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.
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.
Cell Host Microbe. 2017 Dec 13;22(6):757-765.e3. doi: 10.1016/j.chom.2017.10.020. Epub 2017 Nov 30.
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.
杀菌抗生素通过改变微生物代谢来发挥其致死作用，同时还可能损伤哺乳动物细胞中的线粒体。此外，抗生素敏感性对外界代谢物很敏感，但目前尚不清楚感染部位的代谢物是否会影响治疗效果或免疫功能。本研究中，我们定量分析了腹腔大肠杆菌感染后抗生素治疗对宿主微环境局部代谢的影响。抗生素治疗通过直接作用于宿主细胞，在微生物组独立的情况下引起局部代谢物的变化，但不会引起感染部位以外的代谢物变化。在治疗过程中诱导的代谢物，如 AMP，会降低抗生素的疗效，并增强吞噬作用。此外，抗生素治疗通过抑制免疫细胞的呼吸活动来损害免疫功能。总的来说，这些结果强调了抗生素的免疫调节潜力，并揭示了局部代谢微环境是感染缓解的一个重要决定因素。
