@article{953c91f251f74038a1a0aaeebd2d1d0a,
title = "Antibiotic-Induced Changes to the Host Metabolic Environment Inhibit Drug Efficacy and Alter Immune Function",
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. Antibiotic susceptibility is sensitive to metabolites, but how this affects in vivo treatment efficacy remains unexplored. Yang, Bhargava et al. characterize antibiotic-induced changes to the metabolic environment during infection and find that direct actions of antibiotics on host cells induce metabolites that impair drug efficacy and enhance phagocytic activity.",
keywords = "LC-MS/MS, antibiotic, germ-free, immunomodulation, metabolic environment, metabolomics, phagocytosis, respiration, systems biology",
author = "Yang, {Jason H.} and Prerna Bhargava and Douglas McCloskey and Ning Mao and Palsson, {Bernhard O.} and Collins, {James J.}",
note = "Funding Information: This work was supported by grant HDTRA1-15-1-0051 from the Defense Threat Reduction Agency, grants K99GM118907 and U01AI124316 from the NIH, grant NNF16CC0021858 from the Novo Nordisk Foundation, the Paul G. Allen Frontiers Group, and the Wyss Institute for Biologically Inspired Engineering. The authors thank Dr. Lynn Bry and the Gnotobiotic and Microbiology Core Facility of the Massachusetts Host-Microbiome Center at Brigham and Women's Hospital for their assistance in performing experiments on the GF mice. Immortalized SV129 mouse macrophages were generously gifted by Dr. Chih-Hao Lee (Harvard Chan School of Public Health). J.J.C. is scientific co-founder and scientific advisory board chair of Enbiotix, an antibiotics startup company. Funding Information: This work was supported by grant HDTRA1-15-1-0051 from the Defense Threat Reduction Agency , grants K99GM118907 and U01AI124316 from the NIH , grant NNF16CC0021858 from the Novo Nordisk Foundation , the Paul G. Allen Frontiers Group , and the Wyss Institute for Biologically Inspired Engineering . The authors thank Dr. Lynn Bry and the Gnotobiotic and Microbiology Core Facility of the Massachusetts Host-Microbiome Center at Brigham and Women's Hospital for their assistance in performing experiments on the GF mice. Immortalized SV129 mouse macrophages were generously gifted by Dr. Chih-Hao Lee (Harvard Chan School of Public Health). J.J.C. is scientific co-founder and scientific advisory board chair of Enbiotix, an antibiotics startup company. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = dec,
day = "13",
doi = "10.1016/j.chom.2017.10.020",
language = "English (US)",
volume = "22",
pages = "757--765.e3",
journal = "Cell Host and Microbe",
issn = "1931-3128",
publisher = "Cell Press",
number = "6",
}