New research led by a team from the University of Gothenburg has found a metabolite produced by gut bacteria can block the beneficial effects of a popular diabetes medication. The research offers valuable insights into how an individual’s unique microbiome can influence their response to certain drugs.
Back in 2018 a team of Swedish scientists revealed a previously unknown relationship between gut bacteria and type 2 diabetes. The research described how a compound called imidazole propionate is produced when certain gut microbes metabolize histidine, an amino acid mainly derived from the diet.
That earlier research described how imidazole propionate can impair our cellular response to insulin. The findings suggested this mechanism is not a sole cause of all type 2 diabetes cases, but instead may contribute to the severity of the condition in certain subpopulations of patients.
Metformin is one of the most commonly prescribed medicines in the United States. Beyond exercise and dietary interventions, metformin is considered the first-line treatment for those diagnosed with type 2 diabetes. However, the drug is not effective in every patient, and a new study published in the journal Cell Metabolism may offer one reason for the irregularity.
The new study first looked at type 2 diabetes patients who are taking metformin but still register relatively high blood glucose levels. Those patients with a weak metformin response were also found to have high concentrations of imidazole propionate. Moving to mice studies, the researchers homed in on exactly how this microbial metabolite could be inhibiting the action of metformin.
"We found out that imidazole propionate interacts with AMPK, the same molecule as metformin,” explains first author on the study Ara Koh. “But instead of activating AMPK, imidazole propionate inhibits metformin-induced AMPK activation.”
The study also describes a possible mechanism by which the negative effect of imidazole propionate could be blocked. The researchers do make clear there is more work to be done before an explicit causal link can be drawn between this metabolite and impaired metformin action, but it is hypothesized that certain compounds could be added to metformin to enhance its action in unresponsive patients.
“Our study demonstrates clearly that imidazole propionate not only inhibits the effects of insulin but may also reduce the therapeutic action of the metformin," says corresponding author Fredrik Bäckhed, from the University of Gothenburg. "Since imidazole propionate has also been linked to inflammation in the gut, and metformin has several side effects in the form of intestinal problems, it's conceivable that imidazole propionate both blocks the treatment effect and contributes to side effects of metformin. But new studies are needed to verify this hypothesis."
Interestingly, this is not the first study to discover gut bacteria can influence the actions of metformin. Compelling research published last year in the journal Cell suggested a different microbial metabolite, called agmatine, may enhance the potential anti-aging effect of metformin.
Other ongoing research is more generally working to catalog the effects of the gut microbiome on the efficacy of different therapeutic drugs. It is early days for this remarkably complex field of study, but the long-term outcome points to a deeply personalized future of medicine, with treatments specifically tailored to each patient’s unique metabolic and microbiome profile.
The new study was published in the journal Cell Metabolism.
Source: University of Gothenburg
