Findings from the Gut—New Insights into the Human Microbiome
People who like milk chocolate have slightly different microbes in their intestines than those who prefer their chocolate dark, although researchers do not know why. Significant differences in the so-called microbiome are also found in individuals based on whether or not they eat a lot of fiber or take certain medications—such as the diabetes drug metformin, female hormones or antihistamines.
But all these variations account for only a small fraction of the microbial diversity seen in the guts of northern Europeans, according to new research published today in a special section of Science. Of the half-dozen microbiome articles in the journal, two studies stand out as being among the largest ever conducted on the gut microbes that inhabit healthy people’s large intestines and help with digestion and various immune processes—among other things.
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In one, researchers identified 14 different microbial genera that form the core microbiomes of nearly 4,000 people—mainly from northern Europe. This list provides unprecedented insights into the basics of microbial inheritance and evolution, says researcher Martin Blaser, director of the Human Microbiome Program at New York University, who was not involved in either study. “These are fundamental characteristics of us humans,” he says.
Jeroen Raes, senior author of the first paper and a contributing author on the second, says he had hoped that the study would be large enough to offer definitive answers to some key questions, particularly how investigators might manipulate the microbiome to promote greater human health. “I thought I would know the answer by now,” says Raes, who eats lots of fiber and—true to Belgian custom—loves chocolate and beer. But he does not take probiotics, microorganisms that are believed to add to or restore a healthy bacterial balance. Nor does he really know what to make of the fact that so many medications appear to affect the makeup of intestinal bacteria. “It’s one of those ‘hmm, interesting,’ moments,” he says, adding that, nonetheless, he thinks variations in the microbiome will eventually be shown to influence the effectiveness of certain drugs as well as the side effects that they can cause. His research, he says, highlights the complexity of the system as well as likely flaws in earlier research.
The Belgian study, for instance, failed to find a benefit for participants who had been nursed or delivered through the birth canal, compared with those who had been fed formula in bottles or brought into the world via Caesarean sections. Previous experiments looking at newborns had, in fact, found a difference. (Healthy germs from moms are thought to coat their babies who are born vaginally, helping the infants establish a robust bacterial baseline. Some studies suggest that babies delivered by C-section are at higher risk for asthma and allergies—possibly because they lack this early protection.)
Raes, a microbiologist at the University of Leuven and the Flanders Institute of Biotechnology (VIB) in Flanders, Belgium, says he does not think the other studies are wrong but that these early-life advantages may wane with age. Most of the people in his study were in their 40s and 50s, he notes, and thus any early advantages they may have originally enjoyed were now likely to have been wiped out by medications they took, the germophobic approach to life in wealthy Western nations and/or other life events.
More concerning, according to Raes, are some of the characteristics that he and his colleagues found that greatly influence the composition of the microbiome and that have been ignored in previous work. Case in point: the time it takes for someone to digest food, also known as “transit time”. Variations in transit time of as much as a day or so can significantly alter the environment in which the intestinal microbes live. Thus, different transit times may influence which species survive by, for example, limiting how long a bacterium can grow in the gastrointestinal system.
Prior studies looking at Parkinson’s disease, for instance, found a particular microbial signature that investigators have suggested may be used to diagnose the condition in people who are in the early stages of the illness. Given his findings on transit time, however, Raes suggests that it is just as likely that the patients’ microbes changed not because of their Parkinson’s but because of the severe constipation that often accompanies the condition. And so, any diagnostic test based on this particular microbial shift might falsely suggest that anyone who has not been to the bathroom in awhile could be at risk for Parkinson’s. Such cautions are reminders, Raes says, that research into the microbiome is still in its early days and is easily hyped. “Our field is coming into this consolidation phase,” he says. “We can fulfill the promise of the microbiome by doing proper studies.”
Emeran Mayer, a gastroenterologist and gut microbiome researcher at the David Geffen School of Medicine at the University of California, Los Angeles, says he now wants to go back to look at his own research—which suggests there are two types of irritable bowel disease with different microbial signatures—to see if taking transit time into account changes his results. The new findings in the Science study convinced him that all such studies should consider transit time. “Unless transit time is accounted for, which so far has not been done, what you may be seeing is not a correlation with disease process,” says Mayer, whose book The Mind–Gut Connection: How the Hidden Conversation within Our Bodies Impacts Our Mood, Our Choices and Our Overall Health, is due out in July.
The latest research also suggests that most previous microbiome studies were too small. Although Raes and his team looked at more than 1,100 Belgians and compared their results with a similar number of Dutch people, along with previously published studies of other Westerners, they were only able to describe about 7 percent of the microbial variation among individuals. To account for the rest would require a sample size of more than 40,000 people, the researchers estimated—and that is just for groups found in developed, Western economies. Charting normal variation in the microbiomes of people living on farms in rural areas of India or China would presumably require an equivalent sample size.
In the second Science study, which focused on residents of the Netherlands, researchers could explain just 19 percent of the microbial variation among individuals—suggesting there are many influences that have not yet been recognized. Both new studies confirmed that antibiotics have powerful effects on the adult microbiome. Similarly, a large study also out today in Cell found the same in young children.
In an accompanying essay in Science, Blaser argues that clinicians need a new approach to prescribing antibiotics in early childhood. Particularly in the first three years children should probably be prescribed good bacteria along with their antibiotics to restore a healthy microbiome, he says, although we do not yet know which bacteria will be best. Storing children’s pre-antibiotic microbes and then giving them back after antibiotic treatment might also make sense, although this has not been studied, says Blaser, author of Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues. And he called for the development of new, more targeted antibiotics that selectively kill the bad bacteria, rather than also taking out the good. “My concern is that the antibiotics children take affect how their microbiomes will develop and how they will develop immunologically,” Blaser says.
Many activities of modern life, including our obsession with getting rid of germs, deprive us of the microbial diversity that seems to promote long-term health, he says. Low microbial diversity has been associated with several autoimmune disorders, for example, including inflammatory bowel disease, a condition that arises when the body’s own defenses attack the lining of the intestine, and type 1 diabetes, which occurs when the body targets certain cells in the pancreas that produce the insulin hormone.
Genetics also plays a role in the microbiome, although much about the relationship remains to be unraveled. In a review in Science, Ruth Ley, a molecular biologist at Cornell University, examines three recent genetic microbiome studies: a large twin study; a genome-wide association study; and an examination of 200 Hutterites, members of a religious community similar to the Amish. So far, she says, the research does not yet make clear whether genes directly affect people’s microbial populations or whether someone’s microbes are driven by their food preferences, which are known to be genetically linked.
Still, scientists are making some progress in learning how to manipulate the microbiome, says Tommi Vatanen, a graduate student researcher at both the Broad Institute in the U.S. and Aalto University in Finland. “There are very small puzzle pieces that we are starting to understand—maybe the corner pieces of the big puzzle,” says Vatanen, who was a co-author on the Dutch study. If he had small children today, he says, he would give them probiotics with Bifidobacterium, a common component of a healthy microbiome, and get them a dog—which apart from being a great companion also has a microbiome that, studies suggest, may help protect toddlers under a year old against developing certain illnesses later in life.
Ley says she’s not ready to encourage people to take certain probiotics or supplements. But she does avoid antibiotics whenever possible. And she eats yogurt as well as the Korean cabbage dish, kimchi—both of which are known to contain a variety of healthy bacteria.