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How Gut Microbes Shape Our Response to Drugs

The human microbiome activates some medicines, inactivates others and provokes side effects

Credit:

Celia Krampien

Next time you swallow a pill, think about this: you may not be the only one digesting it. You might not even be the first. By now most people are aware that our gastrointestinal tract is teeming with microbes that live mostly in harmony with us, helping us break down food, synthesize vitamins, resist germs, and relay chemical signals to our brain and immune system. But an emerging field of research with a mouthful of a name—pharmacomicrobiomics—is demonstrating that our tiny inner denizens can process our drugs in ways that both help and harm us.

Consider the case of levodopa (L-dopa), a mainstay of treating Parkinson's disease. When it enters the brain, L-dopa is converted into dopamine, a neurotransmitter that is in short supply in Parkinson's patients. It is typically given with carbidopa, a compound that prevents enzymes in the body from breaking it down before it gets to the brain. Even so, the amount of L-dopa that actually reaches its destination varies widely from patient to patient for reasons that only recently became clear. Turns out that certain intestinal microbes can also digest the drug, and, surprisingly, carbidopa does not stop them. It is, in fact, “completely ineffective” against these microbes, according to a 2019 study published in Science. The quantity of these subversive bugs varies from person to person and may explain why some patients get less bang from L-dopa than others do, says Emily Balskus, senior author of the paper and a professor of chemistry at Harvard University.

Microbes can also sabotage the classic cardiac drug digoxin, which is used to treat arrhythmias and heart failure. Doctors have long known that about 10 percent of patients who take it do not benefit, because so much of the drug—more than 50 percent in some cases—is inactivated by a gut bacterium called Eggerthella lenta. Newer research by microbiologist Peter Turnbaugh of the University of California, San Francisco, shows that only a few specific strains of E. lenta have this talent.


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Our inner microbes can work in our favor, too. The drug sulfasalazine, widely used for rheumatoid arthritis, Crohn's disease and ulcerative colitis, does nothing unless gut bacteria metabolize it into an active form by breaking a chemical bond. This is also true of multiple oral antibiotics in the class known as sulfa drugs.

Another drug that gets a microbial helping hand is metformin, the first-line medication for type 2 diabetes. In this case, it's more of a two-way interaction. Recent studies show the drug somehow alters the mix of gut microbes in ways that make metformin more effective. How it does so, Balskus says, “has remained a mystery.”

Perhaps the most exciting work in this nascent field concerns irinotecan, used as part of a cocktail of drugs to fight advanced colon and pancreatic cancers. Irinotecan is a powerful killer of tumor cells but provokes such severe diarrhea and intestinal damage that many patients cannot tolerate enough of it to treat their disease—a phenomenon known as dose-limiting toxicity. Chemist Matthew Redinbo of the University of North Carolina at Chapel Hill has traced the issue to a family of bugs called Enterobacteriaceae (members include Salmonella and Escherichia coli). The drug, given intravenously, circulates to the tumor and gets tagged for excretion in the liver, where it is rendered harmless by the addition of a simple sugar. Unfortunately, Redinbo explains, “microbes love sugar,” so when the neutralized drug hits the GI tract on its way out of the body, the bugs pick off the sugar, reactivating the toxic drug, which then proceeds to “rip the GI tract apart.”

Motivated in part by a young colleague's battle with colon cancer and with irinotecan's side effects, Redinbo has developed a small molecule that stops the microbes from eating the sugar so that the drug passes harmlessly through the gut. It prevents GI toxicity in animal studies, and Redinbo hopes to begin testing it in chemotherapy patients. He and a company he co-founded, Symberix, are also working on a drug that would prevent the intestinal distress and ulceration caused by popular painkillers called nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen. Those side effects, which can be dire in chronic NSAID users, are caused by the same sugar-loving bacteria.

If Redinbo and his colleagues succeed, they will have opened the door to a class of drugs that can modify microbes with great precision. Balskus and her team, meanwhile, are testing a molecule that would stop bacteria from breaking down L-dopa. It is “a whole new area of drug development waiting to be explored,” she says.