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Enrichment of the lung microbiome with oral taxa is associated with lung inflammation of a Th17 phenotype

Nature Microbiology volume 1, Article number: 16031 (2016) Cite this article

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Abstract

Microaspiration is a common phenomenon in healthy subjects, but its frequency is increased in chronic inflammatory airway diseases, and its role in inflammatory and immune phenotypes is unclear. We have previously demonstrated that acellular bronchoalveolar lavage samples from half of the healthy people examined are enriched with oral taxa (here called pneumotypeSPT) and this finding is associated with increased numbers of lymphocytes and neutrophils in bronchoalveolar lavage. Here, we have characterized the inflammatory phenotype using a multi-omic approach. By evaluating both upper airway and acellular bronchoalveolar lavage samples from 49 subjects from three cohorts without known pulmonary disease, we observed that pneumotypeSPT was associated with a distinct metabolic profile, enhanced expression of inflammatory cytokines, a pro-inflammatory phenotype characterized by elevated Th-17 lymphocytes and, conversely, a blunted alveolar macrophage TLR4 response. The cellular immune responses observed in the lower airways of humans with pneumotypeSPT indicate a role for the aspiration-derived microbiota in regulating the basal inflammatory status at the pulmonary mucosal surface.

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Figure 1: Major differences in microbial composition of the lower airways are driven by enrichment with either supraglottic taxa or background taxa.
Figure 2: Comparison of inferred metagenomes of pneumotypeSPT and pneumotypeBPT.
Figure 3: Correlation between the lower airway microbiome and metabolome.
Figure 4: Similarity of the lower airway microbiome with the upper airway microbiome is associated with the percentage of lymphocytes in BAL.
Figure 5: PneumotypeSPT is associated with a blunted TLR4 response of alveolar macrophages.

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Acknowledgements

Research support funding was provided by the National Institute of Allergy and Infectious Diseases (NIAID) K23 AI102970 (to L.N.S.); the National Heart, Lung and Blood Institute (NHLBI) R01 HL125816 (to S.B.K.); NIAID K24 AI080298 (to M.D.W.); the Clinical and Translational Science Institute (CTSI) grant no. UL1 TR000038; the Early Detection Research Network (EDRN) 5U01CA086137-13; the Diane Belfer Program for Human Microbial Ecology; the Michael Saperstein Scholarship Fund; the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) R01DK090989; the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) UH2 AR57506; NIAID U01AI111598; NHLBI R01 HL090339; NHLBI K24 HL123342 (to A.M.); NHLBI U01 HL098962 (to A.M. and E.G.); NHLBI K24HL123342; NHLBI K24 HL087713 (to L.H.); NIAID and the National Cancer Institute (NCI) UO1-AI-35042; 5-MO1-RR-00722 from the General Clinical Research Center (GCRC); UL1TR000124 from the University of California Los Angeles Clinical and Translational Research Center (UCLA CTRC); NIAID UO1-AI-35043; NIAID UO1-AI-37984; NIAID UO1-AI-35039; NIAID UO1-AI-35040; NIAID UO1-AI-37613; NIAID UO1-AI-35041 (Multicenter AIDS Cohort); NIAID and the National Institute of Child Health and Human Development (NICHHD) UO1-AI-35004; NIAID UO1-AI-31834; NIAID UO1-AI-34994; NIAID UO1-AI-34989; NIAID UO1-AI-34993; NIAID UO1-AI-42590; NICHHD UO1-HD-32632; the Women's Interagency HIV Study (WIHS); NHLBI U01-HL098957 and NHLBI R01-HL113252 (to R.G.C.).

The authors also thank H.W. Virgin (Washington University School of Medicine), S. Stone, S. Fong, A. Malki and S. Tokman (University of California San Francisco (UCSF)), C. Kessinger, N. Leo, D. Camp, M.P. George, L. Lucht, M. Gingo, R. Hoffman, M. Fitzpatrick, J. Ries, A. Clarke (Pittsburgh) and J. Dermand and E. Kleerup (UCLA).

Computing was partially supported by the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai.

