A Hygiene Hypothesis
Investigating potential environmental causes of type 1 diabetes
Researcher: Li Wen, MD, PhD
Occupation: Senior Research Scientist, Yale University School of Medicine
Research Funding: ADA Research Grant
In the late 1980s, a British pediatrician named David Strachan made a startling connection. In the developed world, children increasingly live cleaner lives, growing up with smaller families in apartment buildings and pristine suburban homes far from the dirt and pollen of the countryside. And yet rates of childhood allergies, hay fever, and asthma have risen sharply all over Europe and America in the past few decades while remaining almost nonexistent among children growing up in less developed parts of the world.
To find out why, Strachan compared children with few or no siblings to kids with lots of brothers and sisters. He found that the more exposure to microbes and viruses kids had, the less likely they were to have hypersensitive immune reactions like allergies. Strachan suggested that if immune systems are constantly tested—when, for example, lots of runny-nosed older brothers and sisters bring a constant stream of microbes into the house—they somehow learn to distinguish serious invaders from, say, grains of pollen or bits of cat dander. The immune systems that don't get that kind of practice tend to overreact, causing allergies and asthma.
Today, researchers have begun wondering if the phenomenon—now known as the "hygiene hypothesis"—might apply to type 1 diabetes, too. Type 1 diabetes is a classic example of an autoimmune disease. "The immune system gets confused," says Li Wen, MD, PhD, an immunologist at the Yale University School of Medicine. "It considers its own cells as foreign and attacks, killing the beta cells," the pancreas' insulin producers.
Though it's not on a par with the wildfire increase of type 2 diabetes, the number of new type 1 cases in America inches higher every year. "The incidence is rising similar to allergy and asthma," Wen says. Could there be a link between the hygiene hypothesis and diabetes?
On the one hand, genetics plays an important role in both type 1 and type 2 diabetes. But studies of identical twins (who have the exact same genetic makeup) show that both siblings develop diabetes only about a third of the time, a strong clue that there's more at play. Even more curious, new type 1 diabetes cases follow a seasonal pattern. "In the fall or winter, the number of new cases is higher than the rest of the year," Wen says. Coincidence? Probably not: "However, the relationship with viral infections that occur more frequently is complex."
Wen thinks that bacteria may influence the immune system in people already genetically prone to diabetes. With the help of a grant from the American Diabetes Association, she has been working with mice to see whether the hygiene hypothesis could explain why some people get type 1 diabetes. (Mice share a lot with humans, including approximately 80 percent of our genome and many of the same "friendly" bacteria that live in our guts.)
In one experiment, published in the journal Nature last year, Wen put groups of mice specially bred to be prone to type 1 diabetes into three different situations. One group was placed in a normal lab environment.
The mice developed diabetes at a relatively low rate, suggesting that the everyday infections and bacteria of the lab helped train their immune systems not to overreact.
Another group was confined to a super-sterile environment, with no bacteria in their digestive systems or environment. "When they grow up in the super-super-clean conditions, they develop diabetes," Wen says. To make sure she was on the right track, Wen took the offspring of the "clean" mice and fed them with the same sorts of bacteria found in the human gut. The result? A dramatic decrease in the number of diabetic mice, just one generation later. "That suggests those normal, friendly bacteria modulate the immune response to attack beta cells," she says.
The interplay among heredity, genetics, and environmental factors suggests that people with a genetic predisposition toward type 1 diabetes may be like "time bombs," Wen says. We need to understand how the environment shapes the immune system. If she's right, and environmental changes set off type 1 diabetes, understanding exactly how could be crucial: By homing in on how and when the immune system's overreaction is triggered, it might be possible to defuse the situation before it's too late. "Prevention would be ideal," Wen says. "For intervention or reversal, it's more challenging."
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