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The effect of metformin on the gut microbiota
Sun L, Xie C, Wang G, et al. Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Nature Medicine 2018;24:1919–29
Oral administration of metformin leads to high drug levels in the gut and relatively lower levels in serum. This raises the possibility that its mode of action may well be due to intestinal rather than systemic actions. The gut microbiota is altered in metabolic disorders including type 2 diabetes and recent evidence demonstrates that metformin can alter the gut microbiome. Mechanistic evidence of metformin’s effect on the gut microbiome and the host is currently lacking. This recent study assessed individuals with type 2 diabetes before and after exposure to metformin. Metagenomic analysis indicated that metformin treatment drastically modulated gut microbiota composition with a significant reduction in Bacteroides fragilis levels. Metformin treatment altered bile acid metabolism in the same individuals with a significant increase in glycoursodeoxycholic acid (GUDCA). These changes were accompanied by inhibition of intestinal farnesoid X receptor (FXR) signalling. Using in silico docking studies and murine models, the authors showed that GUDCA is an FXR antagonist and that metformin inhibits FXR signalling via the gut microbiota in an AMPK-independent manner. They also showed that metformin upregulates GUDCA levels by downregulating bile salt hydrolase activity in B. fragilis. This in turn altered bile acid composition and ultimately FXR signalling in the gut. Readdition of B. fragilis to the gut microbiota was shown to reverse the improvements in glucose metabolism seen with metformin use. The authors conclude that GUDCA signalling shows promise as a new potential target for the treatment of metabolic disease.
Regulation of iron metabolism in the gut
Schwartz AJ, Das NK, Ramakrishnan SK, et al. Hepatic hepcidin/intestinal HIF-2a axis maintains iron absorption during iron deficiency and overload. Journal of Clinical Investigation 2018. pii: 122 359. doi: 10.1172/JCI122359. (Epub ahead of print) …
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