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Asthma's Inner WorldMichael Glenwood

Asthma's Inner World

Other observational evidence supports the hygiene hypothesis as well, says Wills-Karp. Scientists have shown, for example, that people in developing countries have a more diverse assortment of microbiota in their GI tracts than people in developed countries. Other studies show that children with a lot of siblings, or people who live on farms, have lower rates of asthma, endorsing the view that encountering a panoply of germs in early life reduces asthma risk.

One piece missing from the hygiene hypothesis, though, has been a plausible biological mechanism. Which microbes and which immune pathways incline a child toward developing asthma? Scientists have proposed many theories, says Wills-Karp, but none has held up to close scrutiny. “It’s still an open question.”

In 2001, Wills-Karp published a review of the hygiene hypothesis in Nature Reviews Immunology. The prevailing model for asthma focused on two subclasses of immune cells, T-helper cell 1 (Th1) and T-helper cell 2 (Th2). Reduced exposure to germs early in life skews the immune balance toward producing more Th2 and less Th1. But Wills-Karp suggested that there might be more to the story and proposed that immunologists consider a broader model.

“Everything you’ll ever need to know is within you; the secrets of the universe are imprinted on the cells of your body.”
—Dan Millman

A breakthrough on this idea began in 2008, when Wills-Karp read a journal article by immunology researchers at New York University. The scientists had noticed something strange. They had purchased the same strain of mice from two different popular vendors, Taconic Farms and Jackson Laboratory. But even though the mice were genetically identical, their small intestines contained dramatically different levels of a recently discovered immune cell called T helper cell 17. Taconic mice had a high level of Th17, while the Jackson mice had a low level—a difference reminiscent of Wills-Karp’s Baltimore and Cincinnati mice. In both cases, genetically identical groups showed surprisingly dissimilar results in a health parameter. Some difference in the facilities (Baltimore vs. Cincinnati; Taconic vs. Jackson) must underlie the inconsistent results.

As it happened, Wills-Karp had recently published the results of her own study in mice related to Th17 cells. “We found that Th17 had some connection with severe forms of asthma,” she says. “The more Th17, the more severe the asthma.” She suspected that the Taconic mice would have more severe levels of asthma; studies in her lab confirmed this hypothesis.

Research in people echoed the mouse results, further evidence that an overzealous Th17 response might underlie or augment severe asthma. But that still left a question: What would cause Th17 cells to spike in one mouse and not in its genetically identical cousin?

Around the same time, several studies began to suggest that the answer had something to do with the microbiome. Further studies by the NYU group pointed to one microbe in particular, an elusive bacterium that has not been definitively classified but may belong to the Clostridium genus.

These clostridia-related bacteria live in the small intestine of mice and various other species where they burrow deep inside the epithelial lining. Scientists have not succeeded in replicating this specialized environment in a culture dish, so these bacteria, like many other microbiota members, can’t yet be cultured.

In recent studies, Wills-Karp examined whether the clostridia-related bacteria could indeed be driving the immune change behind severe asthma. Because of the bacteria’s growing constraints, for these experiments she had to devise strategies.

In one experiment, for instance, her team called upon a Japanese company that had developed special mice that have absolutely no germs in their bodies except for the clostridia-related bacteria. They collected fecal material from the mice and shipped it to Wills-Karp’s lab. Presumably, the fecal material would contain the clostridia-related bacteria. Wills-Karp’s team transplanted the fecal material into a common breed of laboratory mice that scientists had shown were free of the clostridia-related bacteria. They then compared the rate of asthma symptoms in those mice to a comparable group of mice that had not received the fecal transplants.

“I know it sounds strange,” says Wills-Karp. “The things scientists do.”

Strange or not, the experiment proved useful. The mice receiving the fecal transplants went on to develop severe asthma, a finding that, along with other results, provided strong evidence that this member of the microbiome may drive severe asthma.

Further studies revealed another interesting aspect of this process. “In mice, this bacteria is cleared during weaning or maturation,” says Wills-Karp. Her initial experiments involved young mice, those still colonized by the clostridia-related bacteria. So her group did a series of experiments to determine whether the immune changes brought about by the bacteria endure.

Indeed they do, her studies showed. “We see that past the time of clearance of that bacteria, this Th17 response persists,” says Wills-Karp. “Whatever happens is changing the immune response indefinitely.” Her studies suggest that the presence of the bacteria in the guts of young mice gets communicated to the bone marrow, the site of immune cell production. This information skews the immune system’s normal balance, biasing it in favor of the production of Th17 cells.

It’s easy to see how the same scenario might occur in people, says Wills-Karp.

“The going assumption with asthma is that the first year of life is critical to the establishment of the disease,” she says. Certain events early in life can disrupt the gut’s normal microbial balance. If a child receives repeated courses of antibiotics, for example, those medicines might skew the balance in a way that allows a clostridia-related species to flourish. As in the mouse, that information would get telegraphed to the immune system, and so on.

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