The gut microbiota plays a protective role in the host defence against pneumococcal pneumonia.
OBJECTIVE
Pneumonia accounts for more deaths than any other infectious disease worldwide. The intestinal microbiota supports local mucosal immunity and is increasingly recognised as an important modulator of the systemic immune system. The precise role of the gut microbiota in bacterial pneumonia, however, is unknown. Here, we investigate the function of the gut microbiota in the host defence against Streptococcus pneumoniae infections.


METHODS
We depleted the gut microbiota in C57BL/6 mice and subsequently infected them intranasally with S. pneumoniae. We then performed survival and faecal microbiota transplantation (FMT) experiments and measured parameters of inflammation and alveolar macrophage whole-genome responses.


RESULTS
We found that the gut microbiota protects the host during pneumococcal pneumonia, as reflected by increased bacterial dissemination, inflammation, organ damage and mortality in microbiota-depleted mice compared with controls. FMT in gut microbiota-depleted mice led to a normalisation of pulmonary bacterial counts and tumour necrosis factor-α and interleukin-10 levels 6 h after pneumococcal infection. Whole-genome mapping of alveolar macrophages showed upregulation of metabolic pathways in the absence of a healthy gut microbiota. This upregulation correlated with an altered cellular responsiveness, reflected by a reduced responsiveness to lipopolysaccharide and lipoteichoic acid. Compared with controls, alveolar macrophages derived from gut microbiota-depleted mice showed a diminished capacity to phagocytose S. pneumoniae.


CONCLUSIONS
This study identifies the intestinal microbiota as a protective mediator during pneumococcal pneumonia. The gut microbiota enhances primary alveolar macrophage function. Novel therapeutic strategies could exploit the gut-lung axis in bacterial infections.
Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Department of Medicine, Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Department of Clinical Chemistry, Hematology and Immunology, Diakonessenhuis Utrecht, The Netherlands.
Tim J
TJ
Schuijt
Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Jacqueline M
JM
Lankelma
Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Brendon P
BP
Scicluna
Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Felipe
F
de Sousa e Melo
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Joris J T H
JJ
Roelofs
Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
J Daan
JD
de Boer
Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Arjan J
AJ
Hoogendijk
Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Regina
R
de Beer
Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Alex
A
de Vos
Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands.
Clara
C
Belzer
Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands Department of Bacteriology & Immunology, Helsinki University, Helsinki, Finland.
Willem M
WM
de Vos
Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Department of Medicine, Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Tom
T
van der Poll
Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Department of Medicine, Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
W Joost
http://orcid.org/0000-0003-2277-1343
WJ
Wiersinga
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D058491:Bacterial Load; D005243:Feces / Q000382:microbiology; D000069196:Gastrointestinal Microbiome / Q000276:immunology*; D018928:Immunity, Mucosal; D016753:Interleukin-10 / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011018:Pneumonia, Pneumococcal / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D018805:Sepsis / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000276:immunology; D059467:Transcriptome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
D000900:Anti-Bacterial Agents; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10
BACTERIAL INFECTION; BACTERIAL PATHOGENESIS; IMMUNOLOGY; INTESTINAL MICROBIOLOGY; SEPSIS