I have a piece in the NYT Sunday Review on the observation that children who grow up on farms, and who drink raw milk, often seem to have a lower prevalence of asthma and allergic disease than their nonfarming peers. This is usually called the “farm effect.” Enough people have heard of it by now that I think it’s been embedded in a vague way in our collective (un)conscious(ness).
The reason I wrote this piece, though, is that while many like chanting “eat dirt,” most don’t realize that the magic of the Farm Effect begins prenatally. The search for the origins of disease is going prenatal these days generally, by the way. Huge determinant of health, it seems. Huge area of scientific inquiry.
I’m sad I never got to meet or interview the originator of the idea, David Barker, who died earlier this year. Kudos to him, though, for advancing this important theory.
So: a number of caveats, nuances, interesting factoids, additional evidence and other things there’s never room for.
About those Amish
First, I know some will wonder: Don’t the Amish live in a completely old-school natural way verging on — well, if not paleo, at least neolithical?
In some ways, yes. But in many important ways, no.
Visiting the Amish country was quite an experience. Really something. Fodder for another piece another time. But mostly, I’ll point out that while every Amish community is different, these Indiana Amish take antibiotics, get vaccinated, go to the hospital. Along with their desire to NOT modernize, they’re also pragmatic. They generally avail themselves of modern medicine if need be. So a total avoidance of modern medicine isn’t what’s protecting them.
What about diet? I had dinner with the Masts. Delicious. But the meal would have sent your average cardiologist into a cold sweat. This was old style country food – full of refined carbs, gravy, sugar, butter and meat. Not anywhere near a Mediterranean diet. So no, judging from my experience, these Amish didn’t eat a diet of whole, healthy grains and fresh veggies recently harvested from the land. Although they do drink untreated milk.
And it’s interesting to speculate what wonders fresh, unprocessed milk may contain aside from pathogens that kill you.
Counterpoint: Farmers who are as allergic as everyone else
In the upper Midwest live a sect of people called the Hutterites. They originally hail from the same region of the world as the Amish — German-speaking central Europe — so they’re genetically related. They also farm. But here’s the thing: They’re as allergic as your average American. Why does the farm effect fail here? Well, although none of this is published, the thinking is that their particular set-up — dictated by their particular set of beliefs — prevents them from optimal exposures. Women don’t work in the cowshed. Neither do children. And the farms, which are enormous, are located far away from where they live. None of those microbes waft into the house from the barn just out back.
Again, none of this is rigorously studied yet, although I think some comparative studies are in the works. It will be interesting to see what differences they find.
Aren’t farming exposures also dangerous?
It doesn’t take much poking around to find all the lousy things that can happen to you when working on a farm, from hay lung to bronchitis to an increased risk, apparently, of certain cancers. It’s certainly possible that the same exposure protect against one set of diseases, but promote another.
That said, other studies find that farm exposures protect against these cancers. Again, the thinking is that by favorably stimulating the immune system, your body is either less likely to develop cancer, or simply better at catching those rogue cell lines before they multiply, metastasize and threaten your organism. (Here’s another study showing a decreased risk of certain cancers among farmers, but an increased risk of blood cancers.)
Part of what’s happening here may have to do with size. Large farms have huge quantities of feed and manure. And they may cause other problems, especially in the enormous quantities of industrial sized farms and feed lots.
The farms that are protective in Europe are unique. They’re small. Generally family run. This size of farm predominates in the Alps in particular because it’s difficult to have big farms in the mountains. One must fit one’s operation in whatever small valley one can.
In Europe, there’s also a politico-cultural factor at work. The government helps out small farms. That’s because Europeans want those farms to dot their countryside. They consider it important. So these historical / cultural / political factors — and topography — seem to have conspired to produce the perfect size farm for preventing allergic disease in middle Europe. But that doesn’t mean, honestly, that they’re purely beneficial all the time for everyone.
