Article Text

Download PDFPDF
Original research
Topographic heterogeneity of lung microbiota in end-stage idiopathic pulmonary fibrosis: the Microbiome in Lung Explants-2 (MiLEs-2) study
  1. Eleanor Valenzi1,
  2. Haopu Yang2,3,4,
  3. John C Sembrat1,
  4. Libing Yang2,4,
  5. Spencer Winters1,5,
  6. Rachel Nettles2,
  7. Daniel J Kass1,
  8. Shulin Qin1,2,
  9. Xiaohong Wang1,2,
  10. Michael M Myerburg1,
  11. Barbara Methé1,2,
  12. Adam Fitch1,2,
  13. Jonathan K Alder1,
  14. Panayiotis V Benos3,
  15. Bryan J McVerry1,2,
  16. Mauricio Rojas1,
  17. Alison Morris1,2,
  18. Georgios D Kitsios1,2
  1. 1 Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
  2. 2 Center for Medicine and the Microbiome, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  3. 3 Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  4. 4 School of Medicine, Tsinghua University, Beijing, China
  5. 5 Bronson Adult Critical Care, Kalamazoo, Michigan, USA
  1. Correspondence to Dr Georgios D Kitsios, Pulmonary Allergy and Critical Care Medicine, University of Pittsburgh Medical Center Health System, Pittsburgh, PA 15260, USA; kitsiosg{at}


Background Lung microbiota profiles in patients with early idiopathic pulmonary fibrosis (IPF) have been associated with disease progression; however, the topographic heterogeneity of lung microbiota and their roles in advanced IPF are unknown.

Methods We performed a retrospective, case-control study of explanted lung tissue obtained at the time of lung transplantation or rapid autopsy from patients with IPF and other chronic lung diseases (connective tissue disease-associated interstitial lung disease (CTD-ILD), cystic fibrosis (CF), COPD and donor lungs unsuitable for transplant from Center for Organ Recovery and Education (CORE)). We sampled subpleural tissue and airway-based specimens (bronchial washings and airway tissue) and quantified bacterial load and profiled communities by amplification and sequencing of the 16S rRNA gene.

Findings Explants from 62 patients with IPF, 15 patients with CTD-ILD, 20 patients with CF, 20 patients with COPD and 20 CORE patients were included. Airway-based samples had higher bacterial load compared with distal parenchymal tissue. IPF basilar tissue had much lower bacterial load compared with CF and CORE lungs (p<0.001). No microbial community differences were found between parenchymal tissue samples from different IPF lobes. Dirichlet multinomial models revealed an IPF cluster (29%) with distinct composition, high bacterial load and low alpha diversity, exhibiting higher odds for acute exacerbation or death.

Interpretation IPF explants had low biomass in the distal parenchyma of all three lobes with higher bacterial load in the airways. The discovery of a distinct subgroup of patients with IPF with higher bacterial load and worse clinical outcomes supports investigation of personalised medicine approaches for microbiome-targeted interventions.

  • idiopathic pulmonary fibrosis
  • bacterial infection
  • lung transplantation

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.


  • Twitter @KitsiosMd

  • Contributors Conception and design: GDK, MR, AM, BJMcV. Acquisition, analysis or interpretation of data: EV, HY, JCS, LY, SW, RN, DJK, SQ, XW, MMM, BM, AF, JKA, PVB, BJMcV, MR, AM, GDK. Clinical cohort characterisation: GDK, EV, SW, MMM, DJK. Drafting of work and/or revising for important intellectual content: EV, HY, JCS, LY, SW, RN, DJK, SQ, XW, MMM, BM, AF, JKA, PVB, BJMcV, MR, AM, GDK. Final approval of version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: EV, HY, JCS, LY, SW, RN, DJK, SQ, XW, MMM, BM, AF, JKA, PVB, BJMcV, MR, AM, GDK.

  • Funding National Institutes of Health (K23 HL139987 (GDK); U01 HL098962 (AM); U01 HL137159 (PVB); R01 HL127349 (PVB); K24 HL123342 (AM); R01 HL123766 (MR), RO1 HL126990 (DK), T32 HL007563-31 (EV), CFF RDP to the University of Pittsburgh (MM)), Breathe Pennsylvania Lung Health Research Grant (GDK).

  • Competing interests BJMcV is a consultant for The VeraMedica Institute and receives research funding from Bayer Pharmaceuticals. GDK has received research funding from Karius. The other authors have no conflicts of interest to declare.

  • Patient consent for publication Not required.

  • Ethics approval The University of Pittsburgh Institutional Review Board and Committee for Oversight of Research and Clinical Training Involving Decedents approved this study.

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

  • Data availability statement Data are available in a public, open access repository. All de-identified sequencing data have been submitted to Sequence Read Archive (SRA) database, with BioSample accession numbers of SAMN13906474-13906711.

Linked Articles