Jacqueline M Lankelma1, Duncan R Cranendonk1, Clara Belzer2, Alex F de Vos1, Willem M de Vos2,3, Tom van der Poll1,4, W Joost Wiersinga1,4. 1. Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 2. Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands. 3. RPU Immunobiology, Department of Bacteriology and Immunology, Helsinki University, Helsinski, Finland. 4. Division of Infectious Diseases, Department of Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Abstract
OBJECTIVE: The gut microbiota is essential for the development of the intestinal immune system. Animal models have suggested that the gut microbiota also acts as a major modulator of systemic innate immunity during sepsis. Microbiota disruption by broad-spectrum antibiotics could thus have adverse effects on cellular responsiveness towards invading pathogens. As such, the use of antibiotics may attribute to immunosuppression as seen in sepsis. We aimed to test whether disruption of the gut microbiota affects systemic innate immune responses during endotoxemia in healthy subjects. DESIGN: In this proof-of-principle intervention trial, 16 healthy young men received either no treatment or broad-spectrum antibiotics (ciprofloxacin, vancomycin and metronidazole) for 7 days, after which all were administered lipopolysaccharide intravenously to induce a transient sepsis-like syndrome. At various time points, blood and faeces were sampled. RESULTS:Gut microbiota diversity was significantly lowered by the antibiotic treatment in all subjects. Clinical parameters, neutrophil influx, cytokine production, coagulation activation and endothelial activation during endotoxemia were not different between antibiotic-pretreated and control individuals. Antibiotic treatment had no impact on blood leucocyte responsiveness to various Toll-like receptor ligands and clinically relevant causative agents of sepsis (Streptococcus pneumoniae, Klebsiella pneumoniae, Escherichia coli) during endotoxemia. CONCLUSIONS: These findings suggest that gut microbiota disruption by broad-spectrum antibiotics does not affect systemic innate immune responses in healthy subjects during endotoxemia in humans, disproving our hypothesis. Further research is needed to test this hypothesis in critically ill patients. These data underline the importance of translating findings in mice to humans. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT02127749; Pre-results). Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
RCT Entities:
OBJECTIVE: The gut microbiota is essential for the development of the intestinal immune system. Animal models have suggested that the gut microbiota also acts as a major modulator of systemic innate immunity during sepsis. Microbiota disruption by broad-spectrum antibiotics could thus have adverse effects on cellular responsiveness towards invading pathogens. As such, the use of antibiotics may attribute to immunosuppression as seen in sepsis. We aimed to test whether disruption of the gut microbiota affects systemic innate immune responses during endotoxemia in healthy subjects. DESIGN: In this proof-of-principle intervention trial, 16 healthy young men received either no treatment or broad-spectrum antibiotics (ciprofloxacin, vancomycin and metronidazole) for 7 days, after which all were administered lipopolysaccharide intravenously to induce a transient sepsis-like syndrome. At various time points, blood and faeces were sampled. RESULTS: Gut microbiota diversity was significantly lowered by the antibiotic treatment in all subjects. Clinical parameters, neutrophil influx, cytokine production, coagulation activation and endothelial activation during endotoxemia were not different between antibiotic-pretreated and control individuals. Antibiotic treatment had no impact on blood leucocyte responsiveness to various Toll-like receptor ligands and clinically relevant causative agents of sepsis (Streptococcus pneumoniae, Klebsiella pneumoniae, Escherichia coli) during endotoxemia. CONCLUSIONS: These findings suggest that gut microbiota disruption by broad-spectrum antibiotics does not affect systemic innate immune responses in healthy subjects during endotoxemia in humans, disproving our hypothesis. Further research is needed to test this hypothesis in critically illpatients. These data underline the importance of translating findings in mice to humans. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT02127749; Pre-results). Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
Authors: Alexander S Zevin; Tiffany Hensley-McBain; Charlene Miller; Elise Smith; Stanley Langevin; Nichole R Klatt Journal: FEMS Microbiol Lett Date: 2017-12-15 Impact factor: 2.742
Authors: Jacqueline M Lankelma; Lonneke A van Vught; Clara Belzer; Marcus J Schultz; Tom van der Poll; Willem M de Vos; W Joost Wiersinga Journal: Intensive Care Med Date: 2016-11-11 Impact factor: 17.440
Authors: Jocelyn M Choo; Guy C J Abell; Rachel Thomson; Lucy Morgan; Grant Waterer; David L Gordon; Steven L Taylor; Lex E X Leong; Steve L Wesselingh; Lucy D Burr; Geraint B Rogers Journal: mSphere Date: 2018-04-18 Impact factor: 4.389