Gut microbiota and intestinal FXR mediate the clinical benefits of metformin
By Lulu Sun, Cen Xie, Guang Wang, Yuehua Wu, Qing Wu, Xuemei Wang, Jia Liu, Yangyang Deng, Jialin Xia, Songyang Zhang and 17 more. Nature Medicine, 2018
865 citations recorded by the source corpus.
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.
Subfields: Epidemiology, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/6bae3675f97bc60d5fb626aec8547bba3d098009
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Citations in the corpus
- Role of gut microbiota in type 2 diabetes pathophysiology (2020, background): “Among these, five cross-sectional studies [3,17 20] show negative associations with disease while three other studies [6,11,21] that involved some type of treatment reported positive associations.”
- Integrating taxonomic, functional, and strain-level profiling of diverse microbial communities with bioBakery 3 (2020, background): “…have increasingly also been combined with other community profiling techniques such as metabolomics (Heinken et al., 2019; Lloyd-Price et al., 2017; Sun et al., 2018) and proteomics (Xiong et al., 2015) to provide richer pictures of microbial community membership, function, and ecology.”
- Benefits of Metformin in Attenuating the Hallmarks of Aging (2020, background): “fragilis, thereby altering intestinal Farnesoid X Receptor (FXR) signaling (Sun et al. 2018).”