title: Short-chain fatty acids affect cystic fibrosis airway inflammation and bacterial growth.
abstract: The hypoxic environment of cystic fibrosis airways allows the persistence of facultative anaerobic bacteria, which can produce short-chain fatty acids (SCFAs) through fermentation. However, the relevance of SCFAs in cystic fibrosis lung disease is unknown. We show that SCFAs are present in sputum samples from cystic fibrosis patients in millimolar concentrations (mean±sem 1.99±0.36 mM).SCFAs positively correlated with sputum neutrophil count and higher SCFAs were predictive for impaired nitric oxide production. We studied the effects of the SCFAs acetate, propionate and butyrate on airway inflammatory responses using epithelial cell lines and primary cell cultures. SCFAs in concentrations present in cystic fibrosis airways (0.5-2.5 mM) affected the release of granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor and interleukin (IL)-6. SCFAs also resulted in higher IL-8 release from stimulated cystic fibrosis transmembrane conductance regulator (CFTR) F508del-mutant compared to wild-type CFTR-corrected bronchial epithelial cells. At 25 mM propionate reduced IL-8 release in control but not primary cystic fibrosis epithelial cells. Low (0.5-2.5 mM) SCFA concentrations increased, while high (25-50 mM) concentrations decreased inducible nitric oxide synthase expression. In addition, SCFAs affected the growth of Pseudomonas aeruginosa in a concentration- and pH-dependent manner.Thus, our data suggest that SCFAs contribute to cystic fibrosis-specific alterations of responses to airway infection and inflammation.
authors.affiliation: Program in Physiology and Experimental Medicine, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada Dept of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada Institute for Infection Immunology, TWINCORE, Hannover, Germany.
authors.forename: Peyman
authors.identifier: http://orcid.org/0000-0002-7398-5141
authors.initials: P
authors.lastname: Ghorbani
authors.affiliation: Program in Physiology and Experimental Medicine, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Prisila
authors.initials: P
authors.lastname: Santhakumar
authors.affiliation: Program in Physiology and Experimental Medicine, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada Dept of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada.
authors.forename: Qingda
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Program in Physiology and Experimental Medicine, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Pascal
authors.initials: P
authors.lastname: Djiadeu
authors.affiliation: Dept of Nutritional Sciences, University of Toronto, Toronto, ON, Canada.
authors.forename: Thomas M S
authors.initials: TM
authors.lastname: Wolever
authors.affiliation: Program in Physiology and Experimental Medicine, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada Dept of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.
authors.forename: Nades
authors.initials: N
authors.lastname: Palaniyar
authors.affiliation: Program in Physiology and Experimental Medicine, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada Dept of Pediatrics, Division of Respiratory Medicine, The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada Hartmut.Grasemann@sickkids.ca.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Grasemann
mesh_terms: D000085:Acetates / Q000737:chemistry; D000293:Adolescent; D001424:Bacterial Infections / Q000150:complications / Q000188:drug therapy; D002087:Butyrates / Q000737:chemistry; D002648:Child; D002849:Chromatography, Gas; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D005232:Fatty Acids, Volatile / Q000737:chemistry*; D005260:Female; D005285:Fermentation; D005541:Forced Expiratory Volume; D005786:Gene Expression Regulation; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D000860:Hypoxia; D007249:Inflammation / Q000188:drug therapy; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000737:chemistry; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011422:Propionates / Q000737:chemistry; D011550:Pseudomonas aeruginosa / Q000254:growth & development; D013183:Sputum / Q000737:chemistry*
chemical_list: D000085:Acetates; D002087:Butyrates; C505032:CFTR protein, human; C508606:CXCL8 protein, human; D005232:Fatty Acids, Volatile; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D011422:Propionates; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D016179:Granulocyte Colony-Stimulating Factor; D009569:Nitric Oxide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II