Het effect van antibiotica en de darmflora op afweerreacties

Rationale: Sepsis ranks among the top ten leading causes of death worldwide. Most nonsurvivors die in a state of immunosuppression. The gut microbiota exerts numerous beneficial functions in the host response against infections. Gut flora components express microorganism-associated molecular patterns (MAMPs) such as lipopolysaccharide (LPS), which are recognized by pattern recognition receptors (PRRs) expressed by neutrophils and macrophages. MAMPs from the intestinal microbiota constitutively translocate to the circulation and prime bone marrow derived neutrophils via PRRs. Antibiotic treatment, which is standard of care for all patients with sepsis, depletes the gut microbiota and leads to a diminished release of MAMPs and other bacteria derived products. This causes diminished priming of systemic immunity, which may attribute to sepsis associated immunosuppression and an increased susceptibility to invading bacteria.



Objective: To investigate the role of the gut microbiota in the systemic priming of immune effector
cells during human endotoxemia



Study design: Randomized, between- and within-subject-controlled intervention study in human
volunteers



Study population: Sixteen healthy male subjects, 18-35 years of age



Intervention: All subjects will receive lipopolysaccharide (endotoxin; 2 ng/kg bodyweight)
intravenously to induce experimental endotoxemia. Eight subjects will be pretreated with broad
spectrum antibiotics (ciprofloxacin, vancomycin, metronidazole) for seven days (washout period of 36 hours before endotoxemia), in order to deplete the gut microbiota. Blood and faeces will be sampled before, during and after endotoxemia.



Main study parameters/endpoints: Laboratory parameters for inflammatory responses, functional
assays and gut microbiota composition.

Broad-spectrum antibiotics, which many patients with infectious diseases receive, deplete the gut microbiota. Several studies suggest that the gut microbiota may have a "priming" effect on the innate immune system. Broad- spectrum antibiotics would thus lead to a decreased innate immune response in disease states such as sepsis or endotoxemia.

Day 0

Day 9: t = 0 and at 0.5, 1, 1.5, 2, 3, 4, 6 and 8 hours after LPS injection

The control group receives no antibiotics
The antibiotics group receives ciprofloxacin 500mg 2dd1, vancomycin 250mg 3dd2 and metronidazole 500mg 3dd1; all during 7 days



Both groups receive (on day 9) LPS (endotoxin) 2 ng/kg intravenously