MICROBES exist everywhere – in water, air, soil, plants and animals, and from the coldest regions of the Antarctic to the boiling hydrothermal vents at the bottom of the sea. According to microbiologist Brett Finlay, there are far more bacteria on Earth than there are stars in the sky, and despite their microscopic size, the Earth’s microbes weigh more than all plants and animals combined. They also predate all other life on Earth.
If you think you can escape microbes in your own life, think again: the human body contains trillions of bacterial cells – most of which reside in your gut. For every one of your human genes, there are roughly 100 bacterial genes; some estimates are as high as 500.
But researchers around the globe say these bugs aren’t something to be feared. In fact, they are finding striking evidence that these personal ecosystems may help to solve the mystery of the rapid rise of multiple diseases, including asthma and food allergies.
For almost three decades, a growing body of research has linked the sharp increases in asthma and allergy rates to “the hygiene hypothesis” – the idea that our urban living environments have become too sterile and germ-free, leading our immune systems to become misguided and reactive.
Now, in some of the biggest advances the field of allergy medicine has seen, scientists are beginning to zero in on exactly what’s happening – and they’re banking on those teeming, minuscule microbes to lead a health revolution that could prevent, and possibly even cure, allergies and asthma.
Collectively, those microbes are known as the human microbiome. This is a field showing so much promise that in 2016, the U.S. government and private industry announced the National Microbiome Initiative – a half-billion-dollar effort to study the vast microbial systems on Earth, and in the human body.
For Finlay, co-author of the book Let Them Eat Dirt: Saving Your Child from an Oversanitized World, uncovering a major piece of the puzzle began in 2007 with a passing conversation over dinner with his wife. The acclaimed University of British Columbia microbiologist had spent his life studying “bad” gut bacteria such as E.coli and salmonella.
As an experiment, his team began feeding antibiotics to mice to find out which microbes were affected. At dinner his wife, who is a pediatric infectious disease specialist, pointed out that children who get antibiotics in the first year of life have higher rates of asthma.
“I thought that was a bit strange, because asthma is a lung disease and we were talking about gut microbes,” he recalls with a laugh. “What do antibiotics have to do with anything?” Still, Finlay checked the research, and found several studies that linked antibiotics and asthma.
Intrigued, he set up an experiment: feed different antibiotics that only act in the gut to germ-free mice, and find out if their asthma rates are affected. With some of the antibiotics, the effect was drastic. “We saw a profound asthmatic reaction,” says Finlay, sitting in his office on the UBC campus. “It was just off the charts. It was really surprising, because we hadn’t done anything other than treat these mice with antibiotics.”
As part of the study, stool samples were collected from kids at birth, three months of age and one year. As the kids grew and some began to develop asthma, the researchers looked back to those frozen early stool samples to see if there was something different in the microbial makeup. Sure enough there was and it came down to four bacteria: Faecalibacterium, Lachnospira, Veillonella and Rothia, which the scientists dubbed “FLVR” (pronounced “flavor”).
“Basically, at three months of age, if you had these four microbes, you had a very low risk of asthma,” explains Finlay. “If you had lower levels of these four microbes, you were in the high-risk group.” The team then took the research a step further, and orally administered those microbes into “germ-free” mice – that is, mice that have no microbes. Mice that received the FLVR microbes had markedly lower levels of lung inflammation and signs of asthma than those that did not.
“We were able to show that if we deliberately gave back the FLVR bacteria, we could protect baby mice from asthma, proving that these bacteria had some functional and protective role,” says Turvey.
“It opens the door for a way to maybe prevent asthma. That’s the Holy Grail,” explains Turvey, while acknowledging this quest still requires a lot of work. “The vision might be for safe versions of the FLVR bacteria that could be given to children early in life to help establish the right microbiome bacterial community, which would help protect them from developing asthma. That’s a huge paradigm change.”
Early Life Opportunity
When it comes to allergy and asthma, researchers believe that most of the protections are conferred very early in life – even in the womb – and that the beneficial microbes actively help to “train” our immune systems.