More counterpoints to the farm effect
Why don’t farms protect in New Zealand (although drinking unpasteurized milk does protect there)? Good question. The first thing you note with that study is that the study is cross sectional. You also note that even here, early-life exposure to animals is protective. Still, current farmers in NZ seem to have a higher risk of allergic disease (although, again, consumption of untreated milk seems to protect.) Could be that’s because Kiwis deal with sheep mostly. It’ not clear that sheep are protective.
But it’s worth pointing out that the farm effect has been studied with such detail in Europe — gene expression profiles, white blood cell subsets, the expression of microbial sensors called toll-like receptors, in vitro experiments spraying white blood cells with barn dust, animal studies — that it’s going to take more than a few cross-sectional counter examples to disprove it. These kids seem to have a different epigenetic profile at birth. It’s possible that whatever’s happening there may be unique to that area — to those types of farms and those types of animals at that lattitude in countries that are otherwise developed. (Except now was have the Amish in the US.)
And yet, a caveat: depending on your genotype, that kind of microbially enriched environ may actually do you harm. Still unclear, that. But the not too surprising that the same medicine isn’t going to help everyone equally. Our immune system is genetically very diverse. We’ll all respond differently to the same stimulus.
What about intermittent versus chronic exposure? These UCSD scientists have an interesting take. They use house dust on mice. And they find that if they give the dust all at once, they induce allergy. But if they give low doses over seven days, the chronic stimulation induces tolerance. A nice way to think about how the same stimulus — the farm environment — can have different effects depending on quantity and chronicity.
Colonization by farm microbes
So far, not enough studies have been done on farmers’ microflora. But this one, which also looked at people who live what’s called an anthroposophic lifestyle in Europe, found the farmers to harbor lots of lactobacilli, but actually LESS diversity over all. It’s an oldish study, but interesting. And this more recent one on the Old Order Amish in Pennsylvania, found farmers to harbor more species associated with livestock compared to craftsmen and Amish with other professions. These scientists were looking at metabolic syndrome, not allergies or asthma.
Actually, though, the most interesting studies trying to emulate the “growing up on a farm” experience and its effect on the microbiota are occurring on pigs. These scientists raised three sets of piglets on a farm, one outside, one inside, and one inside in isolators also fed antibiotics periodically. They sampled their microbiota. And they observed it to develop very differently in each environment. Gene expression was also different, with the inside antibiotics-fed pigs looking mildly inflamed. (Antibiotics-provoked pathobiont expansion, anyone?)
A follow up study showed that the pigs needed continuous seeding from their moms and their environment to acquire the right microbiota. If it was cut off even after an initial inoculation, they didn’t benefit. And another showed that the outside piglets with their outdoors-derived microbiota had more regulatory t-cells than their indoor brethren. Kinda cool. The authors claim it’s the first direct evidence of how the farm effect works, by inducing T-regs, in animals (including humans?). The lesson seems to be that the farm environment seeds animals (including people perhaps) with a very healthy collection of microbes that favorably calibrates their immune function.
The many ways of being born protected
It’s probably wise not to obsess too much about those T-regs evident at birth in farming children. That is, obsess about function — yes — but not form. It’s less important what they’re called and what they look like than what they do.
You need adequate suppressor ability, or things spin out of control. But many types of cells can help apply the brakes.
Case in point: this study on cord blood from children born in the less-developed highlands of Papua New Guinea. Allergy still relative rare there. Mothers are exposed to microbes, parasites, infections etc. These kids are apparently born with an enhanced ability to suppress the immune response. But unlike the European farming children, it’s not via T-regs. Instead, their dendritic cells — the cells that scoop up foreign proteins, chop them up, and present them to the immune system — are tolerogenic. They’re more likely to send a message of tolerance, to not overreact.
Speaking of prenatal influences, this recent paper on mothers with latent TB was pretty interesting. Mothers with latent TB infections had children who had a lower rate of asthma. Was it the M. Tuberculosis protecting them? There’s a long history of arguing about whether M. Tuberculosis protects against asthma. Some observe it to be protective, others not.
