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Cell Host Microbe. 2017 Dec 13;22(6):757-765.e3. doi: 10.1016/j.chom.2017.10.020. Epub 2017 Nov 30.

Antibiotic-Induced Changes to the Host Metabolic Environment Inhibit Drug Efficacy and Alter Immune Function.

Author information

1
Institute for Medical Engineering and Science and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
2
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Building 220, Kemitorvet, 2800 Kongens Lyngby, Denmark.
3
Institute for Medical Engineering and Science and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biomedical Engineering, Boston University, Boston, MA 02115, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
4
Institute for Medical Engineering and Science and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA. Electronic address: jimjc@mit.edu.

Abstract

Bactericidal antibiotics alter microbial metabolism as part of their lethality and can damage mitochondria in mammalian cells. In addition, antibiotic susceptibility is sensitive to extracellular metabolites, but it remains unknown whether metabolites present at an infection site can affect either treatment efficacy or immune function. Here, we quantify local metabolic changes in the host microenvironment following antibiotic treatment for a peritoneal Escherichia coli infection. Antibiotic treatment elicits microbiome-independent changes in local metabolites, but not those distal to the infection site, by acting directly on host cells. The metabolites induced during treatment, such as AMP, reduce antibiotic efficacy and enhance phagocytic killing. Moreover, antibiotic treatment impairs immune function by inhibiting respiratory activity in immune cells. Collectively, these results highlight the immunomodulatory potential of antibiotics and reveal the local metabolic microenvironment to be an important determinant of infection resolution.

KEYWORDS:

LC-MS/MS; antibiotic; germ-free; immunomodulation; metabolic environment; metabolomics; phagocytosis; respiration; systems biology

PMID:
29199098
PMCID:
PMC5730482
[Available on 2018-12-13]
DOI:
10.1016/j.chom.2017.10.020
[Indexed for MEDLINE]

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