Warning: This story could gross you out.
It is about the microscopic bugs that live all over your body – on your skin, in your mouth, in your nose, and in particular your digestive tract. These bugs are so numerous that they outnumber your own cells by a factor of 10. You are vastly more microbe than human.
Before you get so disgusted you stop reading, consider this: many of these bugs are as essential to your life as your own cells. These microbes have been around since before humans existed, and our bodies have evolved to adapt to their presence just as they have adapted to ours.
They are also – to quote one expert – the “last frontier” of medical research, a crucial aspect of our health that scientists rarely considered until recently. It is also one of the most daunting challenges facing biologists today.
“We know next to nothing about this whole universe that we host,” according to Bruce Birren, co-director of the Genome Sequencing and Analysis Program at the Broad Institute, a research collaborative between Harvard and MIT scientists. “It’s as if we’re coming to a planet for the first time and asking: what do we find?”
What experts like Birren are discovering is the powerful role these tiny bugs might be playing in our lives. The 1,000-or-so species of microbes that live in our guts control digestion, and possibly so much more. They are strongly linked with the rise in allergies and asthma, and with digestive problems like Crohn’s disease and colitis. They also influence the immune system, and there is a growing body of evidence suggesting that gut microbes could have an influence on cancer risk. They could also dictate whether we are packing on extra pounds or liable to get diabetes.
And that is not all. Recent studies have shown that germ-free mice are much more vulnerable to stress. Two strains of mice known for their distinct personalities – one warm and friendly, the other aggressive and standoffish – swapped traits when given each other’s gut microbes. Other studies have altered rats’ response to heart attacks by changing the gut microbes they were fed before the attack. And a group of mice fed a high-protein diet had different gut microbes and better memory skills than mice fed a typical diet.
“We can’t really understand human health without understanding how we interact with all these microbes,” says Birren.
This year sees the culmination of two major projects seeking to better understand the full repertoire of bugs that colonize us – what scientists call the microbiome. In 2007, the United States government launched a five-year, $157 million Human Microbiome Project, aimed at sequencing the genomes of microbial populations living in the mouths, guts, armpits and other orifices of 300 healthy Americans.
The following year the European Commission launched a $29 million project called Metagenomics of the Human Intestinal Tract, or MetaHIT, which focuses on gut bacteria only. Initial findings from both efforts were presented at the International Human Microbiome Congress in Paris last month. “Both have made absolutely tremendous progress,” says Dusko Ehrlich, coordinator of MetaHIT and research director at the National Institute for Agricultural Research in France.
While some researchers are wary of overhyping any results, Ehrlich says he and other scientists are confident in the potential of the human microbiome research – even more so than they were a decade ago when all the talk was about the human genome. “It’s hard to be a prophet,” Ehrlich says, “but we see so much more potential in the human-other-genome than in our own genome.”
He cites two reasons for his optimism: genetic diversity and treatability. One person’s genome differs only 0.1% from another’s; while their gut genomes may differ by 50%. “Since there’s so much variability, there is a much greater chance we’ll be able to associate differences with disease,” he says, adding that it should be easier to treat gut microbes than to make genetic changes. And he is also excited about their potential ability to predict disease. Perhaps someday, changes in someone’s gut bugs could be indicators of impending illness – allowing shifts in diet or medications to restore the microbial balance before it leads to a serious health problem.
But while the data pour in, so begin the debates. One of the main discussions at the recent meeting concerned a study published last year, which suggested that people fall into three categories, or enterotypes as they are known, depending on the dominant group of gut bacteria living there. The idea of having a bug version of blood type that could predict a person’s risk of disease is a compelling one, but follow-up results presented in Paris suggest that the boundaries between types might be fuzzier than first imagined.
Ehrlich says the only way around that problem is to study many thousands of people. “Numbers count,” he says, adding that researchers in Europe, China, the United States and elsewhere need to collaborate to make sure their sample sizes are large enough to reflect meaningful differences in the microbiome. This also means researchers around the world need to develop protocols so they are all studying things the same way and their results are comparable.
Tracking the human microbiome also involves manipulating more data than scientists have ever dealt with before. Until recently, scientists had only been able to culture bacteria that could live in a petri dish; once they figured out how to separate the microbial from the human DNA, they began discovering dozens of new species. But they are collecting billions of bases, or gigabases, of DNA sequence data from complex populations – and figuring out which bits of DNA go together is only one part of the puzzle. How do you infer what those organisms are actually doing? How do they work together as an ecological system? How does this relate to human health – either normal or disease states – and how do you know whether the microbes have caused the condition, or whether they are just responding to the changing environment?
Curtis Huttenhower, assistant professor of Computational Biology and Bioinformatics at the Harvard School of Public Health, says the balance of microbes is more likely to matter than the individual strains. A few bad actors like salmonella will make you sick even in small concentrations, but for the most part, the good bacteria keep the bad in check, says Huttenhower, who studies inflammatory bowel disease. And many of us carry the bacteria Clostridium difficile around inside us all the time, with no ill effect. It is only after a shift in the microbe population – say, after a heavy-duty course of antibiotics that disrupts the balance – that the destructive power of C. difficile can be seen, causing symptoms ranging from diarrhoea to life-threatening inflammation of the colon.
