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Gut microbiota and intestinal FXR mediate the clinical benefits of metformin

Nature Medicine volume 24, pages 1919–1929 (2018)Cite this article

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Abstract

The anti-hyperglycemic effect of metformin is believed to be caused by its direct action on signaling processes in hepatocytes, leading to lower hepatic gluconeogenesis. Recently, metformin was reported to alter the gut microbiota community in humans, suggesting that the hyperglycemia-lowering action of the drug could be the result of modulating the population of gut microbiota. However, the critical microbial signaling metabolites and the host targets associated with the metabolic benefits of metformin remained elusive. Here, we performed metagenomic and metabolomic analysis of samples from individuals with newly diagnosed type 2 diabetes (T2D) naively treated with metformin for 3 d, which revealed that Bacteroides fragilis was decreased and the bile acid glycoursodeoxycholic acid (GUDCA) was increased in the gut. These changes were accompanied by inhibition of intestinal farnesoid X receptor (FXR) signaling. We further found that high-fat-diet (HFD)-fed mice colonized with B. fragilis were predisposed to more severe glucose intolerance, and the metabolic benefits of metformin treatment on glucose intolerance were abrogated. GUDCA was further identified as an intestinal FXR antagonist that improved various metabolic endpoints in mice with established obesity. Thus, we conclude that metformin acts in part through a B. fragilis–GUDCA–intestinal FXR axis to improve metabolic dysfunction, including hyperglycemia.

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Fig. 1: Oral metformin modulates the composition of gut microbiota and bile acids in individuals with T2D.
Fig. 2: GUDCA and TUDCA are identified FXR antagonists.
Fig. 3: Metformin-induced downregulation of B. fragilis abundance was negatively correlated with the modulation of bile acid profiles.
Fig. 4: B. fragilis reverses the metabolic improvements of metformin.
Fig. 5: Intestinal FXR signaling is essential for the metformin-induced long-term improvements in metabolic diseases.
Fig. 6: GUDCA supplementation had therapeutic effects in improving glucose tolerance dependent on intestinal FXR.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request. Sequence data are available for download from the Sequence Read Archive with accession number PRJNA486795.

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Acknowledgements

This work was supported by the National Key Research and Development Program of China (2016YFC0903100 and 2016YFC0903102) to C.J., the National Natural Science Foundation of China (91439206 and 91739303 to X.W., and 81522007, 81470554 and 31401011 to C.J.), the National Program for Support of Top-notch Young Professionals (82008Y0005) to C.J., the Fundamental Research Funds for the Central Universities: Clinical Medicine Plus X—Young Scholars Project of Peking University (PKU2018LCXQ013) to C.J., and the National Cancer Institute Intramural Research Program to F.J.G.

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Author notes

  1. These authors contributed equally to this study: Lulu Sun, Cen Xie, Guang Wang and Yue Wu.

Authors and Affiliations

  1. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China

    Lulu Sun, Qing Wu, Xuemei Wang, Jialin Xia, Bo Chen, Songyang Zhang, Chuyu Yun, Guan Lian, Xiujuan Zhang, Xian Wang & Changtao Jiang

  2. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Cen Xie, Jingmin Shi, Xiaoxia Gao, Kristopher W. Krausz & Frank J. Gonzalez

  3. Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China

    Guang Wang, Jia Liu & Heng Zhang

  4. Department of Cardiology, Key Laboratory of Environment and Genes Related to Diseases, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China

    Yue Wu & Yangyang Deng

  5. Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, USA

    William H. Bisson

  6. CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China

    Pupu Ge & Cuihua Liu

  7. Department of Molecular Toxicology, The Pennsylvania State University, University Park, PA, USA

    Robert G. Nichols, Jingwei Cai, Bipin Rimal & Andrew D. Patterson

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Contributions

L.S., C.X., G.W., Y.W., Q.W., Xuemei Wang, J.L., Y.D., J.X., B.C., S.Z., C.Y., G.L., X.Z., H.Z., W.H.B., J.S., X.G., P.G., C.L., K.W.K., R.G.N., J.C., B.R., A.D.P. and Xian Wang performed the experiments and analyzed the data. C.J. designed and supervised the study. L.S., C.X., F.J.G. and C.J. wrote the manuscript. All the authors edited the manuscript and approved the final manuscript.

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Correspondence to Changtao Jiang.

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Sun, L., Xie, C., Wang, G. et al. Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Nat Med 24, 1919–1929 (2018). https://doi.org/10.1038/s41591-018-0222-4

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