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 reactions to 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.”…
