Eradication of Gut Microbiota (ERA)

Eradication of Gut Microbiota - Effects on Postprandial Gut Hormone Secretion, Glucose Metabolism, Bone Metabolism and Gut Microbiome

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.

Study Overview

• Status: Completed
• Conditions: Inflammation; Obesity; Diabetes; Osteoporosis
• Intervention / Treatment: Drug: meropenem, gentamicin, vancomycin (together)

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• Denmark
  • Hellerup, Denmark, 2900
    • Gentofte University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: meropenem, gentamicin, vancomycin	Drug: meropenem, gentamicin, vancomycin (together); 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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
changes in postprandial GLP-1 secretion	plasma level of GLP-1 at baseline and during a 4 hour-meal test	0, 4 and 42 days after antibiotic eradication of gut bacteria

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
changes in postprandial insulin/c-peptide secretion	plasma level of insulin/C-peptide at baseline and during a 4 hour-meal test	0, 4 and 42 days after antibiotic eradication of gut bacteria
changes in postprandial glucose levels	plasma level of glucose at baseline and during a 4 hour-meal test	0, 4 and 42 days after antibiotic eradication of gut bacteria
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	0, 4 and 42 days after antibiotic eradication of gut bacteria
changes in markers of bone formation and resorption	fasting plasma levels of osteocalcin, P1NP, CTX, 1CTP, sklerostin and serotonin	0, 4, 8, 42 and 180 days after antibiotic eradication of gut bacteria
gut microbiome composition	faecal bacterial composition determined from microbiological cultures and deep metagenomic next-generation sequencing of bacterial DNA in feces	0, 4, 8, 42 and 180 days after antibiotic eradication of gut bacteria
changes in markers of systemic inflammation	plasma levels of high sensitive CRP, LPBP, TNF-alfa, IL-6 and PAI	0, 4, 42 and 180 days after antibiotic eradication of gut bacteria
changes in glycated hemoglobin (HbA1c)	plasma level of glycated hemoblobin	42 days after antibiotic eradication of gut bacteria
changes in body weight		0, 4, 8, 42 and 180 days after antibiotic eradication of gut bacteria
changes in basal metabolic rate and respiratory quotient	indirect calorimetry measurements (210 minutes postprandial)	0, 4 and 42 days after antibiotic eradication of gut bacteria
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	0, 4 and 42 days after antibiotic eradication of gut bacteria
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)	0, 4 and 42 days after antibiotic eradication of gut bacteria
appetite, satiety and food intake	the impact of eradication on alimentary processes and appetite regulation will be measured using questionnaires and food intake measures	0, 4, 8, 42 and 180 days after antibiotic eradication of gut bacteria
changes in ketone metabolism	measurement of fasting plasma beta-hydroxybutyrate level	0, 4, 8, 42 and 180 days after antibiotic eradication of gut bacteria
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	0, 4, 8, 42 and 180 days after antibiotic eradication of gut bacteria
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)	0, 4, 8, 42 and 180 days after antibiotic eradication of gut bacteria
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	0, 4, 8, 42 and 180 days after antibiotic eradication of gut bacteria
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.	up to 180 days after antibiotic eradication of gut bacteria
changes in metabolomic profile	plasma and urine samples for metabolomic analysis	0, 4, 8, 42 and 180 days after antibiotic eradication of gut bacteria

Collaborators and Investigators

• Sponsor: University Hospital, Gentofte, Copenhagen
• Collaborators: University of Copenhagen; Steno Diabetes Center Copenhagen; Department of clinical microbiology, Rigshospitalet, Copenhagen
• Investigators: Study Director: Kristian H Mikkelsen, MD, Diabetes Research Unit, Gentofte Hospital

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (ACTUAL): April 1, 2013
• Study Completion (ACTUAL): April 1, 2013

Study Registration Dates

• First Submitted: June 28, 2012
• First Submitted That Met QC Criteria: June 29, 2012
• First Posted (ESTIMATE): July 4, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): December 2, 2015
• Last Update Submitted That Met QC Criteria: November 30, 2015
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Metabolic; Inflammation; Osteoporosis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Protein Synthesis Inhibitors; Vancomycin; Gentamicins; Meropenem
• Other Study ID Numbers: ERA 2012