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Eradication of Gut Microbiota (ERA)

Primary Purpose

Diabetes, Obesity, Osteoporosis

Status
Completed
Phase
Early Phase 1
Locations
Denmark
Study Type
Interventional
Intervention
meropenem, gentamicin, vancomycin (together)
Sponsored by
University Hospital, Gentofte, Copenhagen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Diabetes

Eligibility Criteria

18 Years - 40 Years (Adult)MaleAccepts Healthy Volunteers

Inclusion Criteria:

  • danish caucasian ethnicity
  • informed consent
  • normal fasting plasma glucose
  • normal HbA1c (<6 %)
  • normal serum lipids
  • normal thyroid function
  • normal danish diet
  • non-smoking
  • normal stool habits

Exclusion Criteria:

  • known bone disease
  • liver disease (ALAT or ASAT >2 upper normal value)
  • kidney disease (serum creatinine >130 μM)
  • anaemia
  • BMI <18.5 kg/m2 or BMI >25 kg/m2
  • known gastrointestinal disease (including prior bariatric surgery,lactose -intolerance, celiac disease, inflammatory bowel disease) or known familial disposition for lactose intolerance, celiac disease, inflammatory bowel disease
  • antibiotic treatment within 6 months prior to study including malaria prophylaxis
  • medication which cannot be on hold for the study period
  • contraindications against/allergy towards the used antibiotics (including prior allergic reactions related to beta-lactam antibiotics, aminoglycosides or vancomycin)

Sites / Locations

  • Gentofte University Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

meropenem, gentamicin, vancomycin

Arm Description

Outcomes

Primary Outcome Measures

changes in postprandial GLP-1 secretion
plasma level of GLP-1 at baseline and during a 4 hour-meal test

Secondary Outcome Measures

changes in postprandial insulin/c-peptide secretion
plasma level of insulin/C-peptide at baseline and during a 4 hour-meal test
changes in postprandial glucose levels
plasma level of glucose at baseline and during a 4 hour-meal test
changes in postprandial GLP-2, glucagon, PYY, oxyntomodulin, gastrin, CCK, GIP, leptin, adiponectin and ghrelin secretion
plasma levels of GLP-2, glucagon, PYY, oxyntomodulin, gastrin, CCK, GIP, leptin, adiponectin and ghrelin at baseline and during a 4 hour-meal test
changes in markers of bone formation and resorption
fasting plasma levels of osteocalcin, P1NP, CTX, 1CTP, sklerostin and serotonin
gut microbiome composition
faecal bacterial composition determined from microbiological cultures and deep metagenomic next-generation sequencing of bacterial DNA in feces
changes in markers of systemic inflammation
plasma levels of high sensitive CRP, LPBP, TNF-alfa, IL-6 and PAI
changes in glycated hemoglobin (HbA1c)
plasma level of glycated hemoblobin
changes in body weight
changes in basal metabolic rate and respiratory quotient
indirect calorimetry measurements (210 minutes postprandial)
changes in gastric emptying
1,5 grams of paracetamol will be added to a standardized meal, plasma paracetamol will be measured at baseline and succeeding 4 hours postprandial
changes in gall bladder emptying
ultrasonic determination of gall bladder dimensions at baseline and during a 4 hour-meal test (expressed as gall bladder ejection fraction)
appetite, satiety and food intake
the impact of eradication on alimentary processes and appetite regulation will be measured using questionnaires and food intake measures
changes in ketone metabolism
measurement of fasting plasma beta-hydroxybutyrate level
changes in bile acid deconjugation
measurement of feces bile acid (conjugated and deconjugated) concentration to study the effect of gut microbiome presence on bile acid deconjugation
changes in plasma lipid levels
fasting plasma levels of triglyceride, VLDL, LDL, HDL, total cholesterol, in addition: measurements of free fatty acids during a 4 hour meal 0, 4 and 42 days after eradication (not on day 8 and 180)
microbiome in blood, urine and saliva
measurements on bacteria or bacterial components in blood, urine and saliva to study the effects of gut eradication on blood, urine and saliva microbiome
adverse effects of the used antibiotics
standardized questionaries regarding gastointestinal function are filled out at each study visit (0, 4, 8, 42 and 180 days after antibiotic eradication of gut bacteria) to detect possible adverse effects of antibiotics. In addition, subjects are given a calendar and informed to write down any symptom or illness during the study period.
changes in metabolomic profile
plasma and urine samples for metabolomic analysis

