Metformin-Induced Changes of the Gut Microbiota in Healthy Young Men: Results of a Non-Blinded, One-Armed Intervention Study
Open accessAbstract
AIMS/HYPOTHESIS: Individuals with type 2 diabetes have an altered bacterial composition of their gut microbiota compared with non-diabetic individuals. However, these alterations may be confounded by medication, notably the blood-glucose-lowering biguanide, metformin. We undertook a clinical trial in healthy and previously drug-free men with the primary aim of investigating metformin-induced compositional changes in the non-diabetic state. A secondary aim was to examine whether the pre-treatment gut microbiota was related to gastrointestinal adverse effects during metformin treatment. METHODS: < 39 mmol/mol (5.7%) and plasma creatinine within the normal range. No prescribed medication, including antibiotics, for 2 months prior to recruitment were allowed and no previous gastrointestinal surgery, discounting appendectomy or chronic illness requiring medical treatment. During the intervention the participants were given metformin up to 1 g twice daily. Participants were examined five times in the fasting state with blood sampling and recording of gastrointestinal symptoms. Examinations took place at Frederiksberg Hospital, Denmark before and after the pre-intervention period, halfway through and immediately after the end of intervention and after the wash-out period. Faecal samples were collected at nine evenly distributed time points, and bacterial DNA was extracted and subjected to 16S rRNA gene amplicon sequencing in order to evaluate gut microbiota composition. Subjective gastrointestinal symptoms were reported at each visit. RESULTS: Data from participants who completed visit 1 (n=23) are included in analyses. For the primary outcome the relative abundance of 11 bacterial genera significantly changed during the intervention but returned to baseline levels after treatment cessation. In line with previous reports, we observed a reduced abundance of Intestinibacter spp. and Clostridium spp., as well as an increased abundance of Escherichia/Shigella spp. and Bilophila wadsworthia. The relative abundance at baseline of 12 bacterial genera predicted self-reported gastrointestinal adverse effects. CONCLUSIONS/INTERPRETATION: Intake of metformin changes the gut microbiota composition in normoglycaemic young men. The microbiota changes induced by metformin extend and validate previous reports in individuals with type 2 diabetes. Secondary analyses suggest that pre-treatment gut microbiota composition may be a determinant for development of gastrointestinal adverse effects following metformin intake. These results require further investigation and replication in larger prospective studies. TRIAL REGISTRATION: Clinicaltrialsregister.eu 2015-000199-86 and ClinicalTrials.gov NCT02546050 FUNDING: This project was funded by Danish Diabetes Association and The Novo Nordisk Foundation.
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Metformin use in humans will change the microbiome.
“As for C. elegans, metformin use in humans will change the microbiome.”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [89]
Microbiome change is an important determinant for the anti-hyperglycemic therapeutic effects, the gastrointestinal side effects and possibly the anti-aging effects of metformin.
“This action is an important determinant for the anti-hyperglycemic therapeutic effects, the gastrointestinal side effects and possibly the anti-aging effects of metformin (88, 89).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [89]
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- Authors
- Bryrup, T., Thomsen, C. W., Kern, T., Allin, K. H., Brandslund, I., Jørgensen, N. R., Vestergaard, H., Hansen, T., Hansen, T. H., Pedersen, O., & Nielsen, T.
- Affiliations
- University of Copenhagen (DK)
- University of Southern Denmark (DK)
- Corresponding author
- Pedersen, Oluf
- Nielsen, Trine
- ORCID
- Venue
- Diabetologia
- Published
- 2019-03-23
- Volume
- 62
- Issue
- 6
- Pages
- 1024-1035
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- PMC
- PMC6509092
- OpenAlex
- W2940245003
- Cited by
- 200
- References
- 39
- Citations by year
- 2026: 10 · 2025: 21 · 2024: 41 · 2023: 26 · 2022: 33 · 2021: 33 · 2020: 33 · 2019: 3
- FWCI
- 8.43
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetologia (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion, cc-by)
- Funders
- Novo Nordisk Foundation
- Hagedorn Prize
- Danish Diabetes Association
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
- Keywords
- metformin, gut microbiota, biguanides, gastrointestinal adverse effects, type 2 diabetes, healthy young men, 16S rRNA gene amplicon sequencing, Intestinibacter, Clostridium, Escherichia-Shigella, Bilophila wadsworthia, fecal microbiota
- MeSH terms
- Gastrointestinal Microbiome, Adolescent, Adult, Blood Glucose, Denmark, Diabetes Mellitus, Type 2, Feces, Humans, Hypoglycemic Agents, Male, Metformin, Prospective Studies, RNA, Ribosomal, 16S, Cross-Over Studies, Young Adult
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