“Without the appropriate training, our immune systems get confused, and that’s one of the factors that underlie the development of asthma and allergies,” says Turvey. “When our immune system develops, it can attack anything. That’s good. But it can also attack us, and that’s bad. So that education process helps it to know what’s the good stuff and what’s the bad stuff – and the gut microbiome seems to be really important for that training.”
Finlay says a person’s microbial makeup is mostly set in the first 100 days of life, before babies begin eating solid food. While later exposures to antibiotics, interaction with animals and diet can have a significant impact, those first three months are critical.
As a result, the most effective microbe-related treatments for allergies and asthma are likely going to be preventive – and introduced early.
“If you get antibiotics in the first year of life, you have a 20 percent higher rate of asthma,” he says. “If you were born by caesarean section instead of vaginal delivery, you have a 20 percent higher rate of asthma. If you live on a farm you have a 20 percent lower chance of asthma. If you were breast-fed instead of bottle-fed, it’s 20 percent less,” Finlay continues, noting that the percentages don’t necessarily add up, as there are other factors at play. “But there are enough smoking guns to indicate that these bugs are playing a real role.”
A 2016 study out of the University of California San Francisco and Michigan’s Henry Ford Health System adds to the body of evidence. The researchers found that babies who were lacking particular gut microbes at one month old were three times more likely to develop allergic reactions by age 2, and asthma by age 4. Those missing microbes are thought to play a key role in curbing the body’s inflammatory response.
One of the greatest impacts on the human microbiome has been the proliferation of antibiotics. A recent study of 65,000 American children showed that more than 69 percent received antibiotics by the age of 2, and that those children averaged 11 courses of antibiotics by the age of 5. But it’s not just the medications you get from the doctor that interrupt our intricate systems.
The widespread use of antibiotics in the livestock industry means that people are likely getting low-level doses of antibiotics from consuming many meats, cheeses, milk and other animal products. Antibacterial soaps and antimicrobial products commonly found in everything from cleaning products to hand sanitizers also deplete our stores of beneficial bugs.
Dr. Martin Blaser, director of the Human Microbiome Program at New York University and author of Missing Microbes: How the Overuse of Antibiotics is Fueling Our Modern Plagues, stresses that our society’s love of antibiotics is taking a serious toll. “The loss of microbial diversity on and within our bodies is exacting a terrible price,” he writes.
“Just as the internal combustion engine, the splitting of the atom, and pesticides all have had unanticipated effects, so too does the abuse of antibiotics and other medical or quasi-medical practices (e.g. hand sanitizer use). An even worse scenario is headed our way if we don’t change our behavior,” Blaser warns. “It is one so bleak, like a blizzard roaring over a frozen landscape, that I call it ‘antibiotic winter.’”
To make matters worse, the Western diet, filled with highly refined and sugary foods, is killing off essential microbes that rely on fiber-rich diets to thrive. In one U.S. study, published in the journal Nature, two groups of patients were put on either a meat-based diet or a plant-based regimen that was rich in fruits, vegetables and grains.
In only five days, researchers noticed a marked difference between the gut microbe populations of each group, with the plant group having the healthier microbiomes. In a 2014 study, meantime, Swiss researchers fed mice a high-fiber diet, which fundamentally changed their gut microbes, and found that they produced short-chain fatty acids, which in turn protected their airways against allergic sensitization.
Then there are our urban living environments, where air, humidity, temperature and light are all carefully controlled, and our microbial exposures are significantly limited – especially when compared with previous generations.
“The more traditional medical view – that bacteria are the enemy and we need to hunt them down, name them and kill them with antibiotics – is changing,” says Turvey, who emphasizes that antibiotics remain essential tools when used sparingly and appropriately.
The new research and growing awareness of the human microbiome “means we need to change our relationship with bacteria, realize we’ve co-evolved with them and that they’re really important for our health – and be very thoughtful about things like antibiotics,” he says. “So I think the message is: cherish your bacteria.”
