By Cassandra Willyard
September 13, 2012
The yards of dank tubing in our midsections form a complex, amazing and absolutely pivotal foundation for human health. And the more that scientists come to appreciate this, the more they anticipate that future medical discoveries will come from the lowly gut.
The gut hosts a microbial nation that is far from a neutral observer. Over the last couple of decades, this human microbiome has been implicated in a laundry list of diseases: irritable bowel syndrome, Crohn's disease, allergies, diabetes, obesity and even mood disorders. Researchers have yet to fully decipher the role microbes play in each of these illnesses, but a flurry of research could translate into a slew of new therapies.
"It's very much like finding an organ we didn't know we had," says Michael Fischbach, a assistant professor of bioengineering and therapeutic sciences at UC San Francisco.
The relationship between us and the bacteria that inhabit our guts is exceedingly complex.
"In infectious disease, there's a pathogen that causes [trouble]. It's one bug," says Curtis Huttenhower, who studies the human microbiome at the Harvard School of Public Health in Boston. Wipe out the pathogen and the disease goes away.
But the microbiome consists of trillions of bacteria — and hundreds of species — that interact with one another and their host in complex ways.
In 2007, the National Institutes of Health launched a $150-million initiative aimed at unraveling these complex interactions. A recent raft of research has sought to define the "normal" microbiome — which bugs belong there and which ones don't. The next step will be to identify the microbial fingerprint of sick individuals and figure out what that all means.
"A lot of people are tempted to say, 'Aha! The microbiome is responsible'" for many diseases, says Dr. David Relman, a professor of microbiology and immunology at Stanford University's School of Medicine. But the relationship is likely much more complicated. Genes and environmental factors beyond the gut undoubtedly play important roles in many diseases. In some cases, alterations in the microbiome may be a symptom of the disease rather than the cause.
What is clear is that the microbiome's influence extends far beyond the colon. The gut is a hotbed of immune activity. In fact, scientists have long understood that its microbial inhabitants play a crucial role in training the body's immune system to recognize foreign invaders.
New research suggests the microbiome may also influence distant organs like the brain. The residents in your digestive tract might even help shape your personality. Jane Foster, a neuroscientist at Ontario's McMaster University, and her colleagues found that mice lacking gut microbes — so-called germ-free mice — took more risks than mice with healthy gut flora. The researchers tried to reverse this behavior in adult mice by allowing bacteria to colonize the rodents' guts, but the risk-taking tendencies persisted.
A separate group of researchers found that they could reverse the behavioral changes if they gave germ-free mice the bacteria sooner, when the animals were still young. The findings suggest there is a critical window during which gut microbes help wire the brain.
Dr. Emeran Mayer, a gastroenterologist at UCLA, has been studying the relationship between gut microbes and the brain in people. Some of his key research has yet to be published, but it "seems to confirm this connection even in humans," he says. "If you manipulate something at the gut level, this will be reflected at the brain level."
How the microbiome might influence the brain isn't entirely clear. And the gut itself has much to say, too. The intestine is cloaked in a layer of nerve cells — the enteric nervous system — that is constantly sending signals to the brain. The gut has so many neurons, Foster says, that it's often called a "little brain."
Although research on the microbiome is still in its infancy, scientists and others are already thinking about how to manipulate gut bacteria to promote health and treat disease. Yogurt makers pack their products with "probiotic" bacteria they claim help regulate digestion, and pharmacies sell pills containing many of the same species. But altering the gut microbiome in a lasting way probably isn't as simple as slurping a spoonful of yogurt or popping a pill. The microbes go in, but they don't seem to stick around.
The probiotics of tomorrow "will be more complicated and also more rigorously tested than today's probiotics," Fischbach says. And they probably won't be found in the dairy aisle. "They'll be something that your doctor prescribes," he says.
Tweaking the species composition of the microbiome shouldn't be the ultimate goal, however. Fischbach points out that what the microbiome does may be more important than who is there. "Two unrelated species can actually play a very similar role in the community," he says.
Future therapies might target the microbes rather than the patient. For example, some gut bacteria produce an enzyme called beta-glucuronidase. Unfortunately this enzyme interacts with a chemotherapy drug called CPT-11, causing diarrhea that can be so severe some patients must stop taking the medication. In 2010, a team of researchers figured out how to block this enzyme in mice, thus preventing the diarrhea.
The growing understanding of the microbiome will undoubtedly lead to new treatments, but it may also inspire physicians to rethink how they use existing ones. Many widely prescribed antibiotics kill beneficial bugs as well as pathogens. With helpful bacteria out of the way, harmful germs such as C. difficile can move in.
Infection with C. difficile is "the clearest example of a bad outcome of using antibiotics," says Dr. Alex Khoruts, a gastroenterologist at the University of Minnesota. "This infection has essentially assumed epidemic proportions in the last decade."
Physicians may eventually be able to modify the microbiome to prevent the infection from taking hold. Fischbach envisions a future in which patients required to take a long course of antibiotics will also receive a dose of probiotics to replace the microbes wiped out by the pills. The goal would be to "repopulate the community in a way that helps dictate who's there instead of just leaving the coast clear for any actor — good or bad."
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