New research from an international team of scientists has revealed the effects of a commonly prescribed type 2 diabetes drug are regulated by metabolites produced by certain gut bacteria. The study offers compelling insights into how the microbiome can influence the efficacy of drugs, and more specifically the activity of a drug increasingly under the spotlight for its possible lifespan-extending effects.

Metformin is not a new drug. Classified by the World Heath Organization as an “Essential Medicine”, the drug has been used for several decades to lower blood sugar levels in type 2 diabetes patients. Over the last few years, however, scientists have begun to notice patients on metformin seemed to display lower rates of cancer and longer lifespans than non-diabetics.

An intriguing metastudy published in 2017 reviewed a number of studies and concluded metformin seemed to be associated with health and lifespan extensions independent of its effect on diabetes. Some animal studies have also shown the drug to significantly extend lifespan, but these effects have not been consistent, and this new research explores whether metabolites produced by gut bacteria could be modulating the drug’s efficacy.

After developing a new high-throughput four-way screening approach to examine the interaction between drugs, nutrients, microbes and a host, the researchers conducted a detailed mechanistic investigation in two model organisms. In both fruit flies and worms the study revealed metformin’s lifespan-extending effects seemed to be modulated through the presence of certain bacteria.

Even more specifically, it was discovered that bacterial production of a metabolite called agmatine appeared to primarily mediate the beneficial effects of metformin. The researchers understood the study wouldn’t mean a great deal without exploring how analogous these results were in humans so that was the final step.

“We were intrigued by the results in the worms and wondered whether they also apply to the much more complex microbiota of humans,” explains senior author on the study, Christoph Kaleta. “From the samples we collected, we determined which bacteria could be found in the gut of each participant and translated them into computer simulations of the gut microbiome. From this modeling approach, we found that patients taking metformin and who had E. coli present in their gut microbiome were able to produce more of those nitrogen-containing compounds that can help improve overall host health.”

The new study adds to a rapidly growing area of research investigating the way gut bacteria can influence the efficacy of certain drugs. Impressive work from Yale University earlier this year began the potentially onerous task of cataloguing how different bacteria interact with common medications, while a recent investigation from Harvard University and the University of California San Francisco profiled specifically how certain gut bacteria suppress the activity of Levodopa, a drug treatment for Parkinson’s disease.

One of the big takeaways from the new study is the novel four-way screening approach developed by the research team. It's hoped the method will assist further mechanistic studies helping researchers uncover the causative effects of bacterial activity on the efficacy of specific drugs. In terms of metformin and its possible anti-aging effects, the researchers note that while it is now clear how bacterial metabolites can enhance the activity of the drug, it is still unknown exactly what is going on to generate certain lifespan-extending effects.

“Our new screening technology has helped uncover the metformin specific metabolic and bacterial signaling pathways that regulate host metabolism,” says Filipe Cabreiro, corresponding author on the new research. “However, what is still unknown, is the biological target that metformin inhibits leading to this cascade of events and that is what I am keen to investigate next”.

The new research was published in the journal Cell.

Source: MRC London Institute of Medical Sciences