Some of the Pittsburgh LHMP data in this manuscript were collected by the Multicenter AIDS Cohort Study (MACS) with centres (Principal Investigators) at UCLA (R. Detels, U01-AI35040); University of Pittsburgh (C. Rinaldo, U01-AI35041); the Center for Analysis and Management of MACS, Johns Hopkins University Bloomberg School of Public Health (L. Jacobson, UM1-AI35043). MACS is funded primarily by NIAID, with additional cofunding from the NCI. Targeted supplemental funding for specific projects was also provided by the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute on Deafness and Communication Disorders (NIDCD). MACS data collection was also supported by UL1-TR000424 Johns Hopkins University Clinical and Translational Science Awards (JHU CTSA, https://statepi.jhsph.edu/macs/macs.html). The contents of this publication are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health (NIH).

Some of the Pittsburgh LHMP data in this manuscript were collected by the WIHS. WIHS (principal investigators): U01-AI-103408; Connie Wofsy Women's HIV Study, Northern California (R. Greenblatt, B. Aouizerat and P. Tien). The WIHS is funded primarily by NIAID, with additional cofunding from the Eunice Kennedy Shriver NICHD, the NCI, the National Institute on Drug Abuse (NIDA) and the National Institute on Mental Health (NIMH). WIHS data collection was also supported by UL1-TR000004 (UCSF CTSA).

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Authors and Affiliations

  1. Division of Pulmonary, Critical Care and Sleep Medicine, New York University School of Medicine, New York, USA

    Leopoldo N. Segal, Jun-Chieh J. Tsay, Benjamin G. Wu, Yonghua Li, William N. Rom, Daniel H. Sterman & Michael D. Weiden

  2. Department of Medicine, New York University School of Medicine, New York, New York, USA

    Leopoldo N. Segal, Jun-Chieh J. Tsay, Benjamin G. Wu, Yonghua Li, William N. Rom, Daniel H. Sterman, Martin J. Blaser & Michael D. Weiden

  3. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, USA

    Jose C. Clemente & Nan Shen

  4. Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA

    Jose C. Clemente

  5. Department of Pathology, New York University School of Medicine, New York, New York, USA

    Sergei B. Koralov

  6. Division of Pulmonary and Critical Care Medicine, The Ohio State University, Columbus, Ohio, USA

    Brian C. Keller & Phillip Diaz

  7. Department of Biology, Center for Genomics & Systems Biology, College of Global Public Health, New York University, New York, New York, USA

    Elodie Ghedin

  8. Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pennsylvania, USA

    Alison Morris

  9. Department of Medicine, University of California San Francisco, San Francisco, California, USA

    Laurence Huang

  10. Department of Molecular and Cellular Biology & Genome Center, University of California, Davis, California, USA

    William R. Wikoff

  11. Center for Public Health Research, FISABIO, Valencia, Spain

    Carles Ubeda & Alejandro Artacho

  12. Department of Medicine and Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    Ronald G. Collman

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  1. Leopoldo N. Segal
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Contributions

L.N.S., J.C.C., M.J.B. and M.D.W. conceived and designed the study. L.N.S., J.J.T., A.M., L.H., P.D. and W.R.W. acquired the data. L.N.S., J.C.C, J.J.T., S.B.K., B.G.W., Y.L., N.S., W.R.W., C.U., A.A., B.C.K., R.G.C., M.J.B. and M.D.W. analysed and interpreted the data. L.N.S., J.C.C., J.J.T., S.B.K., E.G., A.M., P.D., L.H., W.R.W., B.C.K., W.N.R., D.H.S., R.G.C., M.J.B. and M.D.W. drafted or revised the article. L.N.S., J.C.C., J.J.T., S.B.K., B.G.W., Y.L., N.S., E.G., A.M., P.D., L.H., W.R.W., C.U., A.A., B.C.K., W.N.R., D.H.S., R.G.C., M.J.B. and M.D.W. approved the final manuscript.

Corresponding authors

Correspondence to Leopoldo N. Segal or Michael D. Weiden.

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Supplementary Methods, Results, References, Figures 1-10 and Tables 1-7. (PDF 9099 kb)

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Segal, L., Clemente, J., Tsay, JC. et al. Enrichment of the lung microbiome with oral taxa is associated with lung inflammation of a Th17 phenotype. Nat Microbiol 1, 16031 (2016). https://doi.org/10.1038/nmicrobiol.2016.31

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