Diabetes, Inflammation, Obesity, Osteoporosis
Conditions
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.
Interventions
DRUGmeropenem, 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)
Sponsors
University of Copenhagen
Steno Diabetes Center Copenhagen
Department of clinical microbiology, Rigshospitalet, Copenhagen
University Hospital, Gentofte, Copenhagen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 40 Years
Healthy volunteers
Yes
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| changes in postprandial GLP-1 secretion | 0, 4 and 42 days after antibiotic eradication of gut bacteria | plasma level of GLP-1 at baseline and during a 4 hour-meal test |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| changes in ketone metabolism | 0, 4, 8, 42 and 180 days after antibiotic eradication of gut bacteria | measurement of fasting plasma beta-hydroxybutyrate level |
| changes in postprandial insulin/c-peptide secretion | 0, 4 and 42 days after antibiotic eradication of gut bacteria | plasma level of insulin/C-peptide at baseline and during a 4 hour-meal test |
| changes in postprandial glucose levels | 0, 4 and 42 days after antibiotic eradication of gut bacteria | 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 | 0, 4 and 42 days after antibiotic eradication of gut bacteria | 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 | 0, 4, 8, 42 and 180 days after antibiotic eradication of gut bacteria | fasting plasma levels of osteocalcin, P1NP, CTX, 1CTP, sklerostin and serotonin |
| gut microbiome composition | 0, 4, 8, 42 and 180 days after antibiotic eradication of gut bacteria | faecal bacterial composition determined from microbiological cultures and deep metagenomic next-generation sequencing of bacterial DNA in feces |
| changes in markers of systemic inflammation | 0, 4, 42 and 180 days after antibiotic eradication of gut bacteria | plasma levels of high sensitive CRP, LPBP, TNF-alfa, IL-6 and PAI |
| changes in glycated hemoglobin (HbA1c) | 42 days after antibiotic eradication of gut bacteria | plasma level of glycated hemoblobin |
| appetite, satiety and food intake | 0, 4, 8, 42 and 180 days after antibiotic eradication of gut bacteria | the impact of eradication on alimentary processes and appetite regulation will be measured using questionnaires and food intake measures |
| changes in basal metabolic rate and respiratory quotient | 0, 4 and 42 days after antibiotic eradication of gut bacteria | indirect calorimetry measurements (210 minutes postprandial) |
| changes in gastric emptying | 0, 4 and 42 days after antibiotic eradication of gut bacteria | 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 | 0, 4 and 42 days after antibiotic eradication of gut bacteria | ultrasonic determination of gall bladder dimensions at baseline and during a 4 hour-meal test (expressed as gall bladder ejection fraction) |
| changes in bile acid deconjugation | 0, 4, 8, 42 and 180 days after antibiotic eradication of gut bacteria | 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 | 0, 4, 8, 42 and 180 days after antibiotic eradication of gut bacteria | 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 | 0, 4, 8, 42 and 180 days after antibiotic eradication of gut bacteria | 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 | up to 180 days after antibiotic eradication of gut bacteria | 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 | 0, 4, 8, 42 and 180 days after antibiotic eradication of gut bacteria | plasma and urine samples for metabolomic analysis |
| changes in body weight | 0, 4, 8, 42 and 180 days after antibiotic eradication of gut bacteria | — |
Countries
Denmark
Outcome results
None listed