BOSTON - June 24, 2019 -- A study by scientists at Boston Children's Hospital and Brigham and Women's Hospital, published today in Nature Medicine, makes a strong case that the national epidemic of food allergy is caused by the absence of certain beneficial bacteria in the human gut. "The loss of these bacteria acts as a switch that makes children susceptible to food allergy," says Talal Chatila, MD, director of the Food Allergy Program at Boston Children's and a senior author on the paper.
But the study, conducted primarily in mice, also points the way toward treatments that may protect children from developing food allergies -- and reverse the disease in people who already have it. "We're hoping this will lead to a treatment for food allergy, not just a preventative approach," says co-senior author Rima Rachid, MD, assistant director of the Food Allergy Program in Boston Children's Division of Immunology.
The study, which also tested human gut bacteria, was carried out by Azza Abdel-Gadir, PhD, a former postdoc, and Emmanuel Stephen-Victor, PhD, a current postdoc in Chatila's lab, both first co-authors on the paper, in collaboration with first co-author Georg Gerber, MD, PhD, and senior co-author Lynn Bry, MD, PhD, both of Brigham and Women's Hospital.
For reasons that remain a mystery, the number of Americans who suffer from food allergy has risen sharply over the last decade to as many 32 million, according to one recent estimate. Nearly 8 percent of children in the U.S. -- about two in every classroom -- are affected.
One hypothesis is that certain Western lifestyle factors -- an increase in births by Caesarean section, a decline in breastfeeding, increased use of antibiotics and smaller family sizes, for example -- is disrupting the normal microbial balance in the gut, depriving babies of the "good" bacteria that prepare the immune system to recognize food as harmless.
Rachid began testing this hypothesis by studying gut bacteria in babies with and without food allergies. Her team collected stool samples from 56 food-allergic patients and 98 matched controls. Gerber and his colleagues at Brigham and Women's Hospital analyzed those samples for changes in bacterial content. The work revealed that the bacteria in the feces of babies with food allergies were different from those of controls. But did those bacterial differences play a role in their food allergies?
To find out, the team transplanted fecal bacteria from the babies into a special strain of allergy-prone mice. They fed the mice small doses of chicken egg protein to sensitize their immune systems to this allergen, then challenged the mice with a large dose.
The results: Mice that had been given fecal bacteria from food-allergic babies went into the life-threatening reaction called anaphylaxis. "The fecal bacteria from food-allergic subjects did not protect against food allergy, whereas the bacteria from control subjects did," Chatila says.
To find out which bacteria might be offering that protection, the team turned to Bry at Brigham and Women's. Bry provided a mix of six bacterial species from the order Clostridiales, which previous studies had suggested might protect against food allergy. When these bacteria were given to the mice, the animals were protected from food allergy to chicken egg protein, whereas mice given other common bacteria were not. "If you give them the right bacteria, the Clostridia, they're completely resistant to food allergy," Chatila says.
Bry then provided a second mix of unrelated bacteria from the order Bacteroidales. It too was protective. And finally, when the team treated mice that already had food allergy with the Clostridiales or Bacteroidales mixes, they found those therapies completely suppressed the animals' allergic reactions.
Chatila believes the study proves that the loss of protective gut bacteria is a critical factor in food allergy. "At the very least it is a fundamental mechanism. And more likely, in my mind, it is the fundamental mechanism on which other things can be layered," he says.
While previous studies have suggested that certain bacteria can protect against food allergies, Chatila and his colleagues go a step further, describing the specific immunological pathway by which the bacteria act in mice. It begins with a protein, known as MyD88, that serves as a "microbial sensor" in the immune system's regulatory T cells.
"You need the bacteria to give particular signals that are picked up by nascent regulatory T cells in the gut," Chatila explains. Those signals trigger a chain reaction that changes the gut regulatory T cells into a specific type, known as ROR-gamma regulatory T cells, that protect against food allergies. As a result of this work, Chatila says, "we now have a fundamental concept of how food allergy happens" -- a theory he hopes other scientists will now test.
Chatila and Rachid believe their findings will eventually lead to new treatments that prevent the development of food allergies in newborns at risk. The treatments might take the form of probiotics -- mixes of beneficial bacteria -- or drugs that prime the immune system in the same way.
And for the millions who already suffer from food allergies, the same treatments may be able to reverse their disease. "Remember," Chatila says, "in adult mice that had become food-allergic, we could suppress their disease by introducing the good bacteria, which means to us there is the potential to treat somebody with established food allergy and reset their immune system in favor of tolerance."
Ultimately, Chatila cautions, the promising results in mice will have to be duplicated in humans. But that may happen soon. Rachid is already conducting a first-of-its-kind clinical trial at Boston Children's to test the safety and efficacy of fecal transplants in adults with peanut allergy. And Chatila notes that several companies are already preparing bacterial mixes for clinical trials. "If the race continues with the same intensity, or accelerates, I think you'll see a product on the market within five years," he predicts.
Two patents stemming from the work described in the Nature Medicine paper have been licensed to Consortia TX, Inc., a firm founded in 2017 by Chatila, Gerber and Bry, who all have equity in the company. (Rachid, an advisor to the company, also has equity.) Two other patent applications are pending.
For a complete list of authors see Nature Medicine. This work was supported by the National Institutes of Health, the Clinical and Translational Science Center/Harvard Catalyst, the Bunning Food Allergy Fund, the Jasmine and Paul Mashikian Fund, the Massachusetts Life Sciences Center, and a Partners Healthcare Innovations Development Grant.
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