Taking the Yuck Out of Microbiome Medicine

I can still remember the shock I felt when I heard about fecal microbiota transplants for the first time. It is not the sort of thing you forget.

At a microbiology conference, a scientist was giving a lecture about the microbiome–the microbes that live harmlessly inside of us. She described one unusual case she was involved in where a doctor named Alexander Khoruts used the microbiome to save a patient’s life. The patient had taken antibiotics for a lung infection. While the drugs cleared that infection, they  also disrupted the ecology of her gut, allowing a life-threatening species of bacteria called Clostridium difficile to take over. The pathogen was causing horrific levels of diarrhea. Khoruts couldn’t stop it, because it was resistant to every antibiotic he tried.

So Khoruts decided to use an obscure method: the fecal transplant. He took some stool from the patient’s husband, mixed it with water, and delivered it to her large intestines like a suppository. In a matter of days she was recovering.

Since I first heard about these transplants in 2010, they’ve hit the big time. Last year, a team of Danish and Finnish doctors reported clinical trials in which the transplants 94 percent effective against C. difficile. It appears that some species in the transplant from a healthy gut will grow quickly and outcompete the pathogen, returning a sick person’s intestines to its former state. Scientists have been exploring using fecal transplants for other disorders of the gut, along with conditions beyond the gut, such as diabetes and obesity.

But there are many obstacles left to putting fecal transplants into widespread practice. For one thing, the FDA is very cautious with this kind of living medicine. For another thing, fecal transplants are conceptually crude. Doctors simply give a patient a random sample of hundreds of different species from a healthy person’s gut, assuming that at least some of them will restore the patient to health. When the patients get better, they can’t say precisely why.

And then there is the yuck factor. In 2012, scientists conducting a survey about attitudes towards feccal transplants, politely summed up the problem this way: “patients recognize the inherently unappealing nature of FMT.”

But now there’s a potentially promising development in the quest to harness the microbiome. At an American Gastroenterological Association conference in Chicago this weekend, researchers will be describing how they cured C. difficile not with a fecal transplant, but with a pill full of bacterial spores.

The pill is the work of a small Boston-area company called Seres Health. They came up with a combination of certain harmless microbe species that naturally live in our gut. These species  all form spores, which are rugged enough to survive inside a pill. Once they reach the warm refuge of the gut, they pop out of their spores and multiply. In previous studies, Seres researchers showed they could treat C. difficile infection effectively in mice and hamsters. (Technology Review described the company’s efforts in this article from last December.)

Recently, doctors at the Mayo Clinic, the Miriam Hospital in Providence, and Massachusetts General Hospital ran a clinical trial on people to see if the pills from Seres were safe and effective. They gave the pill to fifteen people. The results were striking: the overall cure rate was 100 percent. (The detailed abstract pdf is here.)

I contacted Khoruts to see what he thought of the study. “It looks very promising,” he told me.

But Khoruts also raised a few caveats. He pointed out that the authors excluded very sick patients from the study because of the risk of adverse events. So the 100 percent cure rate might be higher than it would be in the real world.

Khoruts also pointed out a few potential problems with taking a pill full of spores as opposed to getting stool from a donor. Scaling it up to industrial production will require making sure that the factory stocks don’t get contaminated by strains of bacteria that would harm patients, for example.

In those factory stocks, Khoruts pointed out, the microbes will continue to evolve and adapt to their surroundings. If they become too well adapted to life in a factory, they may not do as well inside of people’s bodies.

Nor does the initial report on these pills actually explain how these particular species are conquering C. difficile. I’m sure that the fifteen people who were cured of these awful bugs aren’t clamoring for a detailed  mechanistic explanation of what happened when they swallowed the pills.

But if scientists are going to rationally design microbiome treatments for a lot of different conditions, they’re going to have to open this microbial black box.