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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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.
Zhou, G. et al. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108, 1167–1174 (2001).
Rena, G., Hardie, D. G. & Pearson, E. R. The mechanisms of action of metformin. Diabetologia 60, 1577–1585 (2017).
Lien, F. et al. Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk. J. Clin. Invest. 124, 1037–1051 (2014).
Madiraju, A. K. et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510, 542–546 (2014).
Madiraju, A. K. et al. Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo. Nat Med 24, 1384–1394 (2018).
Bailey, C. J., Wilcock, C. & Scarpello, J. H. Metformin and the intestine. Diabetologia 51, 1552–1553 (2008).
Geach, T. Gut microbiota: mucin-munching bacteria modulate glucose metabolism. Nat Rev Endocrinol 13, 66 (2017).
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).
Forslund, K. et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 528, 262–266 (2015).
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).
Lee, H. & Ko, G. Effect of metformin on metabolic improvement and gut microbiota. Appl. Environ. Microbiol. 80, 5935–5943 (2014).
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).
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).
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).
Schroeder, B. O. & Backhed, F. Signals from the gut microbiota to distant organs in physiology and disease. Nat. Med. 22, 1079–1089 (2016).
Matsubara, T., Li, F. & Gonzalez, F. J. FXR signaling in the enterohepatic system. Mol. Cell. Endocrinol. 368, 17–29 (2013).
de Aguiar Vallim, T. Q., Tarling, E. J. & Edwards, P. A. Pleiotropic roles of bile acids in metabolism. Cell Metab. 17, 657–669 (2013).
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).
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).
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).
Li, F. et al. Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nat. Commun. 4, 2384 (2013).
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).
Gonzalez, F. J., Jiang, C. & Patterson, A. D. An intestinal microbiota-farnesoid X receptor axis modulates metabolic disease. Gastroenterology 151, 845–859 (2016).
Jiang, C. et al. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J. Clin. Invest. 125, 386–402 (2015).
Jiang, C. et al. Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nat. Commun. 6, 10166 (2015).
Xie, C. et al. An intestinal farnesoid X receptor-ceramide signaling axis modulates hepatic gluconeogenesis in mice. Diabetes 66, 613–626 (2017).
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).
Singhal, A. et al. Metformin as adjunct antituberculosis therapy. Sci. Transl. Med. 6, 263ra159 (2014).
Cabreiro, F. et al. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell 153, 228–239 (2013).
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).
Napolitano, A. et al. Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus. PLoS ONE 9, e100778 (2014).
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).
Gu, Y. et al. Analyses of gut microbiota and plasma bile acids enable stratification of patients for antidiabetic treatment. Nat. Commun. 8, 1785 (2017).
Olgun, A. “Metformin-resistant” folic acid producing probiotics or folic acid against metformin’s adverse effects like diarrhea. Med. Hypotheses 106, 33–34 (2017).
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).
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).
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).
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).
Parseus, A. et al. Microbiota-induced obesity requires farnesoid X receptor. Gut 66, 429–437 (2017).
Trabelsi, M. S. et al. Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells. Nat. Commun. 6, 7629 (2015).
Ziętak, M. et al. Altered microbiota contributes to reduced diet-induced obesity upon cold exposure. Cell Metab. 23, 1216–1223 (2016).
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).
Zhang, L. et al. Farnesoid X receptor signaling shapes the gut microbiota and controls hepatic lipid metabolism. mSystems 1, e00070–16 (2016).
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).
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).
Schaeffer, L., Pimentel, H., Bray, N., Melsted, P. & Pachter, L. Pseudoalignment for metagenomic read assignment. Bioinformatics 33, 2082–2088 (2017).
Nakada, D., Saunders, T. L. & Morrison, S. J. Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature 468, 653–658 (2010).
Vetizou, M. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079–1084 (2015).
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).
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.
The authors declare no competing interests.
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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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