Article | Published:

Enrichment of the lung microbiome with gut bacteria in sepsis and the acute respiratory distress syndrome

Nature Microbiology volume 1, Article number: 16113 (2016) | Download Citation


Sepsis and the acute respiratory distress syndrome (ARDS) are major causes of mortality without targeted therapies. Although many experimental and clinical observations have implicated gut microbiota in the pathogenesis of these diseases, culture-based studies have failed to demonstrate translocation of bacteria to the lungs in critically ill patients. Here, we report culture-independent evidence that the lung microbiome is enriched with gut bacteria both in a murine model of sepsis and in humans with established ARDS. Following experimental sepsis, lung communities were dominated by viable gut-associated bacteria. Ecological analysis identified the lower gastrointestinal tract, rather than the upper respiratory tract, as the likely source community of post-sepsis lung bacteria. In bronchoalveolar lavage fluid from humans with ARDS, gut-specific bacteria (Bacteroides spp.) were common and abundant, undetected by culture and correlated with the intensity of systemic inflammation. Alveolar TNF-α, a key mediator of alveolar inflammation in ARDS, was significantly correlated with altered lung microbiota. Our results demonstrate that the lung microbiome is enriched with gut-associated bacteria in sepsis and ARDS, potentially representing a shared mechanism of pathogenesis in these common and lethal diseases.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit. Care Med. 29, 1303–1310 (2001).

  2. 2.

    et al. Incidence and outcomes of acute lung injury. N. Engl. J. Med. 353, 1685–1693 (2005).

  3. 3.

    , , & Clinical risks for development of the acute respiratory distress syndrome. Am. J. Respir. Crit. Care Med. 151, 293–301 (1995).

  4. 4.

    et al. Clinical characteristics and outcomes of sepsis-related vs non-sepsis-related ARDS. Chest 138, 559–567 (2010).

  5. 5.

    The microbiome and critical illness. Lancet Respir. Med. 4, 59–72 (2016).

  6. 6.

    , , , & The bacterial factor in traumatic shock. Ann. NY Acad. Sci. 55, 429–445 (1952).

  7. 7.

    , , & The lung lesion in four different types of shock in rabbits. Arch. Surg. 104, 319–322 (1972).

  8. 8.

    et al. The essential role of the intestinal microbiota in facilitating acute inflammatory responses. J. Immunol. 173, 4137–4146 (2004).

  9. 9.

    , & Selective decontamination of the digestive tract: the mechanism of action is control of gut overgrowth. Intens. Care Med. 38, 1738–1750 (2012).

  10. 10.

    , & Influence of the critically ill state on host–pathogen interactions within the intestine: gut-derived sepsis redefined. Crit. Care Med. 31, 598–607 (2003).

  11. 11.

    Gut-origin sepsis: evolution of a concept. Surgeon 10, 350–356 (2012).

  12. 12.

    et al. Gut bacterial translocation via the portal vein: a clinical perspective with major torso trauma. J. Trauma 31, 629–636; 636–628 (1991).

  13. 13.

    , , , & Balance of inflammatory cytokines related to severity and mortality of murine sepsis. Infect. Immun. 64, 4733–4738 (1996).

  14. 14.

    et al. Vegan: Community Ecology Package. R package version 2.0-4 (2012);

  15. 15.

    , , & mvabund—an R package for model-based analysis of multivariate abundance data. Methods Ecol. Evol. 3, 471–474 (2012).

  16. 16.

    et al. Exercise prevents weight gain and alters the gut microbiota in a mouse model of high fat diet-induced obesity. PLoS ONE 9, e92193 (2014).

  17. 17.

    et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/− mice. Nature 487, 104–108 (2012).

  18. 18.

    , , & Lubiprostone decreases mouse colonic inner mucus layer thickness and alters intestinal microbiota. Dig. Dis. Sci. 58, 668–677 (2013).

  19. 19.

    et al. Alterations of lung microbiota in a mouse model of LPS-induced lung injury. Am. J. Physiol. Lung Cell Mol. Physiol. 309, L76–L83 (2015).

  20. 20.

    et al. A genomic view of the human–Bacteroides thetaiotaomicron symbiosis. Science 299, 2074–2076 (2003).

  21. 21.

    et al. Comparison of the gut microbiota composition between obese and non-obese individuals in a Japanese population, as analyzed by terminal restriction fragment length polymorphism and next-generation sequencing. BMC Gastroenterol. 15, 100 (2015).

  22. 22.

    et al. Diversity of the human intestinal microbial flora. Science 308, 1635–1638 (2005).

