Antibiotic-induced gut microbiota disruption during human endotoxemia: a randomised controlled study.
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.



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.



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.



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.



ClinicalTrials.gov (NCT02127749; Pre-results).
Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Jacqueline M
JM
Lankelma
Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Duncan R
DR
Cranendonk
Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands.
Clara
C
Belzer
Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Alex F
AF
de Vos
Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands.|RPU Immunobiology, Department of Bacteriology and Immunology, Helsinki University, Helsinski, Finland.
Willem M
WM
de Vos
Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Division of Infectious Diseases, Department of Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Tom
T
van der Poll
Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Division of Infectious Diseases, Department of Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
W Joost
0000-0003-2277-1343
WJ
Wiersinga
D000328:Adult; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002939:Ciprofloxacin / Q000494:pharmacology*; D016903:Drug Monitoring; D019446:Endotoxemia / Q000188:drug therapy* / Q000382:microbiology; D004926:Escherichia coli / Q000187:drug effects / Q000502:physiology; D000069196:Gastrointestinal Microbiome / Q000187:drug effects / Q000276:immunology; D064368:Healthy Volunteers; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects* / Q000276:immunology; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000502:physiology; D008297:Male; D008795:Metronidazole / Q000494:pharmacology*; D018805:Sepsis / Q000188:drug therapy / Q000276:immunology; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000502:physiology; D016896:Treatment Outcome; D014640:Vancomycin / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D008795:Metronidazole; D002939:Ciprofloxacin; D014640:Vancomycin
ANTIBIOTICS; ENDOTOXIN; ENTERIC BACTERIAL MICROFLORA; IMMUNE RESPONSE; SEPSIS