Impressive new research, spearheaded by a team from Princeton University, has shown how a common diabetes drug can be inactivated by bacterial enzymes produced in the oral and gut microbiome. The researchers speculate this process may explain why the drug is not effective in some diabetic patients.
Perhaps one of the most compelling areas of study in the rapidly emerging field of gut microbiome science is work looking at the way gut bacteria can affect the activity of medicines we take. Some of the earliest discoveries uncovered ways the microbiome can either boost the efficacy of cancer treatments or amplify chemotherapy toxicity.
A recent study from scientists at the European Molecular Biology Laboratory and the University of Cambridge more broadly attempted to begin the massive task of characterizing general drug/bacteria interactions. The first report found a large number of interactions between 15 oral drugs and 25 common strains of gut bacteria.
This new research took on a more focused task. It looked to document, across both molecular and mechanistic levels, how bacteria inside us can influence the activity of a single drug, in this case a common diabetes drug called acarbose.
Acarbose is effective as a diabetes drug because it inhibits enzymes needed to break down carbohydrates. It was originally discovered secreted by bacteria living in soil. The bacteria use the molecule to stifle the growth of other types of bacteria. And it relies on another enzyme, called acarbose kinase, to inactivate the acarbose it secretes so its own growth isn’t hindered.
The researchers wondered whether other types of bacteria also secrete similar enzymes to inactivate acarbose, and whether this mechanism occurs in bacteria living inside humans. The first step was to search DNA sequences from human microbiome bacteria to identify any genes with the potential for making enzymes similar to acarbose kinase.
After homing on a number of potentially influential genes, the researchers focused on the most commonly found gene. Engineering a species of oral bacteria with the identified gene, the researchers discovered it produced significant resistance to acarbose in the form of an enzyme very similar to the acarbose kinase identified in soil bacteria.
This new family of microbiome proteins was dubbed Maks – microbiome-derived acarbose kinases. And once identified, Maks were detected in a large variety of human oral and gut bacteria. But as with plenty of scientific discoveries, the finding raised more questions than answers.
“This did not make sense to us: Why would bacteria living in the human body of healthy humans employ a very specific resistance mechanism to acarbose, given that the vast majority of these individuals would have never been exposed to this drug?” says Mohamed Donia, one of the researchers working on the study.
The investigation led the team to discover there are indeed bacterial species in the human microbiome that produce acarbose. So the current hypothesis is that Maks arose in microbiome bacteria as a way of outcompeting bacteria that make molecules similar to acarbose.
“In our study, we found that bacteria also seem to compete in the human body using acarbose-like molecules, resulting in widespread dissemination of a resistance mechanism that is very specific for this drug among members of the human microbiome,” says Donia. “This mechanism may accidentally affect the response of diabetic patients to this drug as well as shape its impact on the microbiome.”
The final part of the research looked to human diabetic patients to establish whether Maks influence therapeutic responses to acarbose. Data was analyzed from a recent human trial investigating the microbiome and type 2 diabetes, revealing patients with bacteria linked to Maks production did seem to respond less effectively to acarbose therapy.
“Re-analysis of the data in this [study] showed that the patient group whose gut microbiome had the capacity to inactivate acarbose via the kinase discovered by Dr. Donia’s lab got less benefit from the drug compared to the group of patients whose gut microbiome did not have this capacity,” explains Liping Zhao, a microbiologist from Rutgers University working on the study.
The researchers are cautious to note this is just a preliminary study reporting on the discovery of this unexpected bacteria/drug interaction. It isn’t clear what kind of influence Maks could have on the efficacy of acarbose treatment in diabetic patients.
More work will need to dig into this question, but the findings certainly build on the fascinating ways our microbiome can influence the activity of the drugs we take. And this study elegantly shows how the behavior of competing species of bacteria in soil can be mirrored by bacteria living in our bodies.
The new study was published in the journal Nature.
Source: Princeton University