Antibiotic-Induced Gut Microbiota Disruption Decreases TNF-alpha Release by Mononuclear Cells in Healthy Adults

OBJECTIVES: Broad-spectrum antibiotics disrupt the intestinal microbiota. The microbiota is essential for physiological processes, such as the development of the gut immune system. Recent murine data suggest that the intestinal microbiota also modulates systemic innate immune responses; however, evidence in humans is lacking. METHODS: Twelve healthy young men were given oral broad-spectrum antibiotics (ciprofloxacin 500 mg bid, vancomycin 500 mg tid and metronidazole 500 mg tid) for 7 days. At baseline, 1 day, and 6 weeks after antibiotics, blood and feces were sampled. Whole blood and isolated mononuclear cells were stimulated with selected Toll-like receptor agonists and heat-killed bacteria. Microbiota diversity and composition was determined using bacterial 16S rDNA sequencing. RESULTS: One day after the antibiotic course, microbial diversity was significantly lower compared with baseline. After antibiotic therapy, systemic mononuclear cells produced lower levels of tumor necrosis factor (TNF)-alpha after ex vivo stimulation with lipopolysaccharide (LPS). This diminished capacity to produce TNF-alpha was restored 6 weeks after cessation of antibiotic therapy. In whole blood, a reduced capacity to release interleukin (IL)-1 beta and IL-6 was observed after LPS stimulation. Antibiotic treatment did not impact on differential leukocyte counts, phagocytosis, and cell surface markers of neutrophils and monocytes. CONCLUSIONS: In this proof-of-principle study of healthy subjects, microbiota disruption by broad-spectrum antibiotics is reversibly associated with decreased systemic cellular responsiveness towards LPS. The implications of these findings in a clinical setting remain to be determined