University of Chicago immunologist Cathryn Nagler began to suspect that the body’s resident bacteria play a role in food allergies almost two decades ago. A handful of studies of germfree mice in the 1980s and ’90s had suggested that bacteria in the gut, or compounds they produce, such as lipopolysaccharide (LPS), are important in teaching the immune system not to overreact to the foods we eat. But it was a new mouse model of peanut allergy, developed by researchers at Mount Sinai School of Medicine in New York in 2000, that really made Nagler think about whether the gut microbiome might be involved in how humans respond to dietary antigens.
The mouse strain they used, C3H/HeJ, carried a mutation in the toll-like receptor 4 (TLR4). This protein had recently been shown to mediate immune responses triggered by a bacterial antigen known as lipopolysaccharide (LPS), and the mutant mice were consequently nonresponsive to LPS. But according to the 2000 paper, the animals also exhibited anaphylaxis—a sometimes fatal allergic reaction in people—upon exposure to freshly ground peanuts.
It made Nagler wonder if TLR4—and specifically, the propensity of certain gut bacteria to activate it—was the key to tolerance to dietary antigens. Sure enough, when she treated mice with broad-spectrum antibiotics to deplete their intestinal bacteria, even animals with wildtype TLR4 had severe reactionsto food allergens. “That established a role of signaling by bacteria in the gut in regulating responses to food,” she says. “And then all of the studies we’ve done since then, over 15 years, have built on that.”
The fact that food allergies have been rising in recent decades really implores us to try to figure out as much as possible what could be contributing to this.
—Supinda Bunyavanich, Icahn School of Medicine at Mount Sinai
These days, there is little doubt that the body’s resident bacteria have a big say in how the immune system responds to food allergens. Research into the underlying causes of food allergies has blossomed to parallel the condition’s growing prevalence: an estimated 6 percent of children and up to 10 percent of adults in the US have an allergy to some food. Scientists have identified connections between a person’s microbial makeup and whether or not that person has a food allergy. Microbiome differences also help determine which children will outgrow their food allergies and which won’t, notes Supinda Bunyavanich, a physician scientist at Icahn School of Medicine at Mount Sinai. “So it suggests that there is an impact of these microbiota on the clinical outcomes.”
Further research in mice has demonstrated a causal relationship between the microbiome and allergic reactions to food. In January, Nagler and her colleagues published the results of an experiment in which they transferred fecal samples from healthy human infants and from infants with cow’s milk allergy to germfree mice. Control animals that did not receive a fecal transplant, as well as mice that received samples from the allergic babies, became sensitized to the milk protein β-lactoglobulin, developing an allergic response upon repeated exposure to the protein. Mice that had received transplants from healthy infants, on the other hand, tolerated the dietary antigen without any issues.
Exploring the microbiomes of the mice, the researchers identified one particular bacterial species, Anaerostipes caccae, that was significantly reduced in rodents that demonstrated an allergic response to cow’s milk. The team also showed that transferring this species “to germfree mice is sufficient to protect against an allergic response to” cow’s milk, Nagler says.