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Metformin-induced changes of the gut microbiota in patients with type 2 diabetes mellitus: results from a prospective cohort study

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Abstract

Background

The influence of the microbiota on hypoglycemic agents is becoming more apparent. The effects of metformin, a primary anti-diabetes drug, on gut microbiota are still not fully understood.

Research design and methods

This prospective cohort study aims to investigate the longitudinal effects of metformin on the gut microbiota of 25 treatment-naïve diabetes patients, each receiving a daily dose of 1500 mg. Microbiota compositions were analyzed at baseline, and at 1, 3, and 6 months of medication using 16S rRNA gene sequencing.

Results

Prior to the 3-month period of metformin treatment, significant improvements were noted in body mass index (BMI) and glycemic-related parameters, such as fasting blood glucose (FPG) and hemoglobin A1c (HbA1c), alongside homeostasis model assessment indices of insulin resistance (HOMA-IR). At the 3-month mark of medication, a significant reduction in the α-diversity of the gut microbiota was noted, while β-diversity exhibited no marked variances throughout the treatment duration. The Firmicutes to Bacteroidetes ratio. markedly decreased. Metformin treatment consistently increased Escherichia-Shigella and decreased Romboutsia, while Pseudomonas decreased at 3 months. Fuzzy c-means clustering identified three longitudinal trajectory clusters for microbial fluctuations: (i) genera temporarily changing, (ii) genera continuing to decrease (Bacteroides), and (iii) genera continuing to increase(Lachnospiraceae ND3007 group, [Eubacterium] xylanophilum group, Romboutsia, Faecalibacterium and Ruminococcaceae UCG-014). The correlation matrix revealed associations between specific fecal taxa and metformin-related clinical parameters HbA1c, FPG, Uric Acid (UA), high-density lipoproteincholesterol (HDL-C), alanine aminotransferase (ALT), hypersensitive C-reactive protein (hs-CRP), triglyceride (TG) (P < 0.05). Metacyc database showed that metformin significantly altered 17 functional pathways. Amino acid metabolism pathways such as isoleucine biosynthesis predominated in the post-treatment group.

Conclusions

Metformin’s role in glucose metabolism regulation may primarily involve specific alterations in certain gut microbial species rather than an overall increase in microbial species diversity. This may suggest gut microbiota targets in future studies on metabolic abnormalities caused by metformin.

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Data availability

Supplementary data are available online at https://pan.baidu.com/s/1uL5Mm-eRUyp3aLlKIaOdJg?pwd=t4ph.

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Author notes

  1. These authors contributed equally: Weigang Zhao, Baoli Zhu

Authors and Affiliations

  1. Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

    Yuting Gao, Tao Yuan, Yong Fu & Weigang Zhao

  2. Department of Physical Examination Center, China-Japan Friendship Hospital, Beijing, China

    Tianyi Zhao

  3. Institute of Microbiology, Chinese Academy of Sciences, Beijing, China

    Na Lv & Baoli Zhu

  4. Department of Pathology, China-Japan Friendship Hospital, Beijing, China

    Shixuan Liu

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Contributions

Conceptualization, W.Z. T.Y., and B.Z.; methodology, B.Z., W.Z. and Y.G.; software, N.L. and Y.G.; validation, T.Z., and N.L.; formal analysis, S.L., N.L., T.Z. and Y.G.; investigation, S.L., T.Z., Y.F. and Y.G.; resources, S.L., T.Z., N.L. and Y.G.; data curation, S.L., T.Z. and Y.G.; writing—original draft preparation, Y.G.; writing—review and editing, W.Z., T.Y., and Y.G.; visualization, N.L. and Y.G.; supervision, Y.F., T.Y., and W.Z; project administration, W.Z. and B.Z. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Weigang Zhao or Baoli Zhu.

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The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board of PUMCH (JS-2579/202009.22). Informed consent was obtained from all subjects involved in the study.

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Gao, Y., Zhao, T., Lv, N. et al. Metformin-induced changes of the gut microbiota in patients with type 2 diabetes mellitus: results from a prospective cohort study. Endocrine (2024). https://doi.org/10.1007/s12020-024-03828-x

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