Researchers Describe Process By Which Gut Microbes Inactivate Certain Drugs

Doctors have long known that microbes in the human gut can affect how different drugs work by activating and inactivating certain compounds, but only recently has a picture of why that is started to emerge.

Leading the discovery are Harvard's Peter Turnbaugh, a Bauer Fellow at the Center for Systems Biology in the Faculty of Arts and Sciences (FAS), and postdoctoral fellow Henry Haiser, who together in a study published in the journal Science identify a pair of genes that appear to be responsible for allowing a specific strain of bacteria to break down a common cardiac drug into an inactive compound.

Even more exciting, the scientists report, is that by doing so they believe they may have found a way to stop it.

"The traditional view of microbes in the gut relates to how they influence the digestion of our diet," Turnbaugh told the Harvard Gazette. "But we also know that there are over 40 different drugs that can be influenced by gut microbes."

To better understand why that is, Turnbaugh and his colleagues chose to focus on digoxin, one of the oldest known cardiac glycosides frequently prescribed to treat heart failure 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.

This fact was clearly demonstrated at Columbia University during the 1980s, and though scientists even went to so far as to identify the bacterium behind it (Eggerthella lenta), they could never show that testing bacterial samples from a person's gut could predict whether or not the drug would be inactivated.

And there, Turnbaugh says, is largely where the research sat for years.

In hopes of ending this stall, the Harvard team grew samples of E. lenta both in the presence of digoxin and others in its absence and tested to see if certain genes were activated by 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."

Ultimately, the researchers found that only the strain of E. lenta that contained the two genes they identified earlier was capable of inactivating digoxin. And in tests using human samples, bacterial communities showing high levels of these genes were able to inactivate the drug.

"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."

Knowing this, the scientists say they may have discovered a way to halt the process.

Previous research has shown that E. Lenta grows on the amino acid arginine in lab cultures and that as more of the latter is added, digoxin inactivation is inhibited. Furthermore, tests on mice show that when fed a high-protein diet -- and thus a high-arginine diet -- the animals showed higher levels of the drug in their blood when compared to those mice on 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 drug with an inhibitor like arginine, ensuring a more reliable dosage."