WILL the cure for allergies come from the cowshed?
Allergies are often seen as an accident. Your immune system misinterprets a harmless protein like dust or peanuts as a threat, and when you encounter it, you pay the price with sneezing,wheezing, and in the worst cases, death.
What prompts some immune systems to err like this, while others never do? Some of the vulnerability is surely genetic. But comparative studies highlight the importance of environment, beginning, it seems, in the womb. Microbes are one intriguing protective factor. Certain ones seem to stimulate a mother’s immune system during pregnancy, preventing allergic disease in children.
By emulating this naturally occurring phenomenon, scientists may one day devise a way to prevent allergies.
This task, though still in its infancy, has some urgency. Depending on the study and population, the prevalence of allergic disease and asthma increased between two- and threefold in the late 20th century, a mysterious trend often called the “allergy epidemic.”
These days, one in five American children have a respiratory allergy like hay fever, and nearly one in 10 have asthma.
Nine people die daily from asthma attacks. While the increase in respiratory allergies shows some signs of leveling off, the prevalence of food and skin allergies continues to rise. Five percent of children are allergic to peanuts, milk and other foods, half again as many as 15 years ago. And each new generation seems to have more severe, potentially life-threatening allergic reactions than the last.
Some time ago, I visited a place where seemingly protective microbes occurred spontaneously. It wasn’t a spotless laboratory in some university somewhere. It was a manure-spattered cowshed in Indiana’s Amish country.
My guide was Mark Holbreich, an allergist in Indianapolis. He’d recently discovered that the Amish people who lived in the northern part of the state were remarkably free of allergies and asthma.
About half of Americans have evidence of allergic sensitization, which increases the risk of allergic disease. But judging from skin-prick tests, just 7.2 percent of the 138 Amish children who Dr. Holbreich tested were sensitized to tree pollens and other allergens. That yawning difference positions the Indiana Amish among the least allergic populations ever described in the developed world.
This invulnerability isn’t likely to be genetic. The Amish originally came to the United States from the German-speaking part of Switzerland, and these days Swiss children, a genetically similar population, are about as allergic as Americans.
Ninety-two percent of the Amish children Dr. Holbreich tested either lived on farms or visited one frequently. Farming, Dr. Holbreich thinks, is the Amish secret. This idea has some history. Since the late 1990s, European scientists have investigated what they call the “farm effect.”
The working hypothesis is that innocuous cowshed microbes, plant material and raw milk protect farming children by favorably stimulating their immune systems throughout life, particularly early on. That spring morning, Dr. Holbreich gave me a tour of the bonanza of immune stimuli under consideration.
We found our hosts, Andrew Mast and his wife, Laura, hard at work milking cows in the predawn chill.
Dr. Holbreich, slight and bespectacled, peppered them with questions. At what age did Mr. Mast begin working in the cowshed? “My first memory is of milking,” he said, at about the age of 5. What about his children, two straw-haired girls, then ages 2 and 3; did they spend time in the cowshed? The elder girl came to the barn at 3 months of age, he said. “People learn to walk in here.” Do expectant mothers work in the barn? “Yes,” Laura said. “We work.”
Dr. Holbreich had made his point: whatever forces were acting here, they were chronic, and they began before birth. As the sun rose, Dr. Holbreich and I sniffed the damp, fermented feed (slightly malty); shoveled fresh cow manure (“Liquid gold,” Dr. Holbreich said only half-jokingly, “the best medicine you could think of”); and marveled at the detritus floating in the air. Extrapolating from previous research, with each breath we were inhaling perhaps 1,000 times more microbes than usual. By breakfast time, grime had collected under our nails, hay clung to our clothes, and muck to our boots. “There’s got to be bacteria, mold and plant material,” Dr. Holbreich said. “You do this every day for 30 years, 365 days a year, you can see there are so many exposures.”
The challenge of identifying the important exposures — and getting them into a bottle — is a pressing one. In parts of the developing world, where allergic disease was once considered rare, scientists have noted an uptick, especially in urban areas. China offers a dramatic case in point. A 2009 study found a more than threefold difference in allergic sensitization (as judged by skin-prick tests) between schoolchildren in rural areas around Beijing and children in the city proper. Doctor-diagnosed asthma differed sixfold. Maybe not coincidentally, 40 percent of the rural children had lived on farms their whole lives.
Immigrants from the developing world to the developed tend to be less allergic than average. But the longer they reside in their adopted countries, the more allergic they become. And their native-born children seem to gain the vulnerability to asthma, sometimes surpassing it. All of which highlights a longstanding question in the allergy field. As Dr. Holbreich puts it, “What is it about westernization that makes people allergic?”
When hay fever first emerged as a common complaint among the upper classes of Britain in the 19th century — and became a badge of refinement — farmers, who were exposed to more pollen than probably anyone else, seemed relatively invulnerable to the new affliction. In the 1990s, European scientists rediscovered the phenomenon in the small alpine farms of Switzerland. A bevy of studies followed, comprising thousands of subjects across Switzerland, Germany, Austria and elsewhere. Critically, by comparing children living in the same rural areas, scientists could discount urban pollution. Everyone was breathing the same country air.