It might be that the magic happens prenatally, and that’s why different studies give different results. No one has been looking in the right place. It was the mothers that mattered. M Tuberculosis corresponds with both a mild activation and suppression of the immune system. The latter allows you to keep it from spreading, the former allows it to establish chronic infection. This is tolerance as a survival strategy. The cold war strategy. Containment, not outright war. That profile of cytokines may then imprint favorably on the developing fetal immune system. It’s another version, perhaps, of what happens in the farm effect.
Or it could be that TB is a marker for something else — like H. pylori or a farm-like environment — or orofecal infections generally, which are also associated with a lower risk of all these diseases.
Farming mothers’ breast milk
There’s some evidence that farming women have different profile of immune signals and antibodies in their milk. The immune stimulation of the environment presumably changes their breast milk. That probably also plays a role in their children’s protection from allergies. But the finds are inconsistent. In Italy, they find more anti-inflammatory cytokines. But in Middle European farms, they didn’t find those cytokines to correlate with protection form allergies. They did find more secretory IgA, though – which is sometimes called the friendly antibody. Whatever it binds you, it signals not to worry about it too much.
Meanwhile, scientists studying how breast milk compares between Swedes (high allergy) and Estonians (low allergy, but rising) find some pretty interesting differences. Estonian mothers have more IgA, as well as IL10 (anti-inflammatory) and IFN-gamma, which is important for fighting off microbes. They surmise that the Estonian profile is due to a higher microbial load there. All very nebulous still, but at any rate, it suggests that aside from acting prenatally via the maternal immune system, environmental microbes continue affecting infant immune maturation by changing the makeup of immune signaling molecules in breast milk. If only we could emulate this. More on the attempts to do so with probiotics another time.
For now, though, here’s an interesting placebo-controlled study by scientists at Charité Hospital in Berlin. They orally gave heat-killed bacteria to infants at risk for allergic disease. This is like non-specific immune stimulation. It’s like having your innate immune system caressed. And it cut the rate of eczema in half — but only among children with one allergic parents. It didn’t help children with two allergic parents. Maybe their genetic vulnerability was too strong. It’s an interesting idea, though, a kind of emulation of what (presumably) happens with the farm effect. We’ll see if anyone can replicate.
Pollution?
What about pollution causing asthma and allergies, especially in that example of urban Beijing and the apparently non-allergic kids in the countryside around Beijing? Given the horrific stories of pollution — of not being able to see; ash collecting on everything — coming from China generally, shouldn’t we blame pollution in this case?
(By the way, an interesting comparative study of sensitization in three Chinese cities — Hong Kong, Beijing and Guangzhou. Hong Kong is most allergic, Guangzhou least.)
Well, here’s the thing about pollution. There’s no doubt it’s bad for you. And it often correlates respiratory problems, like bronchitis. Many also suspect it in cardiovascular disease. Particulate pollution can lead to a low-grade systemic inflammation that’s just unhealthy any way you spin it.
But the literature really hasn’t made a convincing case that airborne pollution caused the allergy epidemic. First is the question of timing. Air quality in Western Europe and North America generally improved in the late 20th century, during the same period that we saw this explosion of allergic disease.
Here’s what the George Washington Bridge in NYC used to look like (from the EPA).
Moreover, one of the seminal observations of Erika Von Mutius back in the early 1990s was that once the Berlin Wall fell, contrary to her expectations, East Germans were much less allergic than West Germans. And that was DESPITE the fact that they lived in a far more polluted environment.
This baffling pattern was observed in other Eastern Bloc countries, it turned out. People were just less allergic than in the West. That started changing almost immediately. Now the rates with each younger generation are beginning to inch up toward those of Western Europeans.
So anyway, pollution may play a role. But is it responsible for the late 20th century “epidemic”? I think it may have an unfavorable effect prenatally in particular. But the epidemiology just doesn’t match more generally.
