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The Role of the Gut Microbiota in the Systemic Immune Response During Human Endotoxemia (MISSION-2)

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ClinicalTrials.gov Identifier: NCT02127749
Recruitment Status : Completed
First Posted : May 1, 2014
Last Update Posted : December 30, 2015
Sponsor:
Information provided by (Responsible Party):
W.J. Wiersinga, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Study Description
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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.

Condition or disease Intervention/treatment Phase
Endotoxemia Drug: Endotoxin Drug: Vancomycin, Metronidazole, Ciprofloxacin Not Applicable

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 16 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: The Role of the Gut Microbiota in the Systemic Immune Response During Human Endotoxemia
Study Start Date : June 2014
Actual Primary Completion Date : December 2015
Actual Study Completion Date : December 2015

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Control
Subjects are not pretreated with antibiotics Subjects receive 2 ng/kg endotoxin intravenously
 Drug: Endotoxin
Both groups will receive 2 ng/kg LPS (endotoxin) intravenously
Other Name: LPS
Experimental: Antibiotics
Subjects are pretreated with broad-spectrum antibiotics: Vancomycin, Metronidazole, Ciprofloxacin Subjects receive 2 ng/kg endotoxin intravenously
 Drug: Endotoxin
Both groups will receive 2 ng/kg LPS (endotoxin) intravenously
Other Name: LPS

Drug: Vancomycin, Metronidazole, Ciprofloxacin
ciprofloxacin 500mg 2 times per day, vancomycin 500mg 3 times per day metronidazole 500mg 3 times per day All together during 7 days


Outcome Measures
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Primary Outcome Measures :
  1. Cytokine production in blood [ Time Frame: within 8 hours after LPS administration ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years to 35 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02127749


Locations
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Netherlands
Academic Medical Centre
Amsterdam, Netherlands, 1105 AZ
Sponsors and Collaborators
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Investigators
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Principal Investigator: W. J. Wiersinga, MD, PhD Academic Medical Centre, Amsterdam
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: W.J. Wiersinga, MD, PhD, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ClinicalTrials.gov Identifier: NCT02127749    
Other Study ID Numbers: NL45198.018.13
NL45198.018.13 ( Other Identifier: CCMO (Centrale Commissie voor Mensgebonden Onderzoek) )
First Posted: May 1, 2014    Key Record Dates
Last Update Posted: December 30, 2015
Last Verified: December 2015
Keywords provided by W.J. Wiersinga, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):
antibiotics
gut microbiota
endotoxemia
innate immunity
Additional relevant MeSH terms:
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Endotoxemia
Bacteremia
Sepsis
Infections
Toxemia
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Metronidazole
Vancomycin
Ciprofloxacin
 Anti-Infective Agents
Anti-Bacterial Agents
Antiprotozoal Agents
Antiparasitic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Cytochrome P-450 CYP1A2 Inhibitors
Cytochrome P-450 Enzyme Inhibitors