And earlier this year, some of Dr. Holbreich’s collaborators, from the University of Basel in Switzerland, made a strong case that physical activity couldn’t explain the disparity either. They had rural children wear devices that measured movement for a week. There was little difference in physical activity between farming and nonfarming children.
What matters then? Erika von Mutius, a doctor and epidemiologist at Munich University in Germany who has led much of this research, suspects diversity is important. Farms with the greatest array of microbes, including fungi, appear to be the most protective against asthma. At the Mast farm, the cowshed wasn’t more than 60 feet from the house. In Europe, scientists found that microbes waft from cowsheds into homes.
In one study, they showed that an infant’s risk of eczema was inverse to the microbial load in her mother’s mattress.
Timing seems to matter tremendously. The earlier exposure begins, it seems, the greater the protection — and that includes during pregnancy. Children born to mothers who work with livestock while pregnant, and who lug their newborns along during chores, seem the most invulnerable to allergic disease later.
Here, the farm effect dovetails with the burgeoning science on the prenatal origins of disease generally. What happens to your mother during the nine months before your birth may affect your vulnerability to many diseases decades later, from heart disease and obesity to schizophrenia.
Allergies and asthma seem to follow the rule as well.
Susan Prescott, a doctor and researcher at the University of Western Australia in Perth,has noted differences in the placentas of children who later develop allergies. A critical subset of white blood cells — called regulatory T-cells — seems relatively scarce at birth. Rather than enabling aggression, these cells help the immune system restrain itself when facing substances that are not true threats. A healthy population of these and other “suppressor” cells is important, scientists now suspect, in preventing allergies and asthma. So it seems significant that European farming children are born with a comparative surfeit of these cells. Bianca Schaub, a doctor and researcher at Munich University, has found that farming newborns have more regulatory T-cells in cord blood than babies of nonfarmers. In test tubes, these cells more effectively quash allergic-type reactions. And that suppressive ability increases with the number of different types of animals the mother tended while pregnant. The more cows, pigs and chickens a mother encounters, essentially, the more easily her offspring may tolerate dust mites and tree pollens.
Animal studies demonstrate how this might work. Some years back, scientists at Philipps University of Marburg in Germany sprayed pregnant mice with microbes originally isolated from Bavarian cowsheds. The exposure induced favorable changes in gene expression at the placenta. The pups born to these mice were protected against asthma.
This research suggests that farming mothers might benefit from a naturally occurring immunotherapy, one that preprograms the developing fetus against allergic disease. Yet how to apply that therapy deliberately remains unclear. Is “microbial pressure” what matters — a stiff microbial wind in our sails? Or do certain cowshed microbes actually colonize farmers, and favorably calibrate their immune function?
There’s evidence to support both explanations, which aren’t mutually exclusive anyway.
Before you rush to the nearest farm, however, a word of caution. Some studies indicate that if you grow up in an urban environment, occasional visits to the farm may exacerbate allergic propensities. If you haven’t matured with abundant microbial stimulation, the thinking goes, encountering it intermittently may push you into overdrive, prompting the misery you seek to avoid.
And yet, a prospective study from Denmark published this month suggests that it’s never too late. Young adults who began farming (with livestock) were less likely to develop new allergic sensitivities than rural peers who chose other professions. Existing allergies didn’t disappear. Rather, the farming environment seemed to prevent new sensitizations.
Which brings us to farm milk. In Europe, the consumption of unpasteurized milk has repeatedly correlated with protection against allergic disease. In America, 80 percent of the Amish studied by Dr. Holbreich consume raw milk. In a study published earlier this year, Dr. Schaub’s group showed that European children who consumed farm milk had more of those regulatory T-cells, irrespective of whether they lived on farms. The higher the quantity of those cells, the less likely these children were to be given diagnoses of asthma. Here, finally, is something concrete to take off the farm.
None of these scientists recommend that people consume raw milk; it can carry deadly pathogens. Rather, they hope to identify what’s protective in the milk and either extract it or preserve the ingredients during processing. Microbes may not be the key ingredient in this case. Instead, farm milk may act as a prebiotic — selectively feeding good microbes within. Another possibility is that as with human breast milk, antibodies and immune-signaling proteins in cow’s milk influence the human immune system, steering it toward tolerance.
As a whole, this research reframes the question of what prompted the late 20th-century allergy epidemic. Is the problem one of exposure to allergens, many of which aren’t exactly new to human experience? Or is the problem one of increasing sensitivity to whatever allergens are present?
The science suggests the latter. The Mast cowshed, with its rich array of microbial stimuli, probably resembles the world in which the human immune system evolved more than, say, an apartment high above Manhattan. The Amish in Indiana, who for reasons of religious faith have maintained a 19th-century-like lifestyle, may not be less allergic. Rather, during the dramatic reordering of human existence that began with the Industrial Revolution, everyone else may have become more allergic. Immunologically speaking, the farming Amish and farmers generally may more closely resemble an evolutionary norm for our species.