Gut Microbiota and Intestinal FXR Mediate the Clinical Benefits of Metformin

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2018 Nov 7

PMID 30397356

Citations 436

Authors

Lulu Sun

Cen Xie

Guang Wang

Yue Wu

Qing Wu

Xuemei Wang

Jia Liu

Yangyang Deng

Jialin Xia

Bo Chen

Songyang Zhang

Chuyu Yun

Guan Lian

Xiujuan Zhang

Heng Zhang

William H Bisson

Jingmin Shi

Xiaoxia Gao

Pupu Ge

Cuihua Liu

Kristopher W Krausz

Robert G Nichols

Jingwei Cai

Bipin Rimal

Andrew D Patterson

Xian Wang

Frank J Gonzalez

Changtao Jiang

Affiliations

Soon will be listed here.

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.

Citing Articles

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References

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. 2014; 7(1):12-8. DOI: 10.1016/j.celrep.2014.02.032. View

Deschasaux M, Bouter K, Prodan A, Levin E, Groen A, Herrema H . Depicting the composition of gut microbiota in a population with varied ethnic origins but shared geography. Nat Med. 2018; 24(10):1526-1531. DOI: 10.1038/s41591-018-0160-1. View

Gu Y, Wang X, Li J, Zhang Y, Zhong H, Liu R . Analyses of gut microbiota and plasma bile acids enable stratification of patients for antidiabetic treatment. Nat Commun. 2017; 8(1):1785. PMC: 5702614. DOI: 10.1038/s41467-017-01682-2. View

Mueller M, Thorell A, Claudel T, Jha P, Koefeler H, Lackner C . Ursodeoxycholic acid exerts farnesoid X receptor-antagonistic effects on bile acid and lipid metabolism in morbid obesity. J Hepatol. 2015; 62(6):1398-404. PMC: 4451470. DOI: 10.1016/j.jhep.2014.12.034. View

Xie C, Jiang C, Shi J, Gao X, Sun D, Sun L . An Intestinal Farnesoid X Receptor-Ceramide Signaling Axis Modulates Hepatic Gluconeogenesis in Mice. Diabetes. 2017; 66(3):613-626. PMC: 5319721. DOI: 10.2337/db16-0663. View

Schroeder B, Backhed F . Signals from the gut microbiota to distant organs in physiology and disease. Nat Med. 2016; 22(10):1079-1089. DOI: 10.1038/nm.4185. View

Fujita K, Iguchi Y, Une M, Watanabe S . Ursodeoxycholic Acid Suppresses Lipogenesis in Mouse Liver: Possible Role of the Decrease in β-Muricholic Acid, a Farnesoid X Receptor Antagonist. Lipids. 2017; 52(4):335-344. DOI: 10.1007/s11745-017-4242-5. View

Jiang C, Xie C, Lv Y, Li J, Krausz K, Shi J . Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nat Commun. 2015; 6:10166. PMC: 4682112. DOI: 10.1038/ncomms10166. View

Bauer P, Duca F, Waise T, Rasmussen B, Abraham M, Dranse H . Metformin Alters Upper Small Intestinal Microbiota that Impact a Glucose-SGLT1-Sensing Glucoregulatory Pathway. Cell Metab. 2017; 27(1):101-117.e5. DOI: 10.1016/j.cmet.2017.09.019. View

10.

Friedman S, Neuschwander-Tetri B, Rinella M, Sanyal A . Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018; 24(7):908-922. PMC: 6553468. DOI: 10.1038/s41591-018-0104-9. View

11.

Matsubara T, Li F, Gonzalez F . FXR signaling in the enterohepatic system. Mol Cell Endocrinol. 2012; 368(1-2):17-29. PMC: 3491147. DOI: 10.1016/j.mce.2012.05.004. View

12.

Kim I, Ahn S, Inagaki T, Choi M, Ito S, Guo G . Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine. J Lipid Res. 2007; 48(12):2664-72. DOI: 10.1194/jlr.M700330-JLR200. View

13.

Napolitano A, Miller S, Nicholls A, Baker D, Van Horn S, Thomas E . Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus. PLoS One. 2014; 9(7):e100778. PMC: 4079657. DOI: 10.1371/journal.pone.0100778. View

14.

Sayin S, Wahlstrom A, Felin J, Jantti S, Marschall H, Bamberg K . Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 2013; 17(2):225-35. DOI: 10.1016/j.cmet.2013.01.003. View

15.

Akwabi-Ameyaw A, Bass J, Caldwell R, Caravella J, Chen L, Creech K . Conformationally constrained farnesoid X receptor (FXR) agonists: Naphthoic acid-based analogs of GW 4064. Bioorg Med Chem Lett. 2008; 18(15):4339-43. DOI: 10.1016/j.bmcl.2008.06.073. View

16.

Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J . Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001; 108(8):1167-74. PMC: 209533. DOI: 10.1172/JCI13505. View

17.

Li F, Jiang C, Krausz K, Li Y, Albert I, Hao H . Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nat Commun. 2013; 4:2384. PMC: 6595219. DOI: 10.1038/ncomms3384. View

18.

Rena G, Grahame Hardie D, Pearson E . The mechanisms of action of metformin. Diabetologia. 2017; 60(9):1577-1585. PMC: 5552828. DOI: 10.1007/s00125-017-4342-z. View

19.

Zhang X, Zhao Y, Xu J, Xue Z, Zhang M, Pang X . Modulation of gut microbiota by berberine and metformin during the treatment of high-fat diet-induced obesity in rats. Sci Rep. 2015; 5:14405. PMC: 4585776. DOI: 10.1038/srep14405. View

20.

Geach T . Gut microbiota: Mucin-munching bacteria modulate glucose metabolism. Nat Rev Endocrinol. 2016; 13(2):66. DOI: 10.1038/nrendo.2016.201. View