI1324 94/NIH/NIAID/International GR - U19AI104 209/NIH/NIAID/International GR - U19 AI104209/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20200424 PL - Denmark TA - Allergy JT - Allergy JID - 7804028 RN - 0 (Butyrates) RN - 0 (Receptors, IgE) RN - EC 2.7.10.1 (Protein-Tyrosine Kinases) SB - IM MH - Animals MH - *Butyrates/pharmacology MH - Cell Degranulation MH - Epigenesis, Genetic MH - Guinea Pigs MH - Humans MH - *Mast Cells/metabolism MH - Mice MH - Protein-Tyrosine Kinases/metabolism MH - Receptors, IgE/genetics PMC - PMC7703657 MID - NIHMS1647792 OTO - NOTNLM OT - FcepsilonRI signaling OT - butyrate OT - histone deacetylase OT - mast cells OT - short-chain fatty acids COIS- Conflict of Interest The authors declare that they have no conflicts of interest. EDAT- 2020/03/01 06:00 MHDA- 2021/05/15 06:00 PMCR- 2021/08/01 CRDT- 2020/03/01 06:00 PHST- 2019/10/08 00:00 [received] PHST- 2020/01/24 00:00 [revised] PHST- 2020/02/06 00:00 [accepted] PHST- 2020/03/01 06:00 [pubmed] PHST- 2021/05/15 06:00 [medline] PHST- 2020/03/01 06:00 [entrez] PHST- 2021/08/01 00:00 [pmc-release] AID - 10.1111/all.14254 [doi] PST - ppublish SO - Allergy. 2020 Aug;75(8):1966-1978. doi: 10.1111/all.14254. Epub 2020 Apr 24.