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Original article
Randomised, double-blind, placebo-controlled trial with azithromycin selects for anti-inflammatory microbial metabolites in the emphysematous lung
  1. Leopoldo N Segal1,2,
  2. Jose C Clemente3,
  3. Benjamin G Wu1,
  4. William R Wikoff4,
  5. Zhan Gao2,
  6. Yonghua Li1,
  7. Jane P Ko5,
  8. William N Rom1,2,
  9. Martin J Blaser2,
  10. Michael D Weiden1,2
  1. 1Division of Pulmonary and Critical Care Medicine, New York University School of Medicine, New York, New York, USA
  2. 2Department of Medicine, New York University School of Medicine, New York, New York, USA
  3. 3Department of Genetics and Genomic Sciences and Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
  4. 4Department of Molecular and Cellular Biology & Genome Center, University of California, Davis, California, USA
  5. 5Department of Radiology, New York University School of Medicine, New York, New York, USA
  1. Correspondence to Dr Leopoldo N Segal, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Bellevue Hospital Center/New York University School of Medicine, 462 First Ave 7W54, New York, NY 10016, USA; Leopoldo.Segal{at}nyumc.org; Dr Michael D Weiden, Michael.Weiden{at}nyumc.org

Abstract

Introduction 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.

Methods 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.

Results 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.

Conclusion AZM treatment altered both lung microbiota and metabolome, affecting anti-inflammatory bacterial metabolites that may contribute to its therapeutic effects.

Trial registration number NCT02557958.

  • Bronchoscopy
  • COPD ÀÜ Mechanisms

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Footnotes

  • Contributors Conception and design: LNS, MJB and MDW. Acquisition of data: LNS, ZG, YL and JPK. Analysis and interpretation of data: LNS, JCC, BGW, JPK, MJB and MDW. Drafting or revising of article: LNS, JCC, WNR, MJB and MDW. Final approval of the manuscript: LNS, JCC, BGW, WRW, ZG, YL, JPK, WNR, MJB and MDW.

  • Funding K23 AI102970 (LNS); K24 AI080298 (MDW); CTSI Grant #UL1 TR000038; EDRN 5U01CA086137-13; Diane Belfer Program for Human Microbial Ecology; R01DK090989; U01AI122285-01, UH2 AR57506.

  • Competing interests JPK reports a speaker honorarium from Siemens, AG, outside the submitted work; none of the other authors declare any other competing interests.

  • Ethics approval New York University Institutional Review Board.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement All data are publicly available in Gene Expression Omnibus under accession number GSE74396.

  • This article has an online supplementary data.

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