The Baby Boost
Thanks to new microbiome research, obstetric specialists are also beginning to cherish bacteria in the birthing process. It’s long been understood that babies born by C-section are more likely to develop allergic disease and asthma. But now scientists believe they know why: expectant mothers’ vaginal fluids are packed with protective bacteria – and when babies are delivered vaginally, they receive a hefty dose of helpful microbes. Those same microbes then help to fuel the mother’s breast milk.
Those born through the birth canal had vaginal bacteria in their systems, she noted, but infants born by cesarean were lacking those bacteria. (Interestingly, the C-section babies were shown to have skin bacteria, both from the mother and from hospital cleaners and medical staff.)
So Dominguez-Bello decided to test a theory: if the highly specific bacteria in the vagina at the time of delivery gives a newborn a head start, would swabbing a cesarean-born baby with vaginal fluids offer that same big immune advantage? She began with a small pilot study in Puerto Rico involving 18 babies – seven born vaginally and 11 born by cesarean, four of whom received the vaginal fluids in their mouths and on their skin.
The results were groundbreaking: the babies born by C-section who received the swabbing (or “seeding”) had a microbial makeup similar to that of the babies born vaginally.
“It’s almost common sense: If you expose a newborn to vaginal bacteria, the newborn picks up vaginal bacteria. But it’s beautiful to see it,” says Dominquez-Bello. Exactly what roles the various bacteria play is yet to be determined, but the differences in the microbial makeup of babies born vaginally and those born by C-section is so significant that, beyond the age of one month, a researcher can look at a mouth, skin or fecal sample of the child and identify how he or she was born.
The bacteria also play a key role in boosting breast milk. “The composition of the vaginal microbiome of the mothers, and the fact that all mammals drink milk after being born, are not random, separated events,” she says.“Maternal milk is an amazing, complex substance that is full of compounds that will not only nourish the baby, they will nourish the bacteria. And I find that fascinating.”
Dominguez-Bello is now working on expanded studies to measure the health consequences of “seeding” and whether or not it protects against diseases associated with C-section and early antibiotic exposure, such as obesity and diabetes. Still, much more research needs to be done. In the meantime, she’s regularly fielding calls and emails from patients, doctors and other medical practitioners who are interested in trying the seeding technique.
However, she emphasizes that people should not attempt the procedure without first consulting with their doctor. “This is not a standard practice. And moms that do it alone could be putting the baby at risk because they don’t know if they have infections,” she says. “So definitely go to your doctor.”
Our modern environments are too clean and hygienic, argues the hypothesis, and because we aren’t being exposed to as many infectious agents, our immune systems aren’t being properly trained.
But until very recently technological limitations meant that pinpointing which specific microbes were playing a part was akin to looking for needles in an impossibly enormous haystack.
Fortunately, new DNA sequencing technology – which von Mutius argues is as significant as the invention of the microscope – has changed the game.
Ironically, she and her team are now using those new-world technologies to unravel a microbiome mystery on old-world farms: why children raised in some farm environments have a dramatically lower rate of allergies and asthma.
According to the researcher, who is head of the asthma and allergy division at the Munich University Children’s Hospital, the rate of positive allergy tests among non-farming Swiss children is 44 percent. (The tests show a child is “atopic” – or has the predisposition to become allergic.) Yet in Amish children who grow up on farms in the same region, the rate is roughly 8 percent. “These are enormous, enormous differences – and hay fever is almost nonexistent,” she says of the Amish communities.
The big distinction? The Amish, who don’t use industrialized farming techniques, interact closely with the animals. Von Mutius believes it’s the microbes found in animal barns – particularly in cowsheds but also among poultry and pigs – that likely confer that asthma protection to humans. What’s more, when the researchers took extracts from cowshed dust and put them into mice, they found they could prevent allergic asthma altogether.
“I’ve always been struck by the strength of the effect and by the consistency of the effect. There are more than 40 studies that all show the same thing – that the risk of allergies is halved by these exposures,” says von Mutius, who adds that mothers who are exposed to cowsheds during pregnancy seem to pass the protection along to their babies.