Full Information

First Posted
June 28, 2012
Last Updated
November 30, 2015
Sponsor
University Hospital, Gentofte, Copenhagen
Collaborators
University of Copenhagen, Steno Diabetes Center Copenhagen, Department of clinical microbiology, Rigshospitalet, Copenhagen
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1. Study Identification

Unique Protocol Identification Number
NCT01633762
Brief Title
Eradication of Gut Microbiota
Acronym
ERA
Official Title
Eradication of Gut Microbiota - Effects on Postprandial Gut Hormone Secretion, Glucose Metabolism, Bone Metabolism and Gut Microbiome
Study Type
Interventional

2. Study Status

Record Verification Date
November 2015
Overall Recruitment Status
Completed
Study Start Date
April 2012 (undefined)
Primary Completion Date
April 2013 (Actual)
Study Completion Date
April 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University Hospital, Gentofte, Copenhagen
Collaborators
University of Copenhagen, Steno Diabetes Center Copenhagen, Department of clinical microbiology, Rigshospitalet, Copenhagen

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The aim of the study is to assess the effect of eradication of gut microbiota on 1) glucose metabolism including postprandial plasma responses of the incretin hormones GIP and GLP-1, insulin, C-peptide and glucagon, 2) metabolomic profiles and resting energy expenditure (REE) 3) appetite, satiety, food intake, gastric emptying and gall bladder emptying, 4) levels of markers of bone formation and resorption as well as serotonin, 5) markers of systemic inflammation, and 6) on the (prospective) composition of bacteria in faeces, blood and saliva. Thus, the overall objective is to provide detailed knowledge on the physiological role of gut microbiota combined with bioinformatic analyses of the functional implications of changes in bacteria composition on the level of both species and phylum.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetes, Obesity, Osteoporosis, Inflammation

7. Study Design

Primary Purpose
Basic Science
Study Phase
Early Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
12 (Actual)

