Searching for a ‘Healthy’ Microbiome
By Ed Yong on Wed, 29 Jan 2014
In 2008, a team of doctors and scientists ventured deep within Venezuelan jungle and collected stool samples from twelve people who, until then, had never met anyone outside their own cultural group.
The villagers were Yanomami—hunter-gatherers who live in the Amazon rainforest on the border between Brazil and Venezuela. Many Yanomami have had lots of contact with other groups since the mid-20th century, and much of it negative. They have been murdered by gold-miners, infected by foreign diseases, and mischaracterized by controversial anthropologists. To protect their way of life, the Venezuelan government set up a large nature reserve around their lands in 1991 and barred access to anyone without military permits. Still, given lingering threats from illegal miners and introduced diseases, the Ministry of Health decided to send a team to deliver medicines and vaccines to 11 of these remote communities. Eight of them had never been contacted before, although they knew about the outside world through fellow Yanomami.
The bacteria that make up our microbiome are shaped by everything from what we eat to what medicines we take, which vary significantly across the globe.
When Maria Gloria Dominguez-Bello heard about the mission, she saw a valuable opportunity. A microbiologist at New York University, she was born in Venezuela and has been working in the Amazon for more than 20 years. She studies the microbiome—the hundreds of trillions of bacteria and other microbes that colonize our bodies and outnumber our own cells by a factor of ten.
Over the last decade, the microbiome has emerged as one of the hottest areas of biomedical research. We know these microscopic partners digest the food we eat and provide us with valuable nutrients. They prevent the growth of harmful microbes and regulate our immune system. They influence our risk of obesity, bowel diseases, and other health problems. They determine how effectively we process the medicines we take.
If we are to truly understand our health, we need to understand our microbes, especially since they are under assault from many foibles of modern life. Fatty, calorific diets dramatically change the communities of microbes in our guts. Antibiotics kill them as readily as they do harmful bugs. Even Caesarean sections can radically change the microbes that first colonize our infant skins.
That is why the Yanomami are so important. They offer a glimpse at microbiomes that lie beyond the influence of mainstream human life. Here, Dominguez-Bello recognized, was a perfect chance to see what these microbes look like in people who have never been in touch with mainstream civilization. “We will never have another opportunity like this,” she says.
In 2007, the U.S. National Institutes of Health launched the Human Microbiome Project (HMP)—an ambitious, five-year initiative designed to characterize our microbial menageries. Among its goals, it would work out what a “healthy” microbiome looks like, how it changes with disease, and whether a core group of species exists in everyone. It would do for the microbiome what the Human Genome Project did for our own genomes.
“Today, we don’t have a single hunter-gatherer microbiome published.”
Five years and $173 million later, the first results were published in 2012. The BBC billed it as the “world’s most extensive map of the microbes that live in and on us.” NPR said, “Finally, a map of all the microbes on your body.” But these were gross generalizations. The HMP was an impressive effort, but it only sequenced the microbes of 242 volunteers, who were almost all white Americans. Around 80% of them came from just two cities—St. Louis and Houston. “The HMP should have been called the Western Microbiome Project,” Dominguez-Bello says.
The same bias applies to microbiome research as a whole. By now, scientists have sequenced the microbiomes of thousands of volunteers, and organizations like American Gut and uBiome offer people the chance to order a home sampling kit and get their own microbes sequenced. But all of these initiatives have “been heavily biased towards urban, affluent, European/American individuals,” saysCecil Lewis, Jr., an anthropologist and microbiologist from the University of Oklahoma. “Today, we don’t have a single hunter-gatherer microbiome published.”
The Matsés, a people indigenous to the Peruvian Amazon, live hunter-gatherer lifestyles. Here, one of their villages is seen from the Galvez River.
This lack of diversity is a recurring leitmotif in many fields of human research. In psychology and other social sciences, the participants in most experiments are college students from so-called WEIRD countries—that is, Western, educated, industrialized, rich, and democratic. Such nations include just 12% of the world’s population, and the behaviour of their students—an even narrower stratum—is distinctly unrepresentative of humanity at large.
Only a handful of studies have looked beyond the West.
Likewise, people of European descent make up 96% of the participants of studies that scan genomes for genetic variants related to disease. This overwhelming bias is a problem because associations that crop up in one ethnic group may not apply to another, and many rare disease-associated variants only occur in specific populations. Writing in Nature in 2011, geneticist Carlos Bustamente warned if this lack of diversity continues, “genomic medicine will largely benefit a privileged few.”
It is understandable that microbiome research has carved the same path. “The developed world has the money, science and technology, so it’s logical that the science of microbiomes was born in the West,” Lewis adds. “It’s also logical that we started studying ourselves.”
Only a handful of studies have looked beyond the West. For example, in 2010, Carlotta De Filippo from the Edmund Mach Foundation, an Italian research institute, showed that children from a village in Burkina Faso have very different communities of gut microbes to kids living in Florence, Italy. Two years later, Tanya Yatsunenko from Washington University in St. Louis found similar resultsby comparing farmers from the Venezuelan Amazon and Malawian villages with U.S. city-dwellers.
Women from the village of Tunapuco, who eat a traditional diet, participated in a microbiome study conducted by a team from University of Oklahoma and Universidad Cientifica del Sur.
