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 language | English (US) |
|---|---|
| Pages (from-to) | 1919-1929 |
| Number of pages | 11 |
| Journal | Nature Medicine |
| Volume | 24 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 1 2018 |
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All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)
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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 journal › Article
TY - JOUR
T1 - Gut microbiota and intestinal FXR mediate the clinical benefits of metformin
AU - Sun, Lulu
AU - Xie, Cen
AU - Wang, Guang
AU - Wu, Yue
AU - Wu, Qing
AU - Wang, Xuemei
AU - Liu, Jia
AU - Deng, Yangyang
AU - Xia, Jialin
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
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85055962163&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85055962163&partnerID=8YFLogxK
U2 - 10.1038/s41591-018-0222-4
DO - 10.1038/s41591-018-0222-4
M3 - Article
C2 - 30397356
AN - SCOPUS:85055962163
VL - 24
SP - 1919
EP - 1929
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 12
ER -