Microbes Are Associated with Host Innate Immune Response in Idiopathic Pulmonary Fibrosis

Am J Respir Crit Care Med. 2017 Jul 15;196(2):208-219. doi: 10.1164/rccm.201607-1525OC.


Rationale: Differences in the lung microbial community influence idiopathic pulmonary fibrosis (IPF) progression. Whether the lung microbiome influences IPF host defense remains unknown.

Objectives: To explore the host immune response and microbial interaction in IPF as they relate to progression-free survival (PFS), fibroblast function, and leukocyte phenotypes.

Methods: Paired microarray gene expression data derived from peripheral blood mononuclear cells as well as 16S ribosomal RNA sequencing data from bronchoalveolar lavage obtained as part of the COMET-IPF (Correlating Outcomes with Biochemical Markers to Estimate Time-Progression in Idiopathic Pulmonary Fibrosis) study were used to conduct association pathway analyses. The responsiveness of paired lung fibroblasts to Toll-like receptor 9 (TLR9) stimulation by CpG-oligodeoxynucleotide (CpG-ODN) was integrated into microbiome-gene expression association analyses for a subset of individuals. The relationship between associated pathways and circulating leukocyte phenotypes was explored by flow cytometry.

Measurements and main results: Down-regulation of immune response pathways, including nucleotide-binding oligomerization domain (NOD)-, Toll-, and RIG1-like receptor pathways, was associated with worse PFS. Ten of the 11 PFS-associated pathways correlated with microbial diversity and individual genus, with species accumulation curve richness as a hub. Higher species accumulation curve richness was significantly associated with inhibition of NODs and TLRs, whereas increased abundance of Streptococcus correlated with increased NOD-like receptor signaling. In a network analysis, expression of up-regulated signaling pathways was strongly associated with decreased abundance of operational taxonomic unit 1341 (OTU1341; Prevotella) among individuals with fibroblasts responsive to CpG-ODN stimulation. The expression of TLR signaling pathways was also linked to CpG-ODN responsive fibroblasts, OTU1341 (Prevotella), and Shannon index of microbial diversity in a network analysis. Lymphocytes expressing C-X-C chemokine receptor 3 CD8 significantly correlated with OTU1348 (Staphylococcus).

Conclusions: These findings suggest that host-microbiome interactions influence PFS and fibroblast responsiveness.

Keywords: CpG-oligodeoxynucleotide response; bronchoalveolar lavage microbiome; host immune response and microbial interaction; pattern recognition receptors; peripheral blood mononuclear cell transcriptome.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Bronchoalveolar Lavage
  • Disease-Free Survival
  • Down-Regulation / immunology
  • Female
  • Flow Cytometry
  • Gene Expression / immunology
  • Humans
  • Idiopathic Pulmonary Fibrosis / immunology*
  • Idiopathic Pulmonary Fibrosis / microbiology*
  • Immunity, Innate / immunology*
  • Male
  • Microarray Analysis
  • Microbiota / immunology*
  • Middle Aged