Published On August 13, 2019
BACTERIA HAVE UNDERGONE A PUBLIC RELATIONS MAKEOVER IN RECENT YEARS. Once regarded as interlopers, microorganisms in the body have now been recognized for the vital role they can play in maintaining a proper weight and good mental health and preventing a growing list of harmful conditions. But researchers are also discovering one of bacteria’s less helpful traits: interfering with medications meant for their human hosts.
Not all microorganisms cause such problems, and not all medications are susceptible to bacterial theft. Untangling where and how these interactions happen is a promising new frontier, and it may help explain a great mystery: why drugs work well in some people but not in others.
“The microbiome used to be thought of as just something that helped us digest our food,” says Adam Burgener, associate professor in the departments of Obstetrics & Gynecology and Medical Microbiology at the University of Manitoba. But as technology has allowed scientists to observe bacteria more closely, “a lot of people are studying the problem of drug interactions, and making discoveries left and right,” he says.
In 2013 a Harvard research team led by molecular biologist Henry J. Haiser discovered that a common cardiac medicine called digoxin was inactivated by the gut bacteria Eggerthella lenta. Like most pills, digoxin dissolves as it travels through the intestinal tract, on its way to being absorbed through the intestinal lining and metabolized in the liver. But E. lenta could reduce the levels of the drug in the intestinal tract.
A few years later, Burgener and his colleagues made a similar discovery for an HIV drug called tenofovir, which had been formulated as a vaginal gel. After showing initial promise, the effectiveness of tenofovir gel inserted into the vagina proved disappointing. An overgrowth of a particular species of “bad” bacteria called Gardnerella vaginalis turned out to correlate with the poorest results, and further testing revealed G. vaginalis was metabolizing the drug.
These isolated findings hinted at a broader phenomenon. “Until recently, nobody had really taken a comprehensive approach,” Burgener says. Then in June 2019, a team of scientists at Yale University School of Medicine published the results of a study of 76 human gut bacteria that considered the microorganisms’ abilities to metabolize 271 common oral drugs.
That study, published in Nature, found that some two-thirds of those drugs were vulnerable to bacterial metabolism. The affected drugs included anti-inflammatory medications, hypertensive drugs and even birth control pills. “Over the past decade, there have been several anecdotal examples of such bacterial interactions, but I was kind of surprised at how common they are,” said Michael Zimmermann, who worked on the study in the Microbial Sciences Institute at Yale University School of Medicine.
For the study, drugs were placed in a test tube with the bacterial colonies, then tested for metabolites—the byproducts of bacterial digestion. Next, experiments for selected drugs were replicated in the guts of mice and finally in human fecal samples. Researchers found that under all of these conditions, the drugs were metabolized by bacteria. The researchers also identified the bacterial genes responsible for drug metabolism and are now evaluating their capacity to serve as clinical biomarkers and to help personalize drug treatment regimens.
Still, the authors caution, not all drugs they studied may end up being compromised in the more complex human digestive system. “For each particular drug and indication, further research would be necessary to see if it’s relevant for humans,” says co-author Maria Zimmermann-Kogadeeva, also a researcher at the Yale institute.
One drug that is compromised by the human microbiome, however, is levodopa, a primary treatment for Parkinson’s disease and other diseases of the nervous system. That had been established before the Yale study, but in June, a research team from Harvard University and the University of California, San Francisco were able to identify the exact culprits and how the process takes place. Two bacteria—Enterococcus faecalis and Eggerthella lenta—work in tandem to change levodopa to metatyramine, which may be responsible for some of the side effects of the drug. The abundance of those bacteria in some people may also help explain the dramatic variability in effectiveness among patients taking the drug. The team in that study has identified a possible mechanism for halting this process.
Such research may help shine a light on an entirely new dimension of drug dosing and manufacture. The researchers hope that others can use the information from these and similar studies to test the possible vulnerability of drug candidates to bacterial metabolism. That knowledge might enable physicians to increase or decrease the dose of certain drugs based on the composition of a patient’s microbiome.
“We can’t just think about our bodies in isolation,” Burgener says. “We need to think of ourselves as superorganisms, and we need to think of the microbiome as a very important organ.”
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