Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Gut microbiota and intestinal FXR mediate the clinical benefits of metformin

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

Subjects

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

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.

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.

References

  1. Zhou, G. et al. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108, 1167–1174 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Rena, G., Hardie, D. G. & Pearson, E. R. The mechanisms of action of metformin. Diabetologia 60, 1577–1585 (2017).

    Article  CAS  PubMed  Google Scholar 

  3. Lien, F. et al. Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk. J. Clin. Invest. 124, 1037–1051 (2014).

    Article  CAS  PubMed  Google Scholar 

  4. Madiraju, A. K. et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510, 542–546 (2014).

    Article  CAS  PubMed  Google Scholar 

  5. Madiraju, A. K. et al. Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo. Nat Med 24, 1384–1394 (2018).

    Article  CAS  Google Scholar 

  6. Bailey, C. J., Wilcock, C. & Scarpello, J. H. Metformin and the intestine. Diabetologia 51, 1552–1553 (2008).

    Article  CAS  Google Scholar 

  7. Geach, T. Gut microbiota: mucin-munching bacteria modulate glucose metabolism. Nat Rev Endocrinol 13, 66 (2017).

    Article  CAS  Google Scholar 

  8. Friedman, S. L., Neuschwander-Tetri, B. A., Rinella, M. & Sanyal, A. J. Mechanisms of NAFLD development and therapeutic strategies. Nat. Med. 24, 908–922 (2018).

    Article  CAS  Google Scholar 

  9. Forslund, K. et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 528, 262–266 (2015).

    Article  CAS  PubMed  Google Scholar 

  10. Wu, H. et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat. Med. 23, 850–858 (2017).

    Article  CAS  Google Scholar 

  11. Lee, H. & Ko, G. Effect of metformin on metabolic improvement and gut microbiota. Appl. Environ. Microbiol. 80, 5935–5943 (2014).

    Article  PubMed  Google Scholar 

  12. Zhang, X. et al. Modulation of gut microbiota by berberine and metformin during the treatment of high-fat diet-induced obesity in rats. Sci. Rep. 5, 14405 (2015).

    Article  CAS  PubMed  Google Scholar 

  13. Shin, N. R. et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 63, 727–735 (2014).

    Article  CAS  Google Scholar 

  14. Bauer, P. V. et al. Metformin alters upper small intestinal microbiota that impact a glucose-SGLT1-sensing glucoregulatory pathway. Cell Metab. 27, 101–117 (2018).

    Article  CAS  Google Scholar 

  15. Schroeder, B. O. & Backhed, F. Signals from the gut microbiota to distant organs in physiology and disease. Nat. Med. 22, 1079–1089 (2016).

    Article  CAS  Google Scholar 

  16. Matsubara, T., Li, F. & Gonzalez, F. J. FXR signaling in the enterohepatic system. Mol. Cell. Endocrinol. 368, 17–29 (2013).

    Article  CAS  Google Scholar 

  17. de Aguiar Vallim, T. Q., Tarling, E. J. & Edwards, P. A. Pleiotropic roles of bile acids in metabolism. Cell Metab. 17, 657–669 (2013).

    Article  CAS  PubMed  Google Scholar 

  18. Degirolamo, C., Rainaldi, S., Bovenga, F., Murzilli, S. & Moschetta, A. Microbiota modification with probiotics induces hepatic bile acid synthesis via downregulation of the Fxr-Fgf15 axis in mice. Cell Rep. 7, 12–18 (2014).

    Article  CAS  Google Scholar 

  19. Wahlstrom, A., Sayin, S. I., Marschall, H. U. & Backhed, F. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab. 24, 41–50 (2016).

    Article  Google Scholar 

  20. Kong, B. et al. Mechanism of tissue-specific farnesoid X receptor in suppressing the expression of genes in bile-acid synthesis in mice. Hepatology 56, 1034–1043 (2012).

    Article  CAS  PubMed  Google Scholar 

  21. Li, F. et al. Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nat. Commun. 4, 2384 (2013).

    Article  Google Scholar 

  22. Sayin, S. I. et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 17, 225–235 (2013).

    Article  CAS  Google Scholar 

  23. Gonzalez, F. J., Jiang, C. & Patterson, A. D. An intestinal microbiota-farnesoid X receptor axis modulates metabolic disease. Gastroenterology 151, 845–859 (2016).

    Article  CAS  PubMed  Google Scholar 

  24. Jiang, C. et al. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J. Clin. Invest. 125, 386–402 (2015).

    Article  Google Scholar 

  25. Jiang, C. et al. Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nat. Commun. 6, 10166 (2015).

    Article  CAS  PubMed  Google Scholar 

  26. Xie, C. et al. An intestinal farnesoid X receptor-ceramide signaling axis modulates hepatic gluconeogenesis in mice. Diabetes 66, 613–626 (2017).

    Article  CAS  Google Scholar 

  27. Akwabi-Ameyaw, A. et al. Conformationally constrained farnesoid X receptor (FXR) agonists: naphthoic acid-based analogs of GW 4064. Bioorg. Med. Chem. Lett. 18, 4339–4343 (2008).

