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

Sponsor

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) (Other)

Overall Status

Completed

CT.gov ID

NCT02127749

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

0.9

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Endotoxemia	Drug: Endotoxin Drug: Vancomycin, Metronidazole, Ciprofloxacin	N/A

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

Study Type:

Interventional

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 :

Jun 1, 2014

Actual Primary Completion Date :

Dec 1, 2015

Actual Study Completion Date :

Dec 1, 2015

Arms and Interventions

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 Names: 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 Names: 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

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 Names:

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 Names:

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

Primary Outcome Measures

Cytokine production in blood [within 8 hours after LPS administration]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 35 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Yes

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