Gut microbiota and intestinal FXR mediate the clinical benefits of metformin

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 LiuKristopher W. Krausz, Robert G. Nichols, Jingwei Cai, Bipin Rimal, Andrew D. Patterson, Xian Wang, Frank J. Gonzalez, Changtao Jiang

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1919-1929
Number of pages11
JournalNature Medicine
Volume24
Issue number12
DOIs
StatePublished - Dec 1 2018

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Metformin
Bacteroides fragilis
Glucose Intolerance
Hyperglycemia
Glucose
Metagenomics
Metabolomics
Gluconeogenesis
High Fat Diet
Nutrition
Medical problems
Metabolites
Bile Acids and Salts
Type 2 Diabetes Mellitus
Gastrointestinal Microbiome
Hepatocytes
Obesity
Fats
Liver
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Sun, L., Xie, C., Wang, G., Wu, Y., Wu, Q., Wang, X., ... Jiang, C. (2018). Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Nature Medicine, 24(12), 1919-1929. https://doi.org/10.1038/s41591-018-0222-4
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. / Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. In: Nature Medicine. 2018 ; Vol. 24, No. 12. pp. 1919-1929.
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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.",
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Sun, L, Xie, C, Wang, G, Wu, Y, Wu, Q, Wang, X, Liu, J, Deng, Y, Xia, J, Chen, B, Zhang, S, Yun, C, Lian, G, Zhang, X, Zhang, H, Bisson, WH, Shi, J, Gao, X, Ge, P, Liu, C, Krausz, KW, Nichols, RG, Cai, J, Rimal, B, Patterson, AD, Wang, X, Gonzalez, FJ & Jiang, C 2018, 'Gut microbiota and intestinal FXR mediate the clinical benefits of metformin', Nature Medicine, vol. 24, no. 12, pp. 1919-1929. https://doi.org/10.1038/s41591-018-0222-4

Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. / 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.

In: Nature Medicine, Vol. 24, No. 12, 01.12.2018, p. 1919-1929.

Research output: Contribution to journalArticle

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AU - Deng, Yangyang

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AU - Chen, Bo

AU - Zhang, Songyang

AU - Yun, Chuyu

AU - Lian, Guan

AU - Zhang, Xiujuan

AU - Zhang, Heng

AU - Bisson, William H.

AU - Shi, Jingmin

AU - Gao, Xiaoxia

AU - Ge, Pupu

AU - Liu, Cuihua

AU - Krausz, Kristopher W.

AU - Nichols, Robert G.

AU - Cai, Jingwei

AU - Rimal, Bipin

AU - Patterson, Andrew D.

AU - Wang, Xian

AU - Gonzalez, Frank J.

AU - Jiang, Changtao

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