Gut microbiota and intestinal FXR mediate the clinical benefits of metformin

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 actio...

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Published in:	Nature medicine Vol. 24; no. 12; pp. 1919 - 1929
Main Authors:	Sun, Lulu, Xie, Cen, Wang, Guang, Wu, Yue, Wu, Qing, Wang, Xuemei, Liu, Jia, Deng, Yangyang, Xia, Jialin, Chen, Bo, Zhang, Songyang, Yun, Chuyu, Lian, Guan, Zhang, Xiujuan, Zhang, Heng, Bisson, William H., Shi, Jingmin, Gao, Xiaoxia, Ge, Pupu, Liu, Cuihua, Krausz, Kristopher W., Nichols, Robert G., Cai, Jingwei, Rimal, Bipin, Patterson, Andrew D., Wang, Xian, Gonzalez, Frank J., Jiang, Changtao
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01.12.2018 Nature Publishing Group
Subjects:	631/154/555 631/326/41/2142 692/163/2743/137 692/699/317 Antidiabetics Bacteroides - drug effects Bacteroides - pathogenicity Bile acids Bile Acids and Salts - metabolism Biomedical and Life Sciences Biomedicine Cancer Research Deoxycholic acid Diabetes mellitus Diabetes mellitus (non-insulin dependent) Diabetes Mellitus, Type 2 - drug therapy Diabetes Mellitus, Type 2 - genetics Diabetes Mellitus, Type 2 - microbiology Diabetes Mellitus, Type 2 - pathology Diet, High-Fat - adverse effects Digestive system Gastrointestinal Microbiome - drug effects Gastrointestinal Microbiome - genetics Gastrointestinal tract Gene Expression Regulation, Bacterial - drug effects Gluconeogenesis Glucose Glucose intolerance Glucose Intolerance - drug therapy Glucose Intolerance - genetics Glucose Intolerance - microbiology Glucose tolerance Hepatocytes High fat diet Humans Hyperglycemia Hyperglycemia - drug therapy Hyperglycemia - genetics Hyperglycemia - microbiology Hyperglycemia - pathology Hypoglycemic agents Infectious Diseases Intestinal microflora Intestine Intolerance Metabolic Diseases Metabolism Metabolites Metabolome - drug effects Metabolome - genetics Metabolomics Metagenomics - methods Metformin Metformin - administration & dosage Mice Microbiota Microbiota (Symbiotic organisms) Microorganisms Molecular Medicine Neurosciences Obesity - drug therapy Obesity - genetics Obesity - microbiology Obesity - pathology Receptors, Cytoplasmic and Nuclear - genetics Retirement benefits Signaling Type 2 diabetes Ursodeoxycholic Acid - analogs & derivatives
ISSN:	1078-8956, 1546-170X, 1546-170X
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Summary:	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. Metformin decreases the levels of Bacteroides fragilis while increasing the bile acid GUDCA to antagonize intestinal FXR and improves the metabolic health of humans and mice.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 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. Author contributions
ISSN:	1078-8956 1546-170X 1546-170X
DOI:	10.1038/s41591-018-0222-4