Clostridia bacteria from the human gut that can fight autoimmune disorders. Photo by Kenya Honda.
Clostridia bacteria from the human gut that can fight autoimmune disorders. Photo by Kenya Honda.

A Living Drug Cocktail

We know that the 100 trillion microbes in the human body are important to our health. What’s harder to know is how to use them to make us healthy.

Normally, our resident microbes–the microbiome–carry out a number of important jobs for us, from fighting off pathogens to breaking down food for us. If they get disrupted, we  suffer the consequences. Sometimes antibiotics can upset the ecological balance in our bodies so severely, for example, that rare, dangerous species can take over.

For decades, doctors and scientists have searched for microbes that can promote our health by taking up residence in our bodies. They’ve had some modest success in treating people by giving them a single species at a time. (Don’t be fooled by all the so-called probiotic foods and pills you can buy over the counter–few, if any, have ever been scientifically shown to be effective.) Part of the problem has been that scientists haven’t been terribly systematic about searching for microbes. Very often, their most important standard for a probiotic germ is not its healing power, but its ability to survive in food, or packed into a pill.

Scientists have also had some limited success at the other end of the spectrum, by exploiting much of the microbiome’s diversity at all once. For some people with deadly gut infections, for example, the only cure is to get a so-called fecal transplant from a healthy donor. Fecal transplants show a lot of promise, but scientists don’t have a clear idea of how they work. A stool sample is loaded with hundreds of different species, any one of which might be either essential for overthrowing pathogens or just along for the ride.

In Nature todayIn Nature todayIn Nature today, a team of scientists report taking an important step forward in microbiome-based medicine. They searched for species methodically, in the same way medicinal chemists search for new drugs. They have pinpointed a handful of species living in the human gut that collectively show signs of fighting effectively against some autoimmune diseases.

Scientists have long suspected that the immune system would benefit from microbiome-based medicine. That’s because immune systems depend on the microbiome to develop normally in the first place. As a child’s immune cells grow and divide, they pick up signals from the microbes. Those signals teach the immune system to become tolerant. They can still recognize a dangerous pathogen and kill it, but they spare the beneficial bugs. And they also become less likely to overreact to a harmless molecule or our own tissues.

One important group of immune cell involved in this tolerance are known as Tregs (short for the CD4+ FOXP3+ T regulatory cells). They are abundant in the microbe-packed gut, where they help to broker a truce between host and the germs that live there. Tregs also depend on the microbiome for their very existence. When scientists rear mice without any germs at all, the animals develop very few Tregs. And as a result their immune system becomes prone to raging out of control.

A number of experiments have hinted that abnormal levels of Tregs are behind some autoimmune gut diseases, such as colitis, which causes chronic inflammation in the large intestines and diarrhea. This raises the possibility that a treatment for colitis would be to bring Tregs back to normal levels. Perhaps among all the bacteria in the gut, scientists could find the ones that sent the signals to the Tregs.

Over the past few years, Kenya Honda of the University of Tokyo and his colleagues have been hunting for those species. They started by testing out subsets of the microbiome to find groups of species that could foster the growth of Tregs. Raising healthy mice, they collected the mouse droppings, which contained lots of bacteria. They treated the droppings with chloroform, which kills most bacteria. The only microbes that survived were species that make spores tough enough to withstand the chemical.

When the scientists gave those spore-forming bacteria to germ-free mice, the level of Tregs in the animals went up. That didn’t happen when the scientists gave the mice other kinds of bacteria instead.

This discovery didn’t pinpoint exactly which bacteria were fostering Tregs. But it certainly narrowed down the line-up of suspects dramatically. And it also prompted Honda and his colleagues to start acting more like a drug company testing promising new compounds. In fact, Honda co-founded a company called Vedanta Biosciences for that express purpose.

Their goal now became finding a species, or a group of species, that live in humans, and which promote the growth of Tregs in the gut. Rather than taking the kitchen-sink approach of fecal transplants, they would try to deliver a surgically precise germ.

They took stool samples from a healthy Japanese volunteer and doused them with chloroform, so that once more they only had to contend with spore-forming species. Then they inoculated germ-free mice with different combinations of the surviving bacteria. After letting the bacteria grow in the mice, they then inspected the animals to see if any of them had high levels of Tregs as a result. They did find some of those combinations, and they went on narrowing down the suspects until  they were left with just seventeen species, along belong to a type of bacteria called Clostridia.

One particularly interesting result of the experiment was that they couldn’t get these good results from any fewer than those seventeen species. On its own, each of the species was unable to foster the immune cells. It may be a combination of signals from all seventeen species that promotes the Tregs.

The researchers wondered if these seventeen species played a special role in autoimmune diseases in humans. To find out, they looked at the microbiomes from health people and people with colitis. The seventeen species tended to be rarer in the sick people.  Perhaps, the researchers reasoned, losing this network of microbes weakens the signals that keep Treg levels normal. The immune system spins out of control, leading to colitis.

If that were true, then giving someone a pill with all seventeen species might be an effective way to fight colitis. But Honda and his colleagues weren’t ready to start inoculating people with Clostridia. Clostridia is a huge group of species that includes some very nasty characters that cause diseases like tetanus and botulism. They would have to do some preliminary work first.

All seventeen species were new to science (something that’s pretty typical for microbiome research), so the scientists sequenced their genomes. None of the seventeen species carried genes for toxins or other disease-causing proteins. From an inspection of their DNA, at least, the microbes looked safe.

Next, the scientists tested the bacteria out on mice. They gave the microbes to animals either suffering from colitis or from allergy-triggered diarrhea. In both cases, the bacteria raised the level of Tregs dramatically in the guts of the mice. The mice also partly recovered from their diseases. The mice with colitis had less inflammation, and the mice with diarrhea had healthier stool.

From here, the Vedanta researchers eventually hope to get to clinical trials on humans. As I wrote in April, turning bugs into drugs is a big challenge on many levels. For one thing, the FDA doesn’t have a long tradition of approving such research. And while Honda and his colleagues have certainly gone a long way to pinpointing how microbes foster Tregs, they have yet to work out the precise balance of signals that really matters to the immune system.

Nevertheless, a seventeen-bug cocktail would be appealing in many ways. For one thing, the microbes are regular residents of the human gut, dwelling there for people’s entire lifetime. And they only live in the gut, and not the heart or the liver or some other organ. Both these facts suggest that such a cocktail would be unlikely to cause harmful side effects. What’s more, the microbes would be able to deliver a steady, long-running dose of the chemicals necessary to keep Treg levels healthy.

The new study also points to a way to systematically search the microbiome for treatments for other diseases. It’s possible that small teams of other species handle other jobs in the body. They may nurture other types of immune cells, for example. Or they may send signals into the body that regulate body weight. By winnowing down the microbiome, scientists may be able to deploy those elite units to fight other diseases.

[Update: Nature paper link fixed]