If you are an avid reader of food packaging materials or a parent of an elementary school student, you might get the feeling that food allergies are on the rise. Statistics back up this notion, with the CDC reporting an 18 percent increase [pdf] in child food allergies between 1997 or 2007. That puts current estimates of food allergy prevalence at 4 percent for children and 2 percent for adults, with allergies to peanuts (3.3 million Americans) and shellfish (6.9 million) leading the way.
The factors driving this surge remain a scientific mystery, and answers are even more scarce when it comes to treating or preventing dangerous allergic reactions. Currently, the only way to prevent anaphylaxis caused by a food allergy is avoidance, a strategy that can be very cumbersome for parents raising small children who cannot be exposed to basic food groups. Dave and Denise Bunning faced this challenge with their two children, both of whom were allergic to milk and eggs, leading to “several emergency room visits before the age of 5,” Dave Bunning said. Those experiences inspired the family’s philanthropy for research into the science of food allergies, which included this year’s founding of the Bunning Food Allergy Professorship at the University of Chicago Medical Center.
At the official naming ceremony for the new position, the inaugural Bunning Food Allergy Professor Cathryn Nagler presented her latest research to a large crowd including the Bunning family themselves. Nagler’s intriguing theory about food allergies looks within, at the bacterial universes that exist inside the human body. In parallel with other laboratories on campus looking at the impact of the human “microbiome” upon diseases such as inflammatory bowel disease and diabetes, Nagler is focused on the trillions of bacterial tenants that occupy each of our bodies.
“It’s becoming clear that we are outnumbered,” Nagler said. “There are 10 trillion human cells encoding 20,000 genes [in an individual], but 100 trillion bacterial cells encoding an estimated 2 to 20 million genes. So there are as many E. coli in each of our digestive tracts as there are people on Earth…and that’s not even one of the more popular species.”
All those bacteria, sometimes called the “commensal microbiota” to distinguish them from disease-causing pathogens, could play the environment role in the genes + environment recipe for food allergies. Many of the trappings of modern life, including high-fat diets, antibiotic treatments, and the use of baby formula instead of breastfeeding, can affect the census of our bacterial inhabitants. In food allergies, where the immune system mistakenly treats innocuous dietary proteins as harmful invaders, these microbiota changes might tip the balance towards over-sensitivity to components of peanuts or shrimp.
“An increase in disease prevalence in 10 to 15 years’ time can’t be explained by genetics, so there’s got to be other factors that are driving this increase in disease prevalence,” Nagler said. “All of these environmental variables lead to alterations of the commensal microbiota, which in genetically susceptible individuals could drive allergic responses to food and other antigens.”
To study this model, Nagler’s laboratory gave a long-term treatment of antibiotics to lab mice, finding that this prolonged exposure did indeed trigger an allergic response to peanuts. Using genetic identification methods, her group compared the gut microbiomes of mice treated with antibiotics versus mice who did not receive the drugs, finding several differences in the bacterial populations colonizing their digestive system. One bacterial family, called Clostridia, were reduced in the mice treated with antibiotics, while another was increased — suggesting that reducing or decreasing different species of bacteria might affect the chances of developing food allergy.
Further testing of this hypothesis required Nagler’s laboratory to move into a different animal model: the germ-free mouse. Bacteria colonize an organism at birth, so keeping a mouse free from germs requires highly specialized treatment and housing facilities. But these extreme conditions will allow researchers to test the role of bacteria in developing allergies, by adding back different combinations of bacterial families (such as Clostridia) to see how they affect the immune response.
Nagler’s team has also studied the role of an immune system protein called TLR4, thought to regulate oral tolerance to food antigens. When researchers knock out the gene for TLR4 in mice, they develop allergic responses to food, and produce fewer regulatory T-cells (associated with tolerance against an antigen) in the lining of the gut. Intriguingly, germ free mice also exhibit a reduction in T-regulatory cells, suggesting that the bacteria normally found in the gut may influence the immune system and help prevent food allergies.
“All of this data taken together supports our hypothesis that TLR4-deficient and antibiotic-treated mice are highly susceptible to allergic responses to dietary antigens, because they lack populations of regulatory T-cells induced by mucosal associated bacteria which are present in wild type mice,” Nagler said.
The laboratory is also looking at samples of bacteria from human patients, examining the populations present in children with and without a condition called eosinophilic esophagitis (EoE). In some people who suffer from food allergies, damage occurs to the lining of the esophagus, another region where bacteria thrive. Because an endoscopy is required to diagnose EoE, researchers can take samples of microbiota present in each patient and compare to samples taken from patients who were also scoped, but not diagnosed with the condition. The results so far have emphasized the complexity of the bacterial differences between the sick and the healthy, and suggest that finding a “smoking gun” may be very difficult, Nagler said.
“What we might be looking for here is not broad changes in the population of the microbiome or in the composition of the microbiome, but a particular species that might trigger an inflammatory response that then goes on to be a chronic disease,” Nagler said. “We intend to explore this in detail.”