Those drugs in your cabinet? They’re designed to treat only half of you. The other half — the trillions of microbes throughout your body — haven’t historically interested drug makers.
But as scientists learn more about the microbiome’s role in conditions ranging from allergies to anxiety to cancer, they’re increasingly interested in drugging its constituents. Two teams of US scientists have already tested those drugs in mice, and pharmaceutical companies are paying close attention.
The hope is that by delivering drugs to the microbiome, researchers will be able to treat or prevent some of our most intractable diseases.
Today there are crude ways to medicate the microbiome. Antibiotics kill bacteria broadly; probiotics add additional bacteria in. The gut drugs under development, on the other hand, are precisely targeted and nonlethal. They don’t aim to change the number of microbes, but rather their behavior.
Eating red meat, for instance, increases a person’s risk of heart disease in part because of the gut microbes. They convert a chemical in red meat (and eggs and dairy), called choline, into a chemical called trimethylamine (TMA). TMA becomes trimethylamine N-oxide, or TMAO, which can cause hardening of arteries and increased heart attack risk.
No one has studied that process more than Dr. Stanley Hazen, a physician and researcher at the Cleveland Clinic. And after years of research, his team decided to try to disrupt it.
In a December 2015 Cell paper, Hazen and colleagues described their search for molecules that would block microbes’ choline receptors. One candidate drug, called DMB, which occurs naturally in olive oil and red wine, fit the bill. When the molecule was given to mice, they produced lower levels of harmful TMAO and had healthier arteries. In samples of human gut microbes in a dish, the drug also prevented TMAO production.
“You’re not killing the bacteria,” Hazen says. “You’re just telling the bacteria, ‘You can’t eat this to make this product.’”
Matthew Redinbo, a biochemist at the University of North Carolina, was “thrilled” to see Hazen’s study. In a 2010 Science paper, Redinbo and his coauthors targeted gut microbes for a different purpose: preventing nausea caused by chemotherapy.
Chemotherapy drugs are toxic by definition. Tissues neutralize many toxic molecules by sticking a sugar molecule onto them. But in the gut, microbes may munch off that sugar. That leaves a highly toxic chemical sitting exposed in the intestine. In the case of the cancer drug that Redinbo studied, removal of those sugars causes intestinal damage and severe diarrhea. As a result, doctors often choose to limit the dose of the drug they give to patients.
So Redinbo and his team tried to drug the microbes. “It was really the first demonstration that the microbiota contain druggable targets,” Redinbo says. They found a molecule that would inhibit the sugar-lopping enzymes. When they fed the inhibitor to mice along with the chemotherapy drug, the mice had less bloody diarrhea.
“You’re not killing the bacteria. You’re just telling the bacteria, ‘You can’t eat this.’”
Dr. Stanley Hazen
Redinbo’s group is now researching ways to minimize the side effects of other drugs. For example, ibuprofen can cause intestinal ulcers when bacteria chew off its protective sugars. Redinbo has founded a startup, Symberix Pharmaceuticals, to commercialize that work. The company is specifically developing nonlethal drugs for the microbiome — an approach it calls a “new drug discovery paradigm.”
More established companies are also interested in drugs for microbes. Peter McLean, a director of gastrointestinal drug discovery at Takeda Pharmaceuticals, said such drugs are especially promising for treating gut diseases such as irritable bowel syndrome. But other conditions including diabetes and central nervous system disorders have been linked to microbiome changes. The challenge, he explained, is finding the right target for a drug. “For most of these, it is unclear if the changes represent a cause or effect of the disease.”
McLean says nonlethal drugs for microbes are a relatively small part of the booming field of medicinal microbiome research. Other areas include fecal transplantation, engineering bacteria to produce drugs, and creating microbe-inspired drugs for humans.
“There’s going to be a plethora of approaches,” said Arpita Maiti, who oversees research into inflammation and immunology at Pfizer. At this point, she said, the company is investing in basic research to better understand the mechanisms that link microbes to health. In May 2014, the company announced a partnership with Second Genome, a San Francisco-based clinical research company, to study the role of the microbiome in obesity and metabolic disease. “We can at least try to chip away at that understanding,” she said.
Maiti added that all of these approaches to microbiome-based therapies are generating excitement in the pharmaceutical industry. More investments, and more scientific advances, are likely coming soon.
As for the academic researchers, Hazen says DMB, the olive-oil molecule from his study, is too weak to put into a pill. He’s working on creating stronger inhibitors. In the future you could potentially pop a pill alongside a steak dinner, preventing its artery-hardening effects.
Recent research “sets the stage for what will no doubt be an enormous opportunity” for new medical treatments, said Dr. Joseph Loscalzo, chair of the department of medicine at Boston’s Brigham and Women’s Hospital. “The risks are, however, not insignificant.”
That’s because most of what happens within the gut microbiome remains mysterious. When scientists tinker with one part of that ecosystem, there’s no way to predict what else might happen.
For instance, Hazen saw that even without noticeably killing off bacteria, his drug changed the bacterial makeup in mouse guts. That means some sort of selection is taking place, Hazen said, raising the possibility that microbes could evolve resistance to these drugs as they do to antibiotics.
Still, drugging gut microbes is a tantalizing prospect. Gut bacteria, after all, are intimately connected to health. And with millions of possible gene targets, Redinbo said, “the implications are vast.”