Microbes Are Associated with Host Innate Immune Response in Idiopathic Pulmonary Fibrosis.
Differences in the lung microbial community influence idiopathic pulmonary fibrosis (IPF) progression. Whether the lung microbiome influences IPF host defense remains unknown.



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



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.



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).



These findings suggest that host-microbiome interactions influence PFS and fibroblast responsiveness.
1 Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Illinois.
Yong
Y
Huang
1 Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Illinois.
Shwu-Fan
SF
Ma
2 Pulmonary and Critical Care Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
Milena S
MS
Espindola
1 Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Illinois.
Rekha
R
Vij
3 Pulmonary and Critical Care Medicine, University of California at Davis, Sacramento, California.
Justin M
JM
Oldham
4 Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan.
Gary B
GB
Huffnagle
4 Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan.
John R
JR
Erb-Downward
4 Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan.
Kevin R
KR
Flaherty
4 Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan.
Beth B
BB
Moore
4 Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan.
Eric S
ES
White
5 Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada.
Tong
T
Zhou
6 University of Arizona Health Sciences at the University of Arizona, Tucson, Arizona.
Jianrong
J
Li
6 University of Arizona Health Sciences at the University of Arizona, Tucson, Arizona.
Yves A
YA
Lussier
4 Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan.
MeiLan K
MK
Han
7 Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut; and.
Naftali
N
Kaminski
6 University of Arizona Health Sciences at the University of Arizona, Tucson, Arizona.
Joe G N
JGN
Garcia
2 Pulmonary and Critical Care Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
Cory M
CM
Hogaboam
8 Weill Cornell Medical College, Cornell University, New York, New York.
Fernando J
FJ
Martinez
1 Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Illinois.
Imre
I
Noth
D018893:Bronchoalveolar Lavage; D018572:Disease-Free Survival; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000276:immunology* / Q000382:microbiology*; D007113:Immunity, Innate / Q000276:immunology*; D008297:Male; D046228:Microarray Analysis; D064307:Microbiota / Q000276:immunology*; D008875:Middle Aged
CpG-oligodeoxynucleotide response; bronchoalveolar lavage microbiome; host immune response and microbial interaction; pattern recognition receptors; peripheral blood mononuclear cell transcriptome