Hygiene Hypothesis Study Suggests More Microbes Might Not Be the Answer to Allergies

A new study has raised a “warning” that the hygiene hypothesis, which suggests exposure to a diversity of microbes in early life can protect against allergies by strengthening the immune system, might not capture the whole picture of why these inappropriate immune responses are on the rise.

The research was published in Science Immunology.

Allergies on the rise

Allergic reactions cover everything from mild rashes to life-threatening anaphylaxis. They can be provoked by a wide variety of substances in our environment, from pollen, dust mites, nuts, shellfish, sesame and egg to mango, corn and marshmallows. The biology underlying allergic reactions is equally complex. Part of what makes allergic responses so alarming is their rapid onset.

This speed is driven by antibodies, explains senior author Jonathan Coquet, an associate professor in both the Skin Immunology Research Center at the University of Copenhagen and the Department of Microbiology, Tumor and Cell Biology at Karolinska Institutet in Sweden. These molecules circulate around our body, waiting for markers of external threats called antigens to appear. Antibodies bind to specific antigens, kickstarting a cascade that activates immune sentinels called mast cells, says Coquet.

This causes histamine and other immune mediators to spew out into the body, resulting in an allergic response. This rapid element of allergy is only a small part of the story, says Coquet. What he calls a “slow burn” allergic reaction can begin far earlier in life, where groups of immune cells called T cells are exposed to allergen molecules. This exposure causes new cell populations to form. These cells are incredibly sensitive to further allergen exposure over long periods of time and can release molecules that make the “rapid” immune response possible.

Despite this complexity and variation, a single, simple idea to explain why allergies are on the rise has taken hold in recent years: the hygiene hypothesis.

A simple solution to allergy?

This theory proposes that a lack of exposure to microbes in our early years makes the immune system hypersensitive to non-threatening allergens in our environment. By increasing our exposure to these allergens in early life, the hygiene hypothesis suggests we might be able to cut the incidence of life-threatening allergies.

Coquet’s new study goes against the grain of this neat theory. The study looked at the incidence of allergy-like symptoms in two mouse populations. One group was raised in traditional lab conditions – environments that are almost entirely scrubbed of microbial content – and the other group, so-called “wildling” mice, was exposed to a more naturalistic setting. These mice are genetically identical to lab mice but are raised in “dirty” cages; filled with material from farms that helps create a diverse microbiota in the group.

Coquet’s team tested both groups with exposure to house dust mite allergens. Under the hygiene hypothesis, one would expect the naïve immune systems of the traditional lab mice to mount strong allergic responses, while the wildling mice would prove resilient. Instead, both groups showed spikes in their immune cells indicative of an allergic-like response. “I was a little bit surprised, but not fully,” says Coquet in an interview with Technology Networks. He tells me that his reading of the available literature around the hygiene hypothesis had left him “on the fence”. He does acknowledge that these findings go against the grain of the field. “There's not a person that I've come across that's not been surprised,” says Coquet.

Humans are messier than we like to think

Coquet acknowledges the limits to the study. The “clean” lab mice in the study are poor stand-ins for today’s allergy-prone humans, because while the mice live in a rigorously controlled microbe-free world, “humans are not as clean as we might think they are,” says Coquet. Potentially, he points out, mass air travel has enabled us to become exposed to far more exotic environmental agents than ever before. Additionally, mice don’t naturally develop symptoms of house dust mite allergy like asthma – instead, the research team measured minute changes in airway thickness and mucus production. “I wouldn't say that the mice had allergic disease,” says Coquet.

What do these findings mean for the hygiene hypothesis? Not much, says Prof. Dr. Erika von Mutius, director of the Institute of Asthma and Allergy Prevention at Helmholtz Munich, who was not involved in the study. “The wildling mice were exposed to hay, compost, and fomites from actual wild mice. This is a rather heavy burden of exposure and will not mimic any natural human exposure. In particular, this exposure does not really mimic a farm upbringing where contact to farm animals is an exposure essential for the protective effect. Thus, epidemiological farm studies and this experimental setting are not comparable,” says Mutius.

Instead, she suggests, the findings could indicate the downsides of an exaggerated response to too many microbes in the environment. Coquet disagrees with this assessment, pointing out how their findings contradict three key assumptions of the hygiene hypothesis: that having “good” gut bacteria would shut down inappropriate inflammation, that an incorrect balance of antibodies is to blame for allergies and that uneven numbers of immune T cells are a critical factor. “I'd like people to look at this study and say, ‘that really questions those three mechanisms’,” Coquet adds. “Our study is a bit of a warning. It says it's really not that simple.”

The downsides of dirtiness

Where Coquet and Mutius appear to agree is that the solution to the rise of allergies doesn’t lie in abandoning hygiene standards. “If you want to live a dirty lifestyle,” concludes Coquet, “you're going to have more problems than you're going to create solutions, because more stuff is going to kill you.”

What seems certain is that these findings make our understanding of allergy that bit murkier – much debate is sure to follow. “It's been an absolute pain to get this published because it pushes a lot of buttons,” says Coquet. “I would have been much happier if we had a nice clean result.”

Reference: Ma J, Urgard E, Runge S, et al. Laboratory mice with a wild microbiota generate strong allergic immune responses. Sci Immunol. 2023;8(87):eadf7702. doi:10.1126/sciimmunol.adf7702