These studies showed that, just as WEIRD students present a peculiar view of human behavior, WEIRD microbes paint a distorted portrait of the human microbiome. The bacteria in the African and South American guts were dominated by plant-digesting specialists, which strongly activated genes for breaking down complex sugars and starches. By contrast, the American and European bacteria excelled at digesting the simple sugars found in processed food, and the amino acids from a diet rich in animal protein. Both teams also found that the rural populations had more diverse communities of gut bacteria, while the urbanites were dominated by microbes that are linked to obesity.
It is increasingly clear that the Western lifestyle has left us with a gentrified microbiome—one with shadows of its former diversity and lorded over by different species. No one knows exactly why this is. It may be because our sanitized food, water and living areas deprive us of an influx of new microbes. It may be that we select for species that are better at crowding others out. Either way, Dominguez-Bello says, “We’re now wondering what we’ve lost and whether that’s related to the new epidemics of the modern cosmopolitan world.”
Into the Amazon
To find out, her team are now analyzing the samples they collected from the Yanomami. They are planning on publishing the results soon. For now, Dominguez-Bello says that the Yanomami harbor twice as much microbial diversity in their guts and skins as an American city-dweller. The communities look distinct even from the other rural populations that have been studied, and the dominant bugs include species and strains that are completely undetectable in Western samples.
Bizarrely, some of these strains have antibiotic-resistance genes, although they themselves are sensitive to the drugs. They have the right defenses, but are not using them yet. This fits with other studies which show that bacteria have beenresisting antibiotics long before humans started using them. Even ancient microbes that have been frozen for tens of thousands of years show some resistance to modern drugs. But finding resistance genes among susceptible bacteria inside a human body, is a “major new discovery,” says Dominguez-Bello. “If bacteria don’t show resistance, it doesn’t mean they don’t have the genes. Presumably with exposure to antibiotics, they could quickly become resistant.”
Lewis has been involved in a similar project with the Matsés, an indigenous tribe from the Peruvian Amazon. They are also extremely isolated and still live as hunter-gatherers who eat traditional diets, but they have occasional contact with outside groups. So, unlike Dominguez-Bello’s team, who had to rely on a one-off expedition, Lewis’ team could keep going back to meet the people they were studying.
The Matsés' traditional diet is significantly different from Western diets, and it shapes their microbiome.
Starting in 2010, they spent two years working with the communities before they took a single swab or stool sample. Their priority was education. They taught the villagers about simple interventions like boiling water, dished out anti-parasitic drugs, and acted as liaisons between them and the Peruvian Institute of Health. The community was already familiar with tiny parasites like worms, but Lewis’s team introduced them to a world of even smaller microbes, and beneficial ones at that, by bringing microscopes into the villages. “I think it was very exciting for them to see the microbes with their own eyes,” he says.
Lewis’s goal was to get true informed consent before collecting any samples—to ensure that the villagers knew why these outsiders were interested in their bodies and what they might eventually get out of it. There is good reason to tread carefully. In the 1990s, geneticists from Arizona State University collected blood samples from Havasupai Indians to decipher their high incidence of diabetes. But when the tribe learned that the same samples went towards studies of their ancestry, things got ugly. They argued that the scientists had improperly informed them about what their DNA would be used for. The courts agreed and awarded them $700,000 in damages. Controversies like this can put a chill on research involving indigenous groups, and Lewis was keen to avoid a repeat.
A Matsés man peers into a microscope, studying the microbes that make up his and his fellow villagers’ microbiomes as a part of the Metagenomics and Social Inclusion project.
He was also concerned about hype. In Western circles, there are now frequent claims that microbiome research will lead to new ways of treating important diseases, from diabetes to cancer to mental illnesses. It will take years before such applications become a reality, and even longer for them to filter down to rural and isolated populations. “We wanted to give them some benefits regardless of the downstream results,” Lewis says. “They got infrastructural support too. We weren’t just there to collect samples and leave.”
The team has now analyzed the results, and after getting the green light from the communities they worked with, are about to publish them. As with Dominguez-Bello’s work, Lewis says he has “seen something that’s very different to what we see from the other world populations we’ve seen so far.”
These studies will become ever more important as scientists move from describing microbiomes to actively changing them. If the communities inside us affect our risk of disease, perhaps we can restore them to a healthier state?
This is what probiotics try to do, but there is little evidence that they do much good, or even that the bacteria they contain stick around after being swallowed.Fecal transplants, in which doctors transfer feces from one person’s intestines into another’s, are more effective. Though unsavory, they have been enormously successful at curing stubborn infections of Clostridium difficile—a bacterium that causes severe diarrhea.
We are like conservationists who are trying to restore a forest when they have only ever seen deserts.
Still, such interventions are “shots in the dark,” Lewis says. Fixing a microbiome is not like popping a pill to treat a vitamin deficiency. It is a feat of ecological engineering, an attempt to repair a damaged ecosystem. You cannot do that without knowing what the default “healthy” state looks like: which species were lost, what roles they played, how they interact with one another, or how to bring them back.
Fecal transplants work because the “healthy” state is obvious: a gut without C. difficile. When it comes to chronic diseases that are part of our Western lifestyles, what is the baseline? We do not know, because we have mostly studied Western microbiomes. We are like conservationists who are trying to restore a forest when they have only ever seen deserts.
The only way out is to expand the reach of microbiome research beyond its urban comfort zone and into humanity at its broadest. Scientists like Lewis and Dominguez-Bello are trying to do just that, but they’re on the clock. The march of globalization means that the number of people whose lifestyles are not westernized is shrinking, and their unique reservoirs of microbial diversity are disappearing faster than we can catalogue them. “We are losing something valuable,” says Dominguez-Bello, “and we need it to understand our own health.”