The Role of the Gut Microbiota in the Systemic Immune Response During Human Endotoxemia

Overview

The purpose of this study is to determine whether treatment with antibiotics, which harm the gut flora, causes the immune system to be less effective.

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 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.

Conditions

Interventions

Eligibility

Locations (1)

Outcomes