The Effect of Metformin on Composition of Human Gut Bacteria

Study Overview
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Brief Summary
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OBJECTIVE: Investigate structural changes in the human gut microbiota and associated changes in metabolic markers in urine, saliva, blood and fecal samples following metformin treatment. DESIGN: An, 18 week, one-armed cross over intervention trial consisting of a 6-week pre-intervention period, 6-week intervention period and a 6-week post-intervention period. 25 healthy young men will be included in the trial. INTERVENTION: Six-week Metformin treatment to young healthy men.

Detailed Description
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An, 18 weeks, one-armed cross over intervention trial consisting of a 6-weeks pre-intervention period, 6-weeks intervention period and a 6-weeks post-intervention period. 25 healthy young men will be included in the trial. The pre-intervention period is the control period with no treatment. During the intervention period participants will receive 500 mg of metformin once daily the 1st week, then 500 mg twice daily the 2nd week, 1000 mg + 500 mg daily the 3rd week and 1000 mg + 1000 mg daily the remaining three weeks. Post-interventional investigators will examine gut microbiota of the participants 6 weeks after completion of the intervention period. MESUREMENTS: Altered composition of gut microbiota as investigated by 16S rRNA sequencing is the primary outcome of this study. Secondary outcomes are to investigate changes in metabolic and inflammatory markers in blood and fecal samples. Blood, urine, saliva and fecal samples will be stored for future studies.

Official Title
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Effects of Metformin on Human Gut Microbiota

Conditions
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Healthy

Intervention / Treatment
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* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male HbA1c < 5.7 % (39 mmol/mol) Caucasian (self-report of parental ethnicity) Weight stabile with 18.5 kg/m2 < BMI < 27.0 kg/m2 Normal kidney function as evaluated by normal p-creatinine for age Exclusion Criteria: Oral intake of any form of prescribed medication two months prior to recruitment Chronic or acute illness Previous gastro-intestinal operation excluding appendicitis Any other significant medical reason for exclusion as determined by the investigator Unable to give informed consent Need of medical treatment during the study period

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin<br>18 weeks study with intervention during week 6 to 12: the intervention consist of 500 mg of metformin once daily for week 7, then 500 mg twice daily week 8, 1000 mg + 500 mg daily week 9 and 1000 mg + 1000 mg daily for weeks 10-12. | Drug: Metformin<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Structural changes in the human gut microbiota. | Fecal samples are collected in order to characterize the gut microbiota composition. Microbial DNA will be subjected to sequencing, microbial gene analyses, including taxonomic and functional annotation. | Baseline, 4 , 7, 8, 10, 11 , 13, 16, and 18 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in plasma glucose and HbA1c levels | Venous blood will be collected. The samples will be analyzed for plasma glucose and HbA1c, and correlated to changes in gut microbiota composition | Baseline and at week 7,10,13 and 18 | 
| Changes in insulin metabolism | Venous blood will be collected. The samples will be analyzed for serum insulin and C-peptide levels. Changes will be correlated to changes in gut microbiota composition. | Baseline and at week 7,10,13 and 18 | 
| Changes in inflammatory markers in blood samples. | Venous blood will be collected. The samples will be analyzed for markers of inflammation such as high sensitive C-reactive protein. | Baseline and at week 7,10,13 and 18 | 
| Changes in kidney function tests. | Venous blood will be collected. The samples will be analyzed for plasma creatinine and correlated to gut microbiota changes | Baseline and at week 7,10,13 and 18 | 
| Changes in liver function tests. | Venous blood will be collected. The samples will be analyzed for liver function test and correlated to gut microbiota changes | Baseline and at week 7,10,13 and 18 | 
| Serum Cobalamin | Venous blood will be collected. The samples will be analyzed for serum cobalamin and correlated to gut microbiota changes | Baseline and at week 7,10,13 and 18 | 
| Metformin plasma level | Plasma levels of metformin will be measured at visits 3 and 4 in order to test for compliance. Plasma metformin concentrations will be correlated to changes in gut microbiota composition and function | At week 10 and 13. | 
| Blood pressure | Systolic and diastolic blood pressure are measured in the inclined position after a five minute rest using an automated sphygmomanometer. The measurement is repeated three times. Participants are instructed not to talk during the measurements. | Baseline and at week 7,13 and 18 | 
| Heart rate | Heart rate is measured in the inclined position after a five minute rest using an automated sphygmomanometer. The measurement is repeated three times. Participants are instructed not to talk during the measurements. | Baseline and at week 7,13 and 18 | 
| Anthropometrics characteristics | Weight is measured using standardized procedures. | Baseline and at week 7,13 and 18 | 
| Anthropometrics characteristics | Height is measured using standardized procedures. | Baseline and at week 7,13 and 18 | 
| Anthropometrics characteristics | Waist- and hip circumference are measured using standardized procedures. | Baseline and at week 7,13 and 18 | 
| Bio-electrical impedance. | Body composition will be measured through bio-electrical impedance | Baseline and at week 7,13 and 18 | 
| GI symptoms | Changes in gastrointestinal symptoms of participants by validated VAS-questionnaire concerning following parameters: Overall abdominal symptoms, abdominal pain, bloating, flatulence, satisfaction with stool consistence, constipation, diarrhea, tiredness, nausea, metallic taste. | Baseline and at week 7, 10, 13 and 18. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gut microbiota, metformin, Metabolism, Metagenomics, Metabolomics