Gut microbiota and intestinal FXR mediate the clinical benefits of metformin

Nature Medicine

Volumn 24, Issue 12, 2018, Pages 1919-1929

  Sun, Lulu ^a   Xie, Cen ^b   Wang, Guang ^c   Wu, Yue ^d   Wu, Qing ^a   Wang, Xuemei ^a   Liu, Jia ^c   Deng, Yangyang ^d   Xia, Jialin ^a   Chen, Bo ^a   Zhang, Songyang ^a   Yun, Chuyu ^a   Lian, Guan ^a   Zhang, Xiujuan ^a   Zhang, Heng ^c   Bisson, William H ^e   Shi, Jingmin ^b   Gao, Xiaoxia ^b   Ge, Pupu ^f   Liu, Cuihua ^f   Krausz, Kristopher W ^b   Nichols, Robert G ^g   Cai, Jingwei ^g   Rimal, Bipin ^g   Patterson, Andrew D ^g   Wang, Xian ^a   Gonzalez, Frank J ^b   Jiang, Changtao ^a   more..

^a PEKING UNIVERSITY HEALTH SCIENCE CENTER   (China)

^b NATIONAL CANCER INSTITUTE   (United States)

^c CAPITAL MEDICAL UNIVERSITY   (China)

^d THE FIRST AFFILIATED HOSPITAL OF XI AN JIAOTONG UNIVERSITY   (China)

^e OREGON STATE UNIVERSITY   (United States)

^f INSTITUTE OF MICROBIOLOGY   (China)

^g PENNSYLVANIA STATE UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BILE ACID; FARNESOID X RECEPTOR; GLYCOURSODEOXYCHOLIC ACID; METFORMIN; UNCLASSIFIED DRUG; CELL RECEPTOR; FARNESOID X-ACTIVATED RECEPTOR; URSODEOXYCHOLIC ACID;

ANIMAL EXPERIMENT; ARTICLE; BACTERIAL COLONIZATION; BACTEROIDES FRAGILIS; CLINICAL ARTICLE; DISEASE SEVERITY; DRUG EFFICACY; GLUCOSE INTOLERANCE; GLUCOSE METABOLISM; HUMAN; INTESTINE FLORA; LIPID DIET; METABOLOMICS; METAGENOMICS; MOUSE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PRIORITY JOURNAL; SIGNAL TRANSDUCTION; ANALOGS AND DERIVATIVES; BACTEROIDES; DRUG EFFECT; GENE EXPRESSION REGULATION; GENETICS; HYPERGLYCEMIA; METABOLISM; METABOLOME; MICROBIOLOGY; OBESITY; PATHOGENICITY; PATHOLOGY; PROCEDURES;

BACTEROIDES; BILE ACIDS AND SALTS; DIABETES MELLITUS, TYPE 2; DIET, HIGH-FAT; GASTROINTESTINAL MICROBIOME; GENE EXPRESSION REGULATION, BACTERIAL; GLUCOSE INTOLERANCE; HUMANS; HYPERGLYCEMIA; METABOLOME; METAGENOMICS; METFORMIN; OBESITY; RECEPTORS, CYTOPLASMIC AND NUCLEAR; URSODEOXYCHOLIC ACID;

EID: 85055962163     PISSN: 10788956     EISSN: 1546170X     Source Type: Journal    
DOI: 10.1038/s41591-018-0222-4     Document Type: Article

References (49)

1. Zhou, G. et al. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108, 1167–1174 (2001).
2. Rena, G., Hardie, D. G. & Pearson, E. R. The mechanisms of action of metformin. Diabetologia 60, 1577–1585 (2017).
3. Lien, F. et al. Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk. J. Clin. Invest. 124, 1037–1051 (2014).
4. Madiraju, A. K. et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510, 542–546 (2014).
5. Madiraju, A. K. et al. Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo. Nat Med 24, 1384–1394 (2018).
6. Bailey, C. J., Wilcock, C. & Scarpello, J. H. Metformin and the intestine. Diabetologia 51, 1552–1553 (2008).
7. Geach, T. Gut microbiota: mucin-munching bacteria modulate glucose metabolism. Nat Rev Endocrinol 13, 66 (2017).
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).
9. Forslund, K. et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 528, 262–266 (2015).
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).
11. Lee, H. & Ko, G. Effect of metformin on metabolic improvement and gut microbiota. Appl. Environ. Microbiol. 80, 5935–5943 (2014).
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).
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).
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).
15. Schroeder, B. O. & Backhed, F. Signals from the gut microbiota to distant organs in physiology and disease. Nat. Med. 22, 1079–1089 (2016).
16. Matsubara, T., Li, F. & Gonzalez, F. J. FXR signaling in the enterohepatic system. Mol. Cell. Endocrinol. 368, 17–29 (2013).
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).
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).
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).
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).
21. Li, F. et al. Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nat. Commun. 4, 2384 (2013).
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).
23. Gonzalez, F. J., Jiang, C. & Patterson, A. D. An intestinal microbiota-farnesoid X receptor axis modulates metabolic disease. Gastroenterology 151, 845–859 (2016).
24. Jiang, C. et al. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J. Clin. Invest. 125, 386–402 (2015).
25. Jiang, C. et al. Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nat. Commun. 6, 10166 (2015).
26. Xie, C. et al. An intestinal farnesoid X receptor-ceramide signaling axis modulates hepatic gluconeogenesis in mice. Diabetes 66, 613–626 (2017).
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).
28. Singhal, A. et al. Metformin as adjunct antituberculosis therapy. Sci. Transl. Med. 6, 263ra159 (2014).
29. Cabreiro, F. et al. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell 153, 228–239 (2013).
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).
31. Napolitano, A. et al. Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus. PLoS ONE 9, e100778 (2014).
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).
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).
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).
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).
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).
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).
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).
39. Parseus, A. et al. Microbiota-induced obesity requires farnesoid X receptor. Gut 66, 429–437 (2017).
40. Trabelsi, M. S. et al. Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells. Nat. Commun. 6, 7629 (2015).
41. Ziętak, M. et al. Altered microbiota contributes to reduced diet-induced obesity upon cold exposure. Cell Metab. 23, 1216–1223 (2016).
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).
43. Zhang, L. et al. Farnesoid X receptor signaling shapes the gut microbiota and controls hepatic lipid metabolism. mSystems 1, e00070–16 (2016).
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).
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).
46. Schaeffer, L., Pimentel, H., Bray, N., Melsted, P. & Pachter, L. Pseudoalignment for metagenomic read assignment. Bioinformatics 33, 2082–2088 (2017).
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).
48. Vetizou, M. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079–1084 (2015).
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).