We rely on trillions of bacteria, fungi, archaea and viruses in our mouth, on our skin and in our gut to get through the day and to stay healthy. Scientists had no way to study most of these microbes, which do not seem to want to grow in laboratory cultures. Rapidly improving, low-cost genetic-sequencing technologies are finally making it possible, however. By working with our microbes instead of against them, scientists are coming up with intriguing approaches to tackling persistent diseases and improving our overall health.
A few years ago scientists could only dream of studying large communities of microorganisms, but now such experiments are manageable and affordable, says David Relman, a professor at the Stanford University School of Medicine. This new field of metagenomics is giving scientists profiles of what microbe populations look like in the gut of people who are healthy—and in the gut of people who have various conditions and diseases. Armed with these data, scientists are poised to explore the possibility of manipulating the balance of our microbiota as treatments for obesity, inflammatory bowel disease and many other common and uncommon ailments.
For example, researchers have profiled the populations of organisms in people with ulcerative colitis, which forms ulcers in the colon and is linked to changes in the gut's flora. Building on the results, this summer pharmaceutical giant Johnson & Johnson (J&J) announced a $6.5-million deal with Second Genome, a microbiome start-up, to develop treatments. Current approaches, which center on anti-inflammatory drugs, immunosuppressant medications and surgery, are often unsuccessful. A therapy that directly alters the microbiome would potentially create fewer side effects and fend off other infections down the road.
The J&J deal is a watershed, says Rita Colwell, who holds health appointments at the University of Maryland and Johns Hopkins University. “There's a moment for any new biotechnology that's critically important: when it moves from being an area of academic interest to one that companies are founded on,” she notes. “And then there is the next step: when the big pharma money arrives.”
The new treatments would be a big improvement over current attempts to improve the microbiome, which consist mainly of fecal transplants and probiotics—live bacterial cultures in supplements or foods such as yogurt. Fecal transplants have alleviated Clostridium difficile, a tough, often drug-resistant, toxin-producing bacterial infection, but the practice can require multiple transplants, and not all patients are cured. Probiotics have generated only weak evidence for positively changing the gut. Both treatments amount to throwing a bunch of organisms at the gut and seeing what sticks.
Metagenomics is more specific, providing precise genetic profiles of what organisms are in the gut and offering the possibility of deducing how they might be interacting—with one another and with us.
One of the biggest challenges of metagenomics is how to handle the onslaught of data. Now that scientists can rapidly sequence entire swaths of microbial communities, they need to figure out what the information means for our health. Biologists are teaming up with mathematicians to develop new methods of analyzing the DNA fragments they collect from our body. Physicians will then need to understand what changes occur in an individual's microbiome—and why—to protect or improve health.
For example, many people routinely carry Escherichia coli bacteria without getting sick. Relman likens the hope of curating better gut microbiota to maintaining a healthy ecosystem, one that will keep nasty creatures such as the intestinal equivalent of invasive weeds at bay.
Indeed, metagenomics is prompting us to think about caring for our microbial communities as we would cultivate a piece of land. This approach would be a sea change from the one-shot treatments that often have many negative effects. Broad-spectrum antibiotics, for example, wipe out our good bacteria along with the bad—opening up doors for pernicious invaders. Proton-pump inhibitors, sold over the counter to neutralize stomach acid, change the pH in the stomach, which could stress collections of beneficial microbes.
Metagenomic treatments instead might involve a series of interventions calculated to disturb the microbiome in a certain way, by introducing specific organisms that are prevalent in a healthy gut, followed by dietary and lifestyle changes.