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

Abstract

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.

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Figure 1: Altered lung microbiota 24 h after experimental sepsis.
Figure 2: Transient alteration of the lung microbiome after experimental sepsis.
Figure 3: Evidence suggesting gut–lung translocation after experimental sepsis.
Figure 4: Evidence suggesting gut–lung translocation of bacteria in humans with ARDS.

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Acknowledgements

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.

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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.

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Correspondence to Robert P. Dickson.

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Supplementary Table 1, Supplementary Figures 1-8. (PDF 4126 kb)

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Dickson, R., Singer, B., Newstead, M. et al. Enrichment of the lung microbiome with gut bacteria in sepsis and the acute respiratory distress syndrome. Nat Microbiol 1, 16113 (2016). https://doi.org/10.1038/nmicrobiol.2016.113

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