The Role of the Microbiota in the Systemic Immune Response

Healthy Clinical Trial

— MISSION-1  

Official title:

The Role of the Microbiota in the Systemic Immune Response

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02340182
• Other study ID #: NL42072.018.12
• Secondary ID: 2012_283
• Status: Completed
• Phase: N/A
• First received: July 8, 2013
• Last updated: January 15, 2015
• Start date: March 2013
• Est. completion date: September 2013

Study information

• Verified date: January 2015
• Source: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)Netherlands: ZonMw, Netherlands Organisation for Health Research and Development
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: September 2013
• Est. primary completion date: September 2013
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 35 Years

Eligibility

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.

Study Design

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Healthy
• Sepsis

Intervention

Drug:
• Vancomycin
250mg 3dd2
• Ciprofloxacin
500mg 2dd1
• Metronidazole
500mg 3dd1

Locations

Country	Name	City	State
Netherlands	Academisch Medisch Centrum	Amsterdam	Noord-Holland

Sponsors (2)

Lead Sponsor	Collaborator
W.J. Wiersinga, MD, PhD	ZonMw: The Netherlands Organisation for Health Research and Development

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Side effects will be registered using a graded scale		up to week 7	No
Other	A HITchip (human intestinal tract chip; 16S rRNA) analysis will be used to determine microbiome composition		up to week 7	No
Primary	Composite measure of Laboratory parameters for inflammatory responses.	Ex vivo response of whole blood, isolated monocytes or neutrophils to lipopolysaccharide.	up to 7 weeks	No