To investigate the role of the gut microbiota in the systemic priming of immune effector cells during human endotoxemia
ID
Source
Brief title
Condition
- Hepatobiliary neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Laboratory parameters for inflammatory responses, functional assays (ex vivo
stimulation assay) and gut microbiota composition.
Secondary outcome
Not applicable
Background summary
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.
Study objective
To investigate the role of the gut microbiota in the systemic priming of immune
effector cells during human endotoxemia
Study design
Within-subject-controlled intervention study in human volunteers
Intervention
All subjects will receive lipopolysaccharide intravenously (endotoxin; 2 ng/kg
body weight) 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.
Study burden and risks
The burden of this study includes a screening visit, a second visit and one day
hospital admittance. Endotoxemia will induce complaints consisting mainly of
myalgia, headache, fever and nausea that attenuate within 6 hours. Furthermore
blood will be drawn and faeces has to be collected by subjects. Half of the
volunteers will ingest antibiotics, which have potential side effects: mostly
gastrointestinal symptoms and (rarely) allergic reactions. Future patients with
sepsis may benefit from the outcome of this study, as its ultimate aim is to
develop new therapeutic strategies to restore immunity, such as administration
of selective components of the microbiota.
Meibergdreef 9
Amsterdam 1105 AZ
NL
Meibergdreef 9
Amsterdam 1105 AZ
NL
Listed location countries
Age
Inclusion criteria
1. Healthy (medical history, no use of medication; normal physical examination, ECG and laboratory tests)
2. Male between 18 and 35 years of age
3. Normal defecation pattern
Exclusion criteria
1. Recent major illness or chronic medical illness
2. History of malignancy
3. Gastrointestinal and liver diseases
4. Known positive test for hepatitis B or C or HIV
5. Smoking; drug abuse; alcohol abuse
6. Clinically relevant ECG abnormality
7. Subject has received an investigational product within three months of day 1 of the current study
8. Use of prescription or non-prescription drugs
9. Recent (< 12 months) use of antibiotics
10. Allergy to antibiotics
11. Difficultly in donating blood or limitied accessibility of a vein in left or right arm.
12. Subject has donated more than 350 mL of blood in last 3 months
13. Difficulty swallowing pills
14. Body mass index >28 kg/m2
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| CCMO | NL45198.018.13 |
| OMON | NL-OMON27487 |