8. Arms, Groups, and Interventions

Arm Title
meropenem, gentamicin, vancomycin
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
meropenem, gentamicin, vancomycin (together)
Intervention Description
4 days antibiotic treatment, per oral, once daily: vancomycin 500 mg (Vancomycin "Hospira"), powder for concentrate; gentamycin 40 mg ("Hexamycin®"), solution; meropenem 500 mg (Meropenem "Hospira"), powder for concentrate; The three drugs are dissolved and combined to a cocktail (with approximately 100 ml of apple juice)
Primary Outcome Measure Information:
Title
changes in postprandial GLP-1 secretion
Description
plasma level of GLP-1 at baseline and during a 4 hour-meal test
Time Frame
0, 4 and 42 days after antibiotic eradication of gut bacteria
Secondary Outcome Measure Information:
Title
changes in postprandial insulin/c-peptide secretion
Description
plasma level of insulin/C-peptide at baseline and during a 4 hour-meal test
Time Frame
0, 4 and 42 days after antibiotic eradication of gut bacteria
Title
changes in postprandial glucose levels
Description
plasma level of glucose at baseline and during a 4 hour-meal test
Time Frame
0, 4 and 42 days after antibiotic eradication of gut bacteria
Title
changes in postprandial GLP-2, glucagon, PYY, oxyntomodulin, gastrin, CCK, GIP, leptin, adiponectin and ghrelin secretion
Description
plasma levels of GLP-2, glucagon, PYY, oxyntomodulin, gastrin, CCK, GIP, leptin, adiponectin and ghrelin at baseline and during a 4 hour-meal test
Time Frame
0, 4 and 42 days after antibiotic eradication of gut bacteria
Title
changes in markers of bone formation and resorption
Description
fasting plasma levels of osteocalcin, P1NP, CTX, 1CTP, sklerostin and serotonin
Time Frame
0, 4, 8, 42 and 180 days after antibiotic eradication of gut bacteria
Title
gut microbiome composition
Description
faecal bacterial composition determined from microbiological cultures and deep metagenomic next-generation sequencing of bacterial DNA in feces
Time Frame
0, 4, 8, 42 and 180 days after antibiotic eradication of gut bacteria
Title
changes in markers of systemic inflammation
Description
plasma levels of high sensitive CRP, LPBP, TNF-alfa, IL-6 and PAI
Time Frame
0, 4, 42 and 180 days after antibiotic eradication of gut bacteria
Title
changes in glycated hemoglobin (HbA1c)
Description
plasma level of glycated hemoblobin
Time Frame
42 days after antibiotic eradication of gut bacteria
Title
changes in body weight
Time Frame
0, 4, 8, 42 and 180 days after antibiotic eradication of gut bacteria
Title
changes in basal metabolic rate and respiratory quotient
Description
indirect calorimetry measurements (210 minutes postprandial)
Time Frame
0, 4 and 42 days after antibiotic eradication of gut bacteria
Title
changes in gastric emptying
Description
1,5 grams of paracetamol will be added to a standardized meal, plasma paracetamol will be measured at baseline and succeeding 4 hours postprandial
Time Frame
0, 4 and 42 days after antibiotic eradication of gut bacteria
Title
changes in gall bladder emptying
Description
ultrasonic determination of gall bladder dimensions at baseline and during a 4 hour-meal test (expressed as gall bladder ejection fraction)
Time Frame
0, 4 and 42 days after antibiotic eradication of gut bacteria
Title
appetite, satiety and food intake
Description
the impact of eradication on alimentary processes and appetite regulation will be measured using questionnaires and food intake measures
Time Frame
0, 4, 8, 42 and 180 days after antibiotic eradication of gut bacteria
Title
changes in ketone metabolism
Description
measurement of fasting plasma beta-hydroxybutyrate level
Time Frame
0, 4, 8, 42 and 180 days after antibiotic eradication of gut bacteria
Title
changes in bile acid deconjugation
Description
measurement of feces bile acid (conjugated and deconjugated) concentration to study the effect of gut microbiome presence on bile acid deconjugation
Time Frame
0, 4, 8, 42 and 180 days after antibiotic eradication of gut bacteria
Title
changes in plasma lipid levels
Description
fasting plasma levels of triglyceride, VLDL, LDL, HDL, total cholesterol, in addition: measurements of free fatty acids during a 4 hour meal 0, 4 and 42 days after eradication (not on day 8 and 180)
Time Frame
0, 4, 8, 42 and 180 days after antibiotic eradication of gut bacteria
Title
microbiome in blood, urine and saliva
Description
measurements on bacteria or bacterial components in blood, urine and saliva to study the effects of gut eradication on blood, urine and saliva microbiome
Time Frame
0, 4, 8, 42 and 180 days after antibiotic eradication of gut bacteria
Title
adverse effects of the used antibiotics
Description
standardized questionaries regarding gastointestinal function are filled out at each study visit (0, 4, 8, 42 and 180 days after antibiotic eradication of gut bacteria) to detect possible adverse effects of antibiotics. In addition, subjects are given a calendar and informed to write down any symptom or illness during the study period.
Time Frame
up to 180 days after antibiotic eradication of gut bacteria
Title
changes in metabolomic profile
Description
plasma and urine samples for metabolomic analysis
Time Frame
0, 4, 8, 42 and 180 days after antibiotic eradication of gut bacteria

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: danish caucasian ethnicity informed consent normal fasting plasma glucose normal HbA1c (<6 %) normal serum lipids normal thyroid function normal danish diet non-smoking normal stool habits Exclusion Criteria: known bone disease liver disease (ALAT or ASAT >2 upper normal value) kidney disease (serum creatinine >130 μM) anaemia BMI <18.5 kg/m2 or BMI >25 kg/m2 known gastrointestinal disease (including prior bariatric surgery,lactose -intolerance, celiac disease, inflammatory bowel disease) or known familial disposition for lactose intolerance, celiac disease, inflammatory bowel disease antibiotic treatment within 6 months prior to study including malaria prophylaxis medication which cannot be on hold for the study period contraindications against/allergy towards the used antibiotics (including prior allergic reactions related to beta-lactam antibiotics, aminoglycosides or vancomycin)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kristian H Mikkelsen, MD
Organizational Affiliation
Diabetes Research Unit, Gentofte Hospital
Official's Role
Study Director
Facility Information:
Facility Name
Gentofte University Hospital
City
Hellerup
ZIP/Postal Code
2900
Country
Denmark

12. IPD Sharing Statement

Citations:
PubMed Identifier
26562532
Citation
Mikkelsen KH, Frost M, Bahl MI, Licht TR, Jensen US, Rosenberg J, Pedersen O, Hansen T, Rehfeld JF, Holst JJ, Vilsboll T, Knop FK. Effect of Antibiotics on Gut Microbiota, Gut Hormones and Glucose Metabolism. PLoS One. 2015 Nov 12;10(11):e0142352. doi: 10.1371/journal.pone.0142352. eCollection 2015.
Results Reference
derived

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Eradication of Gut Microbiota

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