    Article  CAS  Google Scholar 

  28. Singhal, A. et al. Metformin as adjunct antituberculosis therapy. Sci. Transl. Med. 6, 263ra159 (2014).

    Article  Google Scholar 

  29. Cabreiro, F. et al. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell 153, 228–239 (2013).

    Article  CAS  PubMed  Google Scholar 

  30. Stellwag, E. J. & Hylemon, P. B. Purification and characterization of bile salt hydrolase from Bacteroides fragilis subsp. fragilis. Biochim. Biophys. Acta 452, 165–176 (1976).

    Article  CAS  Google Scholar 

  31. Napolitano, A. et al. Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus. PLoS ONE 9, e100778 (2014).

    Article  PubMed  Google Scholar 

  32. Deschasaux, M. et al. Depicting the composition of gut microbiota in a population with varied ethnic origins but shared geography. Nat. Med. 24, 1526–1531 (2018).

    Article  CAS  Google Scholar 

  33. Gu, Y. et al. Analyses of gut microbiota and plasma bile acids enable stratification of patients for antidiabetic treatment. Nat. Commun. 8, 1785 (2017).

    Article  PubMed  Google Scholar 

  34. Olgun, A. “Metformin-resistant” folic acid producing probiotics or folic acid against metformin’s adverse effects like diarrhea. Med. Hypotheses 106, 33–34 (2017).

    Article  CAS  Google Scholar 

  35. Takahashi, S. et al. Cyp2c70 is responsible for the species difference in bile acid metabolism between mice and humans. J. Lipid Res. 57, 2130–2137 (2016).

    Article  CAS  PubMed  Google Scholar 

  36. Tsuchida, T., Shiraishi, M., Ohta, T., Sakai, K. & Ishii, S. Ursodeoxycholic acid improves insulin sensitivity and hepatic steatosis by inducing the excretion of hepatic lipids in high-fat diet-fed KK-Ay mice. Metabolism 61, 944–953 (2012).

    Article  CAS  Google Scholar 

  37. Mueller, M. et al. Ursodeoxycholic acid exerts farnesoid X receptor-antagonistic effects on bile acid and lipid metabolism in morbid obesity. J. Hepatol. 62, 1398–1404 (2015).

    Article  CAS  PubMed  Google Scholar 

  38. Fujita, K., Iguchi, Y., Une, M. & Watanabe, S. Ursodeoxycholic acid suppresses lipogenesis in mouse liver: Possible role of the decrease in beta-muricholic acid, a farnesoid X receptor antagonist. Lipids 52, 335–344 (2017).

    Article  CAS  Google Scholar 

  39. Parseus, A. et al. Microbiota-induced obesity requires farnesoid X receptor. Gut 66, 429–437 (2017).

    Article  CAS  Google Scholar 

  40. Trabelsi, M. S. et al. Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells. Nat. Commun. 6, 7629 (2015).

    Article  PubMed  Google Scholar 

  41. Ziętak, M. et al. Altered microbiota contributes to reduced diet-induced obesity upon cold exposure. Cell Metab. 23, 1216–1223 (2016).

    Article  PubMed  Google Scholar 

  42. Bauer, P. V. et al. Lactobacillus gasseri in the upper small intestine impacts an ACSL3-dependent fatty acid-sensing pathway regulating whole-body glucose homeostasis. Cell Metab. 27, 572–587e576 (2018).

    Article  CAS  Google Scholar 

  43. Zhang, L. et al. Farnesoid X receptor signaling shapes the gut microbiota and controls hepatic lipid metabolism. mSystems 1, e00070–16 (2016).

    Article  PubMed  Google Scholar 

  44. Pathak, P. et al. Farnesoid X receptor induces Takeda G-protein receptor 5 cross-talk to regulate bile acid synthesis and hepatic metabolism. J. Biol. Chem. 292, 11055–11069 (2017).

    Article  CAS  PubMed  Google Scholar 

  45. Pathak, P. et al. Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism. Hepatology 68, 1574–1588 (2018).

    Article  CAS  Google Scholar 

  46. Schaeffer, L., Pimentel, H., Bray, N., Melsted, P. & Pachter, L. Pseudoalignment for metagenomic read assignment. Bioinformatics 33, 2082–2088 (2017).

    Article  CAS  PubMed  Google Scholar 

  47. Nakada, D., Saunders, T. L. & Morrison, S. J. Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature 468, 653–658 (2010).

    Article  CAS  PubMed  Google Scholar 

  48. Vetizou, M. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079–1084 (2015).

    Article  CAS  PubMed  Google Scholar 

  49. Kim, I. et al. Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine. J. Lipid Res. 48, 2664–2672 (2007).

    Article  CAS  Google Scholar 

Download references

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.

Author information

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

Authors
  1. Lulu Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cen Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yue Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qing Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xuemei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jia Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yangyang Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jialin Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bo Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Songyang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Chuyu Yun
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Guan Lian
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Xiujuan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Heng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. William H. Bisson
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Jingmin Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Xiaoxia Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Pupu Ge
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Cuihua Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Kristopher W. Krausz
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Robert G. Nichols
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Jingwei Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Bipin Rimal
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Andrew D. Patterson
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Xian Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Frank J. Gonzalez
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Changtao Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding author

Correspondence to Changtao Jiang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–12 and Supplementary Tables 1 and 2

Reporting Summary

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41591-018-0222-4

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research