Bacterial blockade: Research explains how gut microbes can inactivate cardiac drugs

July 24, 2013, Harvard University

For decades, doctors have understood that microbes in the human gut can influence how certain drugs work in the body—by either activating or inactivating specific compounds—but questions have remained about exactly how the process works.

Harvard scientists are now beginning to provide those answers.

In a paper published July 19 in Science, Peter Turnbaugh, a Bauer Fellow at the Center for Systems Biology in the Faculty of Arts and Sciences (FAS), and Henry Haiser, a postdoctoral fellow, identify a pair of genes that appear to be responsible for allowing a specific to break down a widely prescribed cardiac drug into an inactive compound, as well as a possible way to turn the process off.

"The traditional view of in the gut relates to how they influence the digestion of our diet," Turnbaugh said. "But we also know that there are over 40 different drugs that can be influenced by . What's really interesting is that although this has been known for decades, we still don't really understand which microbes are involved or how they might be processing these compounds."

To answer those questions, Turnbaugh and his colleagues chose to focus on digoxin, one of the oldest known cardiac glycosides. The medicine is typically prescribed to treat and cardiac arrhythmia.

"It's one of the few drugs that, if you look in a pharmacology textbook, it will say that it's inactivated by gut microbes," Turnbaugh said. "John Lindenbaum's group at Columbia showed that in the 1980s. They found that a single , Eggerthella lenta, was responsible."

Researchers in the earlier study also tried—but failed—to show that testing bacterial samples from a person's gut could be used to predict whether the drug might be inactivated.

"To some degree the research was stalled there for a number of years, and the findings in our paper help to explain why," Turnbaugh said. "Originally, it was hoped that we would simply be able to measure the amount of E. lenta in a person's gut and predict whether the drug would be inactivated, but it's more complicated than that."

Beginning with lab-grown samples of E. lenta—some cultured in the presence of digoxin, some in its absence—Turnbaugh and Haiser tested to see if certain genes were activated by the presence of the drug.

"We identified two genes that were expressed at very low levels in the absence of the drug, but when you add the drug to the cultures … they come on really strong," Turnbaugh said. "What's encouraging about these two genes is that they both express what are called cytochromes—enzymes that are likely capable of converting digoxin to its inactive form."

Though he warned that more genetic testing is needed before the results are definitive, Turnbaugh said other experiments support these initial findings.

The researchers found only a single strain of E. lenta—the only one that contained the two genes they had earlier identified—was capable of inactivating digoxin. In tests using human samples, bacterial communities that were able to inactivate the drug also showed high levels of these genes

"We were able to confirm that simply looking for the presence of E. lenta is not enough to predict which microbial communities inactivate digoxin," Turnbaugh said. "We found detectable E. lenta colonization in all the human fecal samples we analyzed. But by testing the abundance of the identified genes we were able to reliably predict whether or not a given microbial community could metabolize the drug."

In addition to being able to predict whether a given microbial community would inactivate the drug, Turnbaugh and colleagues identified a possible way to halt the process.

"It was previously shown that in the lab E. lenta grows on the amino acid arginine and that as you supply more and more arginine, you inhibit inactivation," he said.

Tests conducted with mice showed that animals fed a diet high in protein, and thereby arginine, had higher levels of the drug in their blood than mice fed a zero-protein diet.

"We think that this could potentially be a way to tune microbial drug metabolism in the gut," Turnbaugh said. "Our findings really emphasize the need to see if we can predict or prevent microbial drug inactivation in cardiac patients. If successful, it may be possible someday to recommend a certain diet, or to co-administer the with an inhibitor like arginine, ensuring a more reliable dosage."

Explore further: Go with your gut: Research sheds light on how microbes can interact with drugs

Related Stories

Go with your gut: Research sheds light on how microbes can interact with drugs

February 15, 2013
Scientists are already working to develop treatments that can be tailored to an individual's genetics, but what about tailoring treatments based on the genetics of the trillions of microbes that live in a person's gut?

A new way to lose weight? Study shows that changes to gut microbiota may play role in weight loss

March 27, 2013
Scientists at Harvard may have new hope for anyone who's tried to fight the battle of the bulge. New research, conducted in collaboration with researchers at Massachusetts General Hospital, has found that the gut microbes ...

Viruses in gut confer antibiotic resistance to bacteria

June 10, 2013
Bacteria in the gut that are under attack by antibiotics have allies no one had anticipated, a team of Wyss Institute scientists has found. Gut viruses that usually commandeer the bacteria, it turns out, enable them to survive ...

Breastfeeding is associated with a healthy infant gut

April 30, 2012
Early colonization of the gut by microbes in infants is critical for development of their intestinal tract and in immune development. A new study, published in BioMed Central's open access journal Genome Biology, shows that ...

Recommended for you

Researchers illustrate how muscle growth inhibitor is activated, could aid in treating ALS

January 19, 2018
Researchers at the University of Cincinnati (UC) College of Medicine are part of an international team that has identified how the inactive or latent form of GDF8, a signaling protein also known as myostatin responsible for ...

Bioengineered soft microfibers improve T-cell production

January 18, 2018
T cells play a key role in the body's immune response against pathogens. As a new class of therapeutic approaches, T cells are being harnessed to fight cancer, promising more precise, longer-lasting mitigation than traditional, ...

Weight flux alters molecular profile, study finds

January 17, 2018
The human body undergoes dramatic changes during even short periods of weight gain and loss, according to a study led by researchers at the Stanford University School of Medicine.

Secrets of longevity protein revealed in new study

January 17, 2018
Named after the Greek goddess who spun the thread of life, Klotho proteins play an important role in the regulation of longevity and metabolism. In a recent Yale-led study, researchers revealed the three-dimensional structure ...

The HLF gene protects blood stem cells by maintaining them in a resting state

January 17, 2018
The HLF gene is necessary for maintaining blood stem cells in a resting state, which is crucial for ensuring normal blood production. This has been shown by a new research study from Lund University in Sweden published in ...

Magnetically applied MicroRNAs could one day help relieve constipation

January 17, 2018
Constipation is an underestimated and debilitating medical issue related to the opioid epidemic. As a growing concern, researchers look to new tools to help patients with this side effect of opioid use and aging.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.