Inner Workings: Microbiota munch on medications, causing big effects on drug activity
Jyoti Madhusoodanan
PNAS first published April 8, 2020
https://doi.org/10.1073/pnas.2003785117
https://www.pnas.org/content/early/2020/04/07/2003785117
Millions of patients with Parkinson’s disease rely on the drug Levodopa for relief from tremors, slowed movement, and other motor symptoms. But many patients experience side effects such as cardiac arrhythmias, nausea, and gastrointestinal problems. Levodopa’s side effects and benefits vary widely among patients. Those puzzling disparities, it turns out, have a lot to do with the microbes in their guts.
Researchers have found that many side effects of the Parkinson’s drug Levodopa were the result of a bacterial decarboxylase enzyme, produced by the commensal gut microbe E. faecalis (pictured in colored-scanning electron micrograph). Image credit: ScienceSource/Dennis Kunkel Microscopy.
Earlier this year, chemist Emily Balskus and her colleagues at Harvard University in Cambridge, MA, found that many side effects were the result of a bacterial decarboxylase enzyme, produced by the gut microbe Enterococcus faecalis. Levodopa is an inactive form of the neurotransmitter dopamine and must be activated by a human decarboxylase enzyme to work. Activate the medicine too soon—before it crosses the blood–brain barrier—and side effects will occur. To block this premature activation, drug makers have long added an enzyme inhibitor known as carbodopa to Levodopa. But Balskus and her colleagues found that although carbodopa works on human enzymes, it does not inhibit bacterial decarboxylase. In fact, the bacterial enzyme acts on the drug in the intestines before it crosses the blood–brain barrier, triggering problematic symptoms (1).
Balskus and others are learning that the interactions among our microbes and medications are far more complex than previously assumed, potentially causing toxic side effects or altering drugs’ activity. Medications left unabsorbed in the body are usually marked for removal in the liver and then transported to the gut. Although human cells no longer recognize these excretory products, intestinal bacteria can act on inactivated drug molecules. This stage could be labeled the “fourth phase of drug metabolism,” says chemist Matthew Redinbo of the University of North Carolina at Chapel Hill. “Bacteria perform incredibly sophisticated chemical reactions that no human systems are able to do.”
Using a combination of chemistry and genomics, researchers are now beginning to identify these mechanisms. As they do, they’re uncovering ways to inhibit the microbial enzymes that cause distressing side effects. The end result could be drugs that are less toxic, as well as better predictions about how patients respond to medications.
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