The Role of the Microbiota in the Systemic Immune Response

NCT ID: NCT02340182

Last Updated: 2015-01-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-03-31
• Study Completion Date: 2013-09-30

Brief Summary

The objective of this study is to investigate the role of the gut microbiota in the systemic priming of immune effector cells. Twelve healthy male volunteers, 18-35 years of age, will be treated with broad spectrum antibiotics (ciprofloxacin, vancomycin, metronidazole) for seven days, in order to deplete the gut microbiota. Blood and faeces will be sampled before, 24 hours and 6 weeks after the 7-day period of antibiotics. Main study endpoints include laboratory parameters for inflammatory responses, functional assays (ex vivo stimulation assay) and gut microbiota composition.

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

Study design: Within-subject-controlled intervention study in human volunteers

Study population: Twelve healthy male subjects, 18-35 years of age

Intervention: All subjects will be treated with broad spectrum antibiotics (ciprofloxacin, vancomycin, metronidazole) for seven days, in order to deplete the gut microbiota. Blood and faeces will be sampled before, 24 hours and 6 weeks after the 7-day period of antibiotics.

Main study parameters/endpoints: Laboratory parameters for inflammatory responses, functional assays (ex vivo stimulation assay) and gut microbiota composition.

Conditions

Healthy; Sepsis

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Antibiotics

All volunteers will self-administer the following antibiotics for 7 consecutive days (concomitantly):

1. Vancomycin 250mg 3dd2;

2. Ciprofloxacin 500mg 2dd1;

3. Metronidazole 500mg 3dd1.

Group Type: EXPERIMENTAL

Vancomycin

Intervention Type: DRUG

250mg 3dd2

Ciprofloxacin

Intervention Type: DRUG

500mg 2dd1

Metronidazole

Intervention Type: DRUG

500mg 3dd1

Interventions

Vancomycin

250mg 3dd2

Intervention Type: DRUG

Ciprofloxacin

500mg 2dd1

Intervention Type: DRUG

Metronidazole

500mg 3dd1

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Healthy
• Male between 18 and 35 years of age
• Capable of giving written informed consent and able to comply with the requirements and restrictions
• Chemistry panel without any clinically relevant abnormality
• Normal defecation pattern (defined as <3x/ day and >3x/week)

Exclusion Criteria

• Major illness in the past 3 months or significant chronic medical illness;
• History of any type of malignancy;
• Past or current gastrointestinal disease which may influence the gut microbiota;
• Known positive test for hepatitis C antibody, hepatitis B surface antigen or HIV;
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities;
• Use of tobacco products;
• History, within 3 years, of drug abuse;
• History of alcoholism and/or drinking more than 3 units of alcohol per day;
• The subject has received an investigational product within three months of day 1;
• Use of prescription or non-prescription drugs and herbal and dietary supplements within 6 months;
• Recent (< 12 months) use of antibiotics (any kind, except for dermal antibiotics);
• Allergy to antibiotics (any kind);
• Difficulty swallowing pills;
• Any other relevant issue.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 35 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: Yes

Sponsors

ZonMw: The Netherlands Organisation for Health Research and Development

OTHER

Sponsor Role: collaborator

W.J. Wiersinga, MD, PhD

OTHER

Sponsor Role: lead

Responsible Party

W.J. Wiersinga, MD, PhD

MD, PhD

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Tom Van der Poll, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

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

Locations

Academisch Medisch Centrum

Amsterdam, North Holland, Netherlands

Countries

Netherlands

Other Identifiers

2012_283

Identifier Type: OTHER

Identifier Source: secondary_id

NL42072.018.12

Identifier Type: -

Identifier Source: org_study_id