New insights on how altered gut microbiota mediates some of metformin’s therapeutic effects

It is well-known that medications could affect the microbiome and therefore host-microbiota interactions are considered a confounding factor that can contribute to therapeutic and side effects of drug treatments. Previous research has shown that gut microbiota may partially mediate both therapeutic and adverse effects of metformin, which is the most prescribed drug for the treatment of individuals with type 2 diabetes (T2D). However, little is known regarding how metformin interacts with gut bacteria in human subjects.

A new randomized, placebo-controlled, double-blind study, led by Prof. Fredrik Bäckhed from the Department of Molecular and Clinical Medicine at Wallenberg Laboratory at the Institute of Medicine in University of Gothenburg (Sweden), has found both clinical and mechanistic evidence that metformin’s improved blood glucose control is achieved through modulation of the gut microbiota.

In order to clarify how the gut microbiota composition and function is affected by metformin, the researchers performed whole-genome shotgun sequencing of faecal samples of patients with new onset T2D (n = 22) before and after 4 months of treatment with 1,700 mg/day of metformin, compared with a placebo-treated group (n = 18). A subset of the placebo group switched to receive metformin (850 or 1,700 mg/day; n = 13) 6 months after the start of the study and their faecal samples were analysed after a further 6 months.

Metformin treatment for 2 and 4 months led to a dramatic change in the composition of the gut microbiota, mostly affecting g-proteobacteria and Firmicutes. Specifically, metformin increased levels of Bifidobacterium adolescentis that was negatively correlated with % haemoglobin A1c (HbA1c), which identifies average plasma glucose concentration and is used as a marker of proper blood glucose control. Besides this, metformin also promoted the growth of B. adolescentis and Akkermansia muciniphila in pure cultures. Earlier studies have shown a relationship between A. muciniphila abundance and improved metabolic features in both mice and humans. The microbial changes observed after 2 and 4 months of metformin treatment correlated with the microbial changes observed in the switched placebo subgroup after 6 months on metformin.

In a related animal experiment, transplantation of faecal samples (obtained before and 4 months after treatment) from metformin-treated human donors to germ-free mice showed that the metformin-modified gut microbiota may partially explain the beneficial effects of metformin on blood glucose control.

Finally, direct effects of metformin on the gut microbiota were investigated by culturing faecal samples in gut simulators and afterwards exposing them to a constant flow of metformin for 1 week. The researchers showed that metformin affected pathways with common biological functions in bacterial species belonging to different phyla. For instance, pathways involved in lipopolysaccharide synthesis, butyrate and pyruvate metabolism, and some pathways related to the metabolism of cofactors and vitamins were enriched by metformin.

In conclusion, these results support the idea that altered gut microbiota may mediate some of metformin’s therapeutic effects in humans. Further studies are needed in order to confirm which pathways are involved in the beneficial effects of drugs on glucose metabolism, taking into account host-microbiota interactions.


Reference:
Wu H, Esteve E, Tremaroli V, et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med. 2017; doi: 10.1038/nm.4345.

Andreu Prados
Andreu Prados
Andreu Prados holds a Bachelor of Science Degree in Pharmacy & Human Nutrition and Dietetics. Science writer specialised in gut microbiota and probiotics, working also as lecturer and consultant in nutrition and healthcare. Follow Andreu on Twitter @andreuprados