Now, an international team led by Professor Markus Ege from the Dr. von Hauner Children’s Hospital at LMU University Hospital and the Institute of Asthma and Allergy Prevention at Helmholtz Munich has answered this question. The researchers have shown for the first time which specific bacteria in barn air trigger the farm effect, which substances within those bacteria mediate the protection, and which receptors in the body they bind to. Their findings have been published in The New England Journal of Medicine – Evidence.

For years we have been hearing about the hygiene hypothesis, which was first proposed in 1989. This came after three decades of dramatic increases in allergies, asthma, and hay fever among children in Western industrialized countries. These are all conditions in which the immune system mounts an exaggerated inflammatory response and mistakenly attacks the body’s own tissues. According to the hygiene hypothesis, this happens because of under-stimulation in early childhood. The immune systems of children who encounter too few environmental microbes and common cold viruses are more likely to malfunction. “Girls and boys who grow up on farms and are exposed to a wider variety of microbes have the problem far less often,” says Ege. As their immune systems constantly contend with bacterial ‘sparring partners’ from barn air, they are trained to avoid excessive inflammatory responses.

However, the hygiene hypothesis has not been definitively proven, as it is largely based on observational studies. “This kind of research can only show more or less convincing correlations,” says epidemiologist Ege. “But with our new study, we can make a much stronger case, because we can identify the individual links in the proposed causal chain: the bacteria, the relevant microbial metabolic products, and the human receptors.”

The researchers analyzed data from more than 1,000 children participating in European studies in rural areas. For all the children, girls and boys, two types of samples had been collected: nasal swabs and mattress dust. In addition, dust samples were taken from cowsheds for 47 farm children. The team examined which bacteria and fungi were present in these samples, how the different microorganisms were related, and whether specific microbial groups protected the children against asthma.

To this end, the epidemiologists and bioinformaticians employed state-of-the-art genetic and metabolic analyses and developed computer models. Through a process of elimination, they eventually identified the key microorganisms. They also investigated whether the children’s own genes influenced this protective effect. To validate their findings, the researchers additionally used data from France and Finland.

We identified a small number of bacteria, which we can now pinpoint down to the species level,” explains Giulia Pagani, first author of the study and bioinformatician at the Institute of Asthma and Allergy Prevention at Helmholtz Munich, “such as Romboutsia timonensis and Glutamicibacter arilaitensis. These gram-positive bacteria together mediate two-thirds of the entire farm effect for asthma protection and half of the effect for hay fever and atopic eczema.” The bacteria originate in the cow’s digestive tract, where they produce or metabolize substances like kynurenine, xanthine, alpha-linolenic acid, and stearidonic acid. These compounds are easily inhaled and recognized by two receptors on human airway cells – AhR and PPARγ. “These receptors,” Ege continues, “have multiple functions, including in the immune system, where they appear to prevent excessive inflammatory responses.” Their role in the farm effect was previously unknown. For the first time, therefore, the complete biological chain is visible: cow → barn air → bacteria → metabolic products → human receptors → protection against asthma.

The new findings can now be used by laboratory researchers to decipher the molecular and cellular mechanisms of the farm effect. This opens up the prospect of developing a drug that mimics the farm effect – without the need for children to spend time in barns.

G. Pagani et al.: Gram-Positive Bacteria and the Inverse Association between Farm Exposure and Childhood Asthma, NEJM Evidence

DOI: https://doi.org/10.1056/EVIDoa2500271