Yong Huang1, Shwu-Fan Ma1, Milena S Espindola2, Rekha Vij1, Justin M Oldham3, Gary B Huffnagle4, John R Erb-Downward4, Kevin R Flaherty4, Beth B Moore4, Eric S White4, Tong Zhou5, Jianrong Li6, Yves A Lussier6, MeiLan K Han4, Naftali Kaminski7, Joe G N Garcia6, Cory M Hogaboam2, Fernando J Martinez8, Imre Noth1. 1. 1 Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Illinois. 2. 2 Pulmonary and Critical Care Medicine, Cedars-Sinai Medical Center, Los Angeles, California. 3. 3 Pulmonary and Critical Care Medicine, University of California at Davis, Sacramento, California. 4. 4 Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan. 5. 5 Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada. 6. 6 University of Arizona Health Sciences at the University of Arizona, Tucson, Arizona. 7. 7 Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut; and. 8. 8 Weill Cornell Medical College, Cornell University, New York, New York.
Abstract
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.
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.
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