The Role of the Gut Microbiota in the Systemic Immune Response During Human Endotoxemia (MISSION-2)
Primary Purpose
Endotoxemia
Status
Completed
Phase
Not Applicable
Locations
Netherlands
Study Type
Interventional
Intervention
Endotoxin
Vancomycin, Metronidazole, Ciprofloxacin
Sponsored by
About this trial
This is an interventional basic science trial for Endotoxemia focused on measuring antibiotics, gut microbiota, endotoxemia, innate immunity
Eligibility Criteria
Inclusion Criteria:
- Healthy
- Male between 18 and 35 years of age
- Capable of giving written informed consent
- Chemistry panel without any clinically relevant abnormality
- Normal defecation pattern
Exclusion Criteria:
- Major illness in the past 3 months or any chronic medical illness
- History of any type of malignancy
- Past or current gastrointestinal disease
- Known positive test for hepatitis C antibody, hepatitis B surface antigen or HIV antibody 1 or 2
- Current or chronic history of liver disease
- Subject uses tobacco products
- History, within 3 years, of drug abuse
- History of alcoholism
- Any clinically relevant abnormality on the 12-lead ECG
- The subject has received an investigational product within three months
- Use of prescription or non-prescription drugs
- Use of antibiotics within 12 months
- Known allergy to antibiotics
- Subject has difficultly in donating blood or accessibility of a vein in left or right arm.
- Subject has donated more than 350 mL of blood in last 3 months
- Difficulty swallowing pills
- Body mass index more than 28
Sites / Locations
- Academic Medical Centre
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Control
Antibiotics
Arm Description
Subjects are not pretreated with antibiotics Subjects receive 2 ng/kg endotoxin intravenously
Subjects are pretreated with broad-spectrum antibiotics: Vancomycin, Metronidazole, Ciprofloxacin Subjects receive 2 ng/kg endotoxin intravenously
Outcomes
Primary Outcome Measures
Cytokine production in blood
Secondary Outcome Measures
Full Information
NCT ID
NCT02127749
First Posted
April 28, 2014
Last Updated
December 29, 2015
Sponsor
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
1. Study Identification
Unique Protocol Identification Number
NCT02127749
Brief Title
The Role of the Gut Microbiota in the Systemic Immune Response During Human Endotoxemia
Acronym
MISSION-2
Official Title
The Role of the Gut Microbiota in the Systemic Immune Response During Human Endotoxemia
Study Type
Interventional
2. Study Status
Record Verification Date
December 2015
Overall Recruitment Status
Completed
Study Start Date
June 2014 (undefined)
Primary Completion Date
December 2015 (Actual)
Study Completion Date
December 2015 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
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.
Detailed Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Endotoxemia
Keywords
antibiotics, gut microbiota, endotoxemia, innate immunity
7. Study Design
Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
16 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Control
Arm Type
Experimental
Arm Description
Subjects are not pretreated with antibiotics Subjects receive 2 ng/kg endotoxin intravenously
Arm Title
Antibiotics
Arm Type
Experimental
Arm Description
Subjects are pretreated with broad-spectrum antibiotics: Vancomycin, Metronidazole, Ciprofloxacin Subjects receive 2 ng/kg endotoxin intravenously
Intervention Type
Drug
Intervention Name(s)
Endotoxin
Other Intervention Name(s)
LPS
Intervention Description
Both groups will receive 2 ng/kg LPS (endotoxin) intravenously
Intervention Type
Drug
Intervention Name(s)
Vancomycin, Metronidazole, Ciprofloxacin
Intervention Description
ciprofloxacin 500mg 2 times per day, vancomycin 500mg 3 times per day metronidazole 500mg 3 times per day All together during 7 days
Primary Outcome Measure Information:
Title
Cytokine production in blood
Time Frame
within 8 hours after LPS administration
10. Eligibility
Sex
Male
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
35 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
Healthy
Male between 18 and 35 years of age
Capable of giving written informed consent
Chemistry panel without any clinically relevant abnormality
Normal defecation pattern
Exclusion Criteria:
Major illness in the past 3 months or any chronic medical illness
History of any type of malignancy
Past or current gastrointestinal disease
Known positive test for hepatitis C antibody, hepatitis B surface antigen or HIV antibody 1 or 2
Current or chronic history of liver disease
Subject uses tobacco products
History, within 3 years, of drug abuse
History of alcoholism
Any clinically relevant abnormality on the 12-lead ECG
The subject has received an investigational product within three months
Use of prescription or non-prescription drugs
Use of antibiotics within 12 months
Known allergy to antibiotics
Subject has difficultly in donating blood or accessibility of a vein in left or right arm.
Subject has donated more than 350 mL of blood in last 3 months
Difficulty swallowing pills
Body mass index more than 28
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
W. J. Wiersinga, MD, PhD
Organizational Affiliation
Academic Medical Centre, Amsterdam
Official's Role
Principal Investigator
Facility Information:
Facility Name
Academic Medical Centre
City
Amsterdam
ZIP/Postal Code
1105 AZ
Country
Netherlands
12. IPD Sharing Statement
Citations:
PubMed Identifier
30418539
Citation
Haak BW, Lankelma JM, Hugenholtz F, Belzer C, de Vos WM, Wiersinga WJ. Long-term impact of oral vancomycin, ciprofloxacin and metronidazole on the gut microbiota in healthy humans. J Antimicrob Chemother. 2019 Mar 1;74(3):782-786. doi: 10.1093/jac/dky471.
Results Reference
derived
PubMed Identifier
27307305
Citation
Lankelma JM, Cranendonk DR, Belzer C, de Vos AF, de Vos WM, van der Poll T, Wiersinga WJ. Antibiotic-induced gut microbiota disruption during human endotoxemia: a randomised controlled study. Gut. 2017 Sep;66(9):1623-1630. doi: 10.1136/gutjnl-2016-312132. Epub 2016 Jun 15.
Results Reference
derived
Learn more about this trial
The Role of the Gut Microbiota in the Systemic Immune Response During Human Endotoxemia
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