Ruth, a college professor in suburban New York, knows this all too well. The 55-year-old, who asked that she be identified only by her first name, took a course of antibiotics in late 2006 for a bladder infection. A few months later, she needed antibiotics again, this time for a dental procedure – and that is when her problems began. She had terrible diarrhoea, and began losing weight and strength. Most troubling for a woman whose students still gave her credit for being “hot” on an online rating system: her hair started falling out in chunks. By May 2007 she was diagnosed with a C. difficile infection and started taking antibiotics to treat it. More than a full year later, she was still taking antibiotics – in much higher doses – and still getting sick every time she stopped.
She was feeling increasingly desperate when, doing some internet research, she came across the idea of a fecal transplant. In a faecal transplant, the faeces from a healthy person is inserted anally into the colon of another. The idea is that the bugs from the healthy person will restore the microbial balance of the sick one.
Though the concept of a faecal transplant may seem disgusting at first, being infected with C. difficile was far worse, she says. “The indignity of it is profound. You really feel dirty and contagious. You’re just walking around feeling like a freak.” Getting a faecal transplant felt like no big deal after dealing with C. difficile for so long.
Faecal donors, usually a family member or significant other, are screened for infectious diseases such as HIV and syphilis, and for lifestyle patterns that might endanger the recipient, like high-risk sexual activity.
Ruth says she felt different almost immediately after the transplant, done during a colonoscopy, and felt “almost normal” within three weeks. She was able to go off antibiotics at last, and the hopelessness she had felt for months slowly disappeared. Today, her hair has grown back, and she has recovered fully.
Her doctor, Lawrence Brandt, professor and emeritus chief of gastroenterology at Albert Einstein College of Medicine in New York, has been doing faecal transplants since 1990. He says he is struck by how successful, inexpensive, and apparently safe the procedure is – with no major adverse reactions reported. His research, some of it still unpublished, suggests faecal transplants have been 91% effective in several hundred cases worldwide. There has not yet been a gold standard, double-blind, placebo-controlled study of transplants, but there is a growing consensus that faecal transplants are a good idea for people with persistent C. difficile infections.
Someday, he predicts, the procedure will be tested and used against many more ailments, too. And eventually, drug companies will figure out how to bottle the right bacteria, and faecal transplants will not be necessary, he says. “Today, we use stool, because we haven’t yet worked out the precise formulaic combinations of organisms that are deficient in each of the diseases we are talking about.”
Faecal transplants, of course, are not the only way to change gut microbes. As Ruth experienced, antibiotics – particularly repeated courses close together – can alter the balance, as can serious illness and shifts in diet. A gene might leave you more or less vulnerable to a bacterial hit, says Huttenhower. “If you’re predisposed and your microbial community by chance enters a high-risk state, those factors could combine to trigger disease.”
For the most part, the populations you have in early childhood will be with you the rest of your life. Even after microbe populations are disrupted by antibiotics, they tend to return to a baseline, says Graham Rook, emeritus professor of medical microbiology at University College London.
Different events, particularly early in life, can affect that baseline. A study published last year found that babies delivered by C-section had different gut microbes than those delivered vaginally – presumably because they were exposed to different bugs on their path out. MetaHIT’s Ehrlich points to other research suggesting that a baby’s microbe population changes continuously, until around two years of age, so it is not clear whether this early difference – or any microbial change in early childhood – has any long-term health implications.
Researchers believe that the microbes of people who live together can begin to resemble each other. “You’re going to share more with each other than you would compared to someone living in Chicago, but still retain a lot of a history of who you are and where you’ve been,” says Gary Huffnagle, an immunologist and professor of internal medicine at the University of Michigan. “The longer you cohabitate, the theory is, the more you’ll begin to look like each other.”
Then there are the countless probiotic yoghurts and drinks marketed under the claim that consuming their “friendly” microorganisms can be good for your health. A study published last year suggests their effects might be subtle only. Comparing DNA stool samples from one identical twin who ate probiotic yoghurt with one who did not showed little difference in the make-up of their gut bacteria, but studies in mice showed probiotic yoghurt did affect the activity of genes that allow gut bacteria to break down carbohydrates.
Scientists do not know yet whether some people might respond better to probiotics and dietary changes than others. The “big promise of the future”, says Ehrlich, is that simple dietary changes could manipulate the balance of our gut bugs before diseases develop. When that time will come is impossible to predict, he says, but, at least the Human Microbiome Project and MetaHIT scientists are beginning to know which questions to ask.
Until that time comes, the 69-year-old researcher has perhaps an unconventional suggestion for younger people. If he were 18 again, he says he would deep-freeze a stool sample at a biobank, in case he ever needed a faecal transplant. See, I told you this story would gross you out.