title: Randomised, double-blind, placebo-controlled trial with azithromycin selects for anti-inflammatory microbial metabolites in the emphysematous lung.
abstract: Azithromycin (AZM) reduces pulmonary inflammation and exacerbations in patients with COPD having emphysema. The antimicrobial effects of AZM on the lower airway microbiome are not known and may contribute to its beneficial effects. Here we tested whether AZM treatment affects the lung microbiome and bacterial metabolites that might contribute to changes in levels of inflammatory cytokines in the airways.
  
  
  
  20 smokers (current or ex-smokers) with emphysema were randomised to receive AZM 250 mg or placebo daily for 8 weeks. Bronchoalveolar lavage (BAL) was performed at baseline and after treatment. Measurements performed in acellular BAL fluid included 16S rRNA gene sequences and quantity; 39 cytokines, chemokines and growth factors and 119 identified metabolites. The response to lipopolysaccharide (LPS) by alveolar macrophages after ex-vivo treatment with AZM or bacterial metabolites was assessed.
  
  
  
  Compared with placebo, AZM did not alter bacterial burden but reduced α-diversity, decreasing 11 low abundance taxa, none of which are classical pulmonary pathogens. Compared with placebo, AZM treatment led to reduced in-vivo levels of chemokine (C-X-C) ligand 1 (CXCL1), tumour necrosis factor (TNF)-α, interleukin (IL)-13 and IL-12p40 in BAL, but increased bacterial metabolites including glycolic acid, indol-3-acetate and linoleic acid. Glycolic acid and indol-3-acetate, but not AZM, blunted ex-vivo LPS-induced alveolar macrophage generation of CXCL1, TNF-α, IL-13 and IL-12p40.
  
  
  
  AZM treatment altered both lung microbiota and metabolome, affecting anti-inflammatory bacterial metabolites that may contribute to its therapeutic effects.
  
  
  
  NCT02557958.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, New York University School of Medicine, New York, New York, USA.|Department of Medicine, New York University School of Medicine, New York, New York, USA.
authors.forename: Leopoldo N
authors.initials: LN
authors.lastname: Segal
authors.affiliation: Department of Genetics and Genomic Sciences and Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Jose C
authors.initials: JC
authors.lastname: Clemente
authors.affiliation: Division of Pulmonary and Critical Care Medicine, New York University School of Medicine, New York, New York, USA.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Wu
authors.affiliation: Department of Molecular and Cellular Biology & Genome Center, University of California, Davis, California, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Wikoff
authors.affiliation: Department of Medicine, New York University School of Medicine, New York, New York, USA.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Division of Pulmonary and Critical Care Medicine, New York University School of Medicine, New York, New York, USA.
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Radiology, New York University School of Medicine, New York, New York, USA.
authors.forename: Jane P
authors.initials: JP
authors.lastname: Ko
authors.affiliation: Division of Pulmonary and Critical Care Medicine, New York University School of Medicine, New York, New York, USA.|Department of Medicine, New York University School of Medicine, New York, New York, USA.
authors.forename: William N
authors.initials: WN
authors.lastname: Rom
authors.affiliation: Department of Medicine, New York University School of Medicine, New York, New York, USA.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Blaser
authors.affiliation: Division of Pulmonary and Critical Care Medicine, New York University School of Medicine, New York, New York, USA.|Department of Medicine, New York University School of Medicine, New York, New York, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Weiden
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017963:Azithromycin / Q000494:pharmacology* / Q000627:therapeutic use; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000382:microbiology; D054360:Chemokine CXCL1 / Q000032:analysis; D016207:Cytokines / Q000032:analysis*; D004311:Double-Blind Method; D005260:Female; D006016:Glycolates / Q000378:metabolism; D006801:Humans; D007210:Indoleacetic Acids / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy; D053762:Interleukin-12 Subunit p40 / Q000032:analysis; D018793:Interleukin-13 / Q000032:analysis; D019787:Linoleic Acid / Q000378:metabolism; D008168:Lung / Q000382:microbiology*; D016676:Macrophages, Alveolar; D008297:Male; D055442:Metabolome / Q000187:drug effects*; D064307:Microbiota / Q000187:drug effects*; D008875:Middle Aged; D011656:Pulmonary Emphysema; D012336:RNA, Ribosomal, 16S / Q000032:analysis*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D000900:Anti-Bacterial Agents; C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D016207:Cytokines; D006016:Glycolates; D007210:Indoleacetic Acids; D053762:Interleukin-12 Subunit p40; D018793:Interleukin-13; D012336:RNA, Ribosomal, 16S; D014409:Tumor Necrosis Factor-alpha; C031149:glycolic acid; C030737:indoleacetic acid; D017963:Azithromycin; D019787:Linoleic Acid
keywords: Bronchoscopy; COPD ÀÜ Mechanisms