“We know that in some areas of the world, asthma and allergies are almost non-existent, and that’s because of environmental exposures. So if we are able to understand what’s going on, it could have a huge impact.”
On The Home Front
Of course, not everyone can run out and buy a farm; and studies show that occasional visits do not offer the same protective effect – but people may be able to bring beneficial microbes into their own homes, with the help of man’s best friend.
Susan Lynch is an associate professor in the department of medicine at the University of California, San Francisco, and she says that because people in the West spend the majority of their time indoors, they are not being introduced to nearly the same diversity of microbes as their grandparents and great grandparents.
“At birth, children exhibit a low level of bacterial diversity, which increases rapidly over the first year of life,” says Lynch. In their work, she and her research colleagues asked: Where is the source of that diversity? “In Western countries we spend almost 90 percent of our time indoors. So we looked at how the source of the microbes that populate the gut microbiome as it develops could come from the built environment, from the home.”
Some of it also comes with the family pet. Studies have shown that kids who grow up in homes with dogs, and to a lesser extent cats, have a lower chance of experiencing allergies and asthma – and now microbiome science is digging up the reason why.
In one study, Lynch and her team collected house dust samples from homes with and without pets and, not surprisingly, found that homes with pets had greater microbial diversity. They set up an experiment in which they took dust from homes with or without pets and fed them to adult mice. (As a control group, they also examined mice that did not receive any dust.)
The mice that received the doggy house dust didn’t react to allergens. “It was like their immune systems never even ‘saw’ the allergens. There was no pathology at all,” says Lynch, who then looked at the gut microbiome of the same mice, and found their makeup was decidedly different than those that did not receive the dust.
“It was very restructured, and enriched with many of the organisms that we associate with protection and health in humans. And conversely, those that were not protected from the allergens were lacking those organisms.”
Food Allergy Factors
To date, much of the microbiome field has centered around asthma, but the groundbreaking science is also helping to explain the dramatic spike in food allergies – and the study results are astounding.
When Cathryn Nagler was growing up, she and her brothers ate peanut butter and jelly almost every day. But by the time her own kids got to elementary school, allergies were so prevalent that peanut-free classrooms had become the norm. Today, as a professor of pathology, medicine and pediatrics at the University of Chicago, Nagler has become a leading researcher in the microbiome field.
She says emerging evidence shows that widespread antibiotic use, high fat and low-fiber diets, reduced exposure to parasites and infectious diseases, cesarean birth and formula feeding are just a few of the modern interventions that have drastically altered the composition of our gut microbes. Those interventions have likely given rise to skyrocketing food allergy rates, which now affect more than 15 million people in the United States, and land Americans in the hospital, on average, every three minutes.
“How do we account for this kind of change in just a generation? That’s the question that we’re trying to tackle. Our hypothesis is that it’s due to changes in the microbiota,” says Nagler. Antibiotics are by far the greatest offenders, she explains, but our food choices have also changed the diets of our bacteria.
“We’ve co-evolved with our microbiota over millennia, and our ancestors were not consuming McDonald’s. So our diet has changed, and our bacteria eat what we eat – and altering their food source has changed them, seemingly for the worse,” Nagler says. These lifestyle shifts have in turn changed the way microbes protect people from food allergies.
Nagler and her team looked at the DNA of thousands of intestinal microbes, and zeroed in on one bacterial family called Clostridia, some of whose members regulate the lining of the digestive tract. In doing so, they increase the production of mucus and natural antibiotics that protect the lining, and keep food molecules from breaking free of the gut and circulating through the body – and potentially leading to allergic reactions.
In one study, Nagler showed that when germ-free mice received Clostridia, they could avoid being sensitized to peanuts, likely because the peanut molecules could not easily pass through the intestinal barrier.
