Anti-Diabetic Drug Could Be Disarmed by Microbes in Patients’ Mouths and Guts

Acarbose, a commonly prescribed anti-diabetic drug, works by blocking human enzymes from breaking down complex carbohydrates into sugar. However, new research from Princeton researcher Mohamed Donia shows that certain bacteria in the mouth and gut are capable of deactivating the drug. The presence of certain bacteria in a patient’s digestive tract, therefore, could greatly affect acarbose’s clinical performance.

“Numerous studies have clearly shown that the human microbiome, the collection of microbes living in and on the human body, can affect our health, disease, and ability to respond to various therapeutic interventions. What is still relatively rare, however, are cases where such effects are defined on molecular and mechanistic levels—this is exactly what we set out to do in this study,” says Mohamed Donia, associate professor at Princeton.

In nature, acarbose is produced by a type of bacteria that lives in the soil. These bacteria produce acarbose to hinder the growth of other bacteria that might compete to live in the same environment, giving themselves a competitive advantage. But they also produce an “antidote”—an enzyme called acarbose kinase that modifies acarbose and makes it inactive.

Researchers hypothesized that it may not just be bacteria in the soil that are able to deactivate acarbose but also bacteria in the human body, making the medication not work as it should.

The team of researchers, led by graduate student Jared Balaich, searched the human microbiome for DNA sequences that they believed may be able to inactivate acarbose.

“Our search identified 70 potentially related genes,” says Balaich.

The team then took their selected subset of genes and synthesized the DNA sequences, resulting in nine enzymes, all but one of which proved to be functionally similar to acarbose kinase in blocking the activity of acarbose.

The researchers picked out the most common of the nine enzymes and added that enzyme’s gene to a type of oral bacteria that doesn’t have acarbose-inactivating enzymes. The result was that the bacteria became resistant to acarbose.

Lastly, the team used x-ray crystallography to investigate how the newly discovered enzyme interacts with acarbose. Testing showed that the new enzyme, dubbed “microbiome-derived acarbose kinase” (Mak), is structurally similar to the acarbose kinase that is created by bacteria in the soil.

Sadly, Maks exist in abundance in the human mouth and gut microbiome in many people around the world. This means that some if not most of the people who are prescribed the anti-diabetic drug acarbose may actually be unknowingly neutralizing it.

“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?” Donia says.

The answer, Donia and colleagues learned, may lie in the fact that the human body’s microbes are also capable of making acarbose to reduce competition with other bacteria. Because they make acarbose, they need to also be able to produce a substance that can neutralize acarbose to keep from sabotaging themselves.

The team used a small subset of data from a clinical trial by Liping Zhao, a professor of applied microbiology at Rutgers University, to analyze the effects of Maks on acarbose therapy in patients with diabetes.

“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 Donia’s lab got less benefit from the drug compared to the group of patients whose gut microbiome did not have this capacity,” Zhao says.

The research team plans to continue studying Maks and their effects on the ability of acarbose to do its job in treating diabetes.

“We’ve known for a long time that bacteria compete for carbohydrates in soil using acarbose, and we humans borrow this molecule to treat diabetes,” Donia says. “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. This mechanism may accidentally affect the response of diabetic patients to this drug as well as shape its impact on the microbiome. The revelation of this complex tale led to more questions than answers, and we are very excited to continue pursuing its molecular details.”

Until researchers learn more and changes are made to acarbose therapy, acarbose may not be the most appropriate choice for some patients with diabetes. Those who take it or are considering going on it should consider talking to their doctors about follow-up testing to determine whether the drug is helping or not.

“I think this study just goes to show that the human microbiome is such an interesting area of study,” Balaich says, “and that we have so much more to learn about how these bacteria are interacting with one another and with us.”