  23. 23.

    et al. Changes in the lung microbiome following lung transplantation include the emergence of two distinct Pseudomonas species with distinct clinical associations. PLoS ONE 9, e97214 (2014).

  24. 24.

    , , & Circulating cytokine/inhibitor profiles reshape the understanding of the SIRS/CARS continuum in sepsis and predict mortality. J. Immunol. 177, 1967–1974 (2006).

  25. 25.

    et al. Tumor necrosis factor and interleukin-1 serum levels during severe sepsis in humans. Crit. Care Med. 17, 975–978 (1989).

  26. 26.

    et al. High bronchoalveolar levels of tumor necrosis factor and its inhibitors, interleukin-1, interferon, and elastase, in patients with adult respiratory distress syndrome after trauma, shock, or sepsis. Am. Rev. Respir. Dis. 145, 1016–1022 (1992).

  27. 27.

    et al. Inflammatory cytokines in the BAL of patients with ARDS. Persistent elevation over time predicts poor outcome. Chest 108, 1303–1314 (1995).

  28. 28.

    et al. Disordered microbial communities in asthmatic airways. PLoS ONE 5, e8578 (2010).

  29. 29.

    et al. Airway microbiota and bronchial hyperresponsiveness in patients with suboptimally controlled asthma. J. Allergy Clin. Immunol. 127, 372–381 (2011).

  30. 30.

    et al. Host response to the lung microbiome in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 192, 438–445 (2015).

  31. 31.

    et al. Neutrophil ageing is regulated by the microbiome. Nature 525, 528–532 (2015).

  32. 32.

    et al. Does the bacteremia observed in hemorrhagic shock have clinical significance? A study in germ-free animals. Ann. Surg. 210, 342–345; 346–347 (1989).

  33. 33.

    et al. Increased intestinal permeability is associated with the development of multiple organ dysfunction syndrome in critically ill ICU patients. Am. J. Respir. Crit. Care Med. 158, 444–451 (1998).

  34. 34.

    , , , & Hemorrhagic shock induces bacterial translocation from the gut. J. Trauma 28, 896–906 (1988).

  35. 35.

    et al. Microbiology of bacterial translocation in humans. Gut 42, 29–35 (1998).

  36. 36.

    et al. Gut microbiota predict pulmonary infiltrates after allogeneic hematopoietic cell transplantation. Am. J. Respir. Crit. Care Med. (2016).

  37. 37.

    et al. Thoracic duct in patients with multiple organ failure: no major route of bacterial translocation. Ann. Surg. 229, 128–136 (1999).

  38. 38.

    et al. Direct analysis of genes encoding 16S rRNA from complex communities reveals many novel molecular species within the human gut. Appl. Environ. Microbiol. 65, 4799–4807 (1999).

  39. 39.

    , , & Lipopolysaccharide causes an increase in intestinal tight junction permeability in vitro and in vivo by inducing enterocyte membrane expression and localization of TLR-4 and CD14. Am. J. Pathol. 182, 375–387 (2013).

  40. 40.

    , , & Factors larger than 100 kD in post-hemorrhagic shock mesenteric lymph are toxic for endothelial cells. Surgery 129, 351–363 (2001).

  41. 41.

    et al. Nosocomial pneumonia in patients with acute respiratory distress syndrome. Am. J. Respir. Crit. Care Med. 157, 1165–1172 (1998).

  42. 42.

    et al. Composition and dynamics of the respiratory tract microbiome in intubated patients. Microbiome 4, 7 (2016).

  43. 43.

    et al. Enterotypes of the human gut microbiome. Nature 473, 174–180 (2011).

  44. 44.

    et al. Comparison of the respiratory microbiome in healthy nonsmokers and smokers. Am. J. Respir. Crit. Care Med. 187, 1067–1075 (2013).

  45. 45.

    et al. Enrichment of the lung microbiome with oral taxa is associated with lung inflammation of a Th17 phenotype. Nature Microbiol. 1, 16031 (2016).

  46. 46.

    & Frequent occurrence of the human-specific Bacteroides fecal marker at an open coast marine beach: relationship to waves, tides and traditional indicators. Environ. Microbiol. 9, 2038–2049 (2007).

  47. 47.

    et al. Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials. Lancet Respir. Med. 2, 611–620 (2014).

  48. 48.

    et al. Membership and behavior of ultra-low-diversity pathogen communities present in the gut of humans during prolonged critical illness. mBio 5, e01361–e01314 (2014).

  49. 49.

    , & The role of the microbiome in exacerbations of chronic lung diseases. Lancet 384, 691–702 (2014).

  50. 50.