Nagler then teamed up with a colleague in Italy who was working on a study involving infants suspected of having cow’s milk allergy. The infants who were fed formula with the cow’s milk protein casein, supplemented with the probiotic Lactobacillus GG, were able to tolerate milk better than those who were given the formula alone. When the researchers looked at the microbiota in the babies’ stool, they found the bacteria in the healthy and the allergic children to be dramatically different.
But what came next is what Nagler calls “the coolest part of the story.” To test the theory that these bugs were giving kids a big immune boost, the team took two groups of germ-free mice. One group was colonized with feces from the allergic kids, and the other got feces from the non-allergic kids. Then they sensitized all of the mice to cow’s milk allergen.
“We found that the mice that received the bacteria from healthy infants are perfectly fine. The mice that received the bacteria from the allergic infants die of anaphylaxis,” says Nagler. She hopes the discoveries will one day lead to the prevention of food allergies, and possibly even the treatment of established allergies, with probiotics or medications. “It’s the most dramatic model we’ve ever had.”
Putting the “Pro” in Probiotics
So if we know which “good” microbes lead to fewer allergies and asthma, we can just put them into a probiotic culture and sell them in products like yogurt, right?
Not yet. While scientists have begun to isolate the microbes associated with particular functions, the bacteria do not act independently. In fact, our gut microbes are like vast civilizations, with millions of different organisms performing different tasks, many of them relying on each other, and their very specific environments, to function. Remove them from their microscopic worlds, and it’s a whole different ball game.
What’s more, much of the money people spend buying many of today’s probiotic products goes right down the toilet. “These are not bacteria that are designed to be normal inhabitants of the gut, and they’re not adhering,” says UBC’s Finlay. “That’s why you have to take so many a day, every day. If they stuck, you would only have to take them once and you would be finished. So you’re just flushing through these huge quantities of bacteria in these products – and they’re not really forming part of the microbial ecosystem,” he says, explaining why they’re not embraced as a medical treatment.
For now, researchers are proceeding with a mix of excitement and extreme caution because they are working with live bacteria, which is relatively uncharted territory, and eventually they will need to test products on newborn babies. “We have a long history of making pills and feeling comfortable with that. But turning live bacteria into helpful medicines is a different paradigm,” says Turvey.
He explains that any treatments will first be tested on adults before they move down the age range to kids and eventually infants. Researchers also hope they will be able to isolate the components of the microbes that offer protection, then adapt them into medications. This would allow the scientists to avoid administering the less predictable live bacteria.
In the meantime, because there is so much buzz about the microbiome, do-it-yourself treatments from probiotics to fecal transplants have begun cropping up on the internet. But Finlay and Turvey strongly caution consumers away from buying into the hype. “Just because they’re live natural bacteria, it doesn’t necessarily mean they’re safe, and it doesn’t necessarily mean they help,” says Turvey. Rigorous clinical trials are the only way to find out what works, and what is safe.
But microbiome pioneers including Finlay and Nagler imagine that, even within as few as five years, a new generation of probiotics – ones that likely contain a range of allergy-fighting microbes – could arrive on the market and be given to patients who are lacking those particular bugs.
In theory, treatments could even be tailored to the microbial needs of individual children. Others are focused on therapeutic drug development, which comes with more regulatory hurdles, and will take longer to hit the market. But already, pharmaceutical giants are injecting millions of dollars into research; and the hope is that one day, children can be screened, and those missing the necessary microbes would receive replacement therapy or some form of supplementation of beneficial bacteria.
With that aim in mind, scientists are pushing to get human clinical trials up and running as soon as possible, and are hopeful they can find a way to prevent, and possibly even cure, asthma and allergies – which could be life-changing for millions of people around the globe.
“It’s not hard to imagine a day when we can identify the high-risk kids, then reconstitute them with the bugs they’re missing so they won’t go on to get asthma; or when a kid has a serious infection and has to have antibiotics, we can use probiotics to put them back on track,” says Finlay. “We’ve already seen some amazing strides forward, and it’s opening a whole new avenue of medicine and ways to go,” he enthuses. “And I’m very optimistic.”