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

Abstract

Background Gut 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.Methods C57BL6 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 intranasal P. aeruginosa strain PAO1. Gut and lung microbiota were studied by next-generation sequencing, and lung infection outcomes were studied at 24h. 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.Results Vancomycin-colistin administration induces widespread cellular immunosuppression in both 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. Conclusions These 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.

Clinical analysis of hospital acquired mycoplasma pneumoniae infection after cardiac surgery: a case series

“…Several factors may have contributed to the impaired immune function of patients in this study. Firstly, most had undergone long-term antibiotic use and combined drug use, and long-term antibiotic use has been shown to impair human immune function (21), Secondly, studies have shown vancomycin use can arouse immunosuppression (22). Glycopeptide antibiotics were used by 13 of the 22 patients in this study prior to fever, with a median cumulative dose of 17 g of vancomycin, while 10 of the 22 had lymphopenia at the time of fever, eight of whom had used vancomycin.…”

Gut colonisation with multidrug-resistant Klebsiella pneumoniae worsens Pseudomonas aeruginosa lung infection

“…Several studies indicate a link between the gut microbiota and the host response to lung infection [4][5][6] . Specifically, the AM response to lung infection by S. pneumoniae was impaired in mice previously treated by broad-spectrum antibiotics for three weeks (targeting both the gut and lung microbiota) 5 .…”

Long-distance relationships - regulation of systemic host defense against infections by the gut microbiota

“…Many of the microbiota-immune connections noted above were discovered, in part, through the demonstration that these mechanisms of systemic host defense fail when the microbiota is disrupted by antibiotics or absent in GF mice [16][17][18][19][20][21][22][23][24] . Intestinal dysbiosis in both animals and humans has been linked to increased susceptibility to bacterial, viral, and fungal pathogens 20,21,[114][115][116][117] . However, failure of microbiota-dependent host defense mechanisms is not the only consequence of intestinal dysbiosis during infection, as it is now appreciated that dysbiosis can also actively induce pathological systemic inflammation and immune-mediated organ damage in response to infection (ie.…”