Antibiotic-related gut dysbiosis induces lung immunodepression and worsens lung infection in mice

Rodrigue Dessein,Rémi Le Guern,Teddy Grandjean,Martin Figeac,Eric Kipnis,Karine Faure,Benoit Guery,Christelle Faveeuw,Delphine Beury,Marvin Bauduin,Philippe Gosset

doi:10.1186/s13054-020-03320-8

Abstract

BackgroundGut dysbiosis due to the adverse effects of antibiotics affects outcomes of lung infection. Previous murine models relied on significant depletion of both gut and lung microbiota, rendering the analysis of immune gut-lung cross-talk difficult.Here, we study the effects of antibiotic-induced gut dysbiosis without lung dysbiosis on lung immunity and the consequences on acute P. aeruginosa lung infection.MethodsC57BL6 mice received 7 days oral vancomycin-colistin, followed by normal regimen or fecal microbial transplant or Fms-related tyrosine kinase 3 ligand (Flt3-Ligand) over 2 days, and then intra-nasal P. aeruginosa strain PAO1. Gut and lung microbiota were studied by next-generation sequencing, and lung infection outcomes were studied at 24 h. Effects of vancomycin-colistin on underlying immunity and bone marrow progenitors were studied in uninfected mice by flow cytometry in the lung, spleen, and bone marrow.ResultsVancomycin-colistin administration induces widespread cellular immunosuppression in both the lung and spleen, decreases circulating hematopoietic cytokine Flt3-Ligand, and depresses dendritic cell bone marrow progenitors leading to worsening of P. aeruginosa lung infection outcomes (bacterial loads, lung injury, and survival). Reversal of these effects by fecal microbial transplant shows that these alterations are related to gut dysbiosis. Recombinant Flt3-Ligand reverses the effects of antibiotics on subsequent lung infection.ConclusionsThese results show that gut dysbiosis strongly impairs monocyte/dendritic progenitors and lung immunity, worsening outcomes of P. aeruginosa lung infection. Treatment with a fecal microbial transplant or immune stimulation by Flt3-Ligand both restore lung cellular responses to and outcomes of P. aeruginosa following antibiotic-induced gut dysbiosis.

Highlights

Gut dysbiosis due to the adverse effects of antibiotics affects outcomes of lung infection
Prior oral non-absorbable antibiotic-induced gut dysbiosis worsens outcomes of P. aeruginosa lung infection First, we assessed if oral non-absorbable antibiotics induced gut dysbiosis
Given the known role of Flt3-Ligand as a major hematopoietic stimulating factor, mainly for monocyte and dendritic cells (DC) progenitors, we studied the effects of antibiotics and fecal microbiota transplant (FMT) on bone marrow monocyte and DC progenitors (Fig. 5b and supplemental figure 5)

Summary

Introduction

Gut dysbiosis due to the adverse effects of antibiotics affects outcomes of lung infection. The microbiome-driven immune cross-talk between the gut and the lung, or “gut-lung axis,” involves both gut and lung microbiota [4] These studies are based on models of antibiotic-induced dysbiosis that rely on very broadspectrum antibiotics using associations of 4 to 5 antibiotics, many with systemic diffusion. Are such models far from mirroring clinical situations, but they result in the form of dysbiosis with significant overall depletion [5], and deplete both the gut and lung microbiota [5, 6]. It is difficult to decipher the respective roles of the lung and gut microbiota on lung immunity and its impact on lung infection

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