    , & Homeostasis and its disruption in the lung microbiome. Am. J. Physiol. Lung Cell Mol. Physiol. 309, L1047–L1055 (2015).

  51. 51.

    et al. IL-10 is a major mediator of sepsis-induced impairment in lung antibacterial host defense. J. Immunol. 162, 392–399 (1999).

  52. 52.

    et al. A randomized trial of recombinant human granulocyte-macrophage colony stimulating factor for patients with acute lung injury. Crit. Care Med. 40, 90–97 (2012).

  53. 53.

    et al. The American–European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am. J. Respir. Crit. Care Med. 149, 818–824 (1994).

  54. 54.

    et al. Cell-associated bacteria in the human lung microbiome. Microbiome 2, 28 (2014).

  55. 55.

    et al. Candida albicans and bacterial microbiota interactions in the cecum during recolonization following broad-spectrum antibiotic therapy. Infect. Immun. 80, 3371–3380 (2012).

  56. 56.

    et al. Global patterns of 16S rRNA diversity at a depth of millions of sequences per sample. Proc. Natl Acad. Sci. USA 108(Suppl 1), 4516–4522 (2011).

  57. 57.

    , , , & Development of a dual-index sequencing strategy and curation pipeline for analyzing amplicon sequence data on the MiSeq Illumina sequencing platform. Appl. Environ. Microbiol. 79, 5112–5120 (2013).

  58. 58.

    454 SOP—mothur (2015);

  59. 59.

    Jumpstart Consortium Human Microbiome Project Data Generation Working Group Human Microbiome Consortium 16S 454 Sequencing Protocol (2010);

  60. 60.

    , & High-throughput sequencing of PCR products tagged with universal primers using 454 life sciences systems. Curr. Protoc. Mol. Biol. Chapter 7, Unit 7.5 (2011).

  61. 61.

    MiSeq SOP—mothur (2015);

  62. 62.

    et al. Introducing mothur: open-source, platform-independent, community-supported software for describing and comparing microbial communities. Appl. Environ. Microbiol. 75, 7537–7541 (2009).

  63. 63.

    R Core Team R: A Language and Environment for Statistical Computing (R Foundation for Statistical Computing, 2013);

  64. 64.

    & Ecologically meaningful transformations for ordination of species data. Oecologia 129, 271–280.

  65. 65.

    et al. Reagent and laboratory contamination can critically impact sequence-based microbiome analyses. BMC Biol. 12, 87 (2014).

Download references


Funding was provided by the National Institutes for Health: UL1TR000433 (to R.P.D.), K23HL130641 (to R.P.D.), T32HL00774921 (to B.H.S.), R01HL123515 (to T.J.S.), UO1HL123031 (to T.J.S.), U01HL098961 (to G.B.H.) and R01HL114447 (to G.B.H.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Support was provided by the Michigan Institute for Clinical & Health Research (to R.P.D.), the Host Microbiome Initiative of the University of Michigan (to R.P.D. and B.H.S.) and the University of Michigan Center for Integrative Research in Critical Care (to R.P.D.). The authors acknowledge the University of Michigan Multidisciplinary Intensive Care Research Workgroup for discussions, and thank A. Bredenkamp for bioinformatic assistance.

Author information

Author notes

    • Theodore J. Standiford
    •  & Gary B. Huffnagle

    These authors contributed equally to this work.


  1. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA

    • Robert P. Dickson
    • , Benjamin H. Singer
    • , Michael W. Newstead
    • , Nicole R. Falkowski
    • , John R. Erb-Downward
    • , Theodore J. Standiford
    •  & Gary B. Huffnagle
  2. Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA

    • Gary B. Huffnagle


  1. Search for Robert P. Dickson in:

  2. Search for Benjamin H. Singer in:

  3. Search for Michael W. Newstead in:

  4. Search for Nicole R. Falkowski in:

  5. Search for John R. Erb-Downward in:

  6. Search for Theodore J. Standiford in:

  7. Search for Gary B. Huffnagle in:


R.P.D. and B.H.S. conceived the experiment. R.P.D., B.H.S., T.J.S. and G.B.H. designed the study. R.P.D., B.H.S., M.W.N. and N.R.F. performed experiments. R.P.D. analysed data. R.P.D., B.H.S., J.R.E.-D., T.J.S. and G.B.H. provided critical analysis and discussions. R.P.D. wrote the first draft and all authors participated in revision.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Robert P. Dickson.

Supplementary information

PDF files

  1. 1.

    Supplementary information

    Supplementary Table 1, Supplementary Figures 1-8.

About this article

Publication history