Clinical Context

Atopic disease constitutes one of the most common and impactful chronic illnesses among children and young people, and the authors of the current review described the “atopic march” from early childhood through adolescence that characterizes this group of illnesses that share some common pathways. The first atopic illness diagnosed among infants and toddlers is atopic dermatitis. In addition, food allergies frequently develop during the first 2 years of life. Later, children may develop asthma and allergic rhinitis. The authors estimated that the prevalence of asthma among children in industrialized countries is 10% to 20%, and the respective prevalence of allergic rhinitis is 30% to 40%.

A growing body of research has found that earlier exposure to antigens may be protective and halt the atopic march among children. The current review by Frei and colleagues highlights the key points describing how being raised in a farm may reduce the risk for atopic disease.

Study Synopsis and Perspective

In the 1990s, a Swiss physician noticed something intriguing: Children in his practice who lived on farms seemed to have far fewer respiratory allergies than nonfarm kids. He teamed with local researchers to probe this observation more rigorously, and sure enough, they found that it held weight -- and has for decades.

Today, more than one-tenth of children in modern industrialized countries have asthma, and about a third have allergic rhinitis. Large studies conducted in Canada and Europe (Illi et al^[1] and Midodzi et al^[2]) suggest that asthma rates are 32% to 78% lower, respectively, among children who live in rural farming environments.

Some of the most dramatic findings^[3] was reported in 2016 in the New England Journal of Medicine.In a study that compared 60 US Amish and Hutterite farm children: 2 groups with similar genetic ancestries and lifestyles, asthma rates were 4 times lower and allergic sensitization (ie, serum immunoglobulin E against common allergens) was 6 times lower among the Amish children.

The 2 farming communities share broad similarities, but there is a key difference: Amish live on single-family dairy farms and use horses for fieldwork and transportation, whereas Hutterites live and work on large, industrialized farms. As a result, as Amish children grow up, they have more contact with animals. They also start eating solid foods earlier and eat a more varied diet that includes raw, unprocessed milk.

The "farm effect" dovetails with the commonly known hygiene hypothesis, a concept introduced in 1989 to explain the rapid rise of atopic diseases in westernized countries. Researchers at the time found that children from large families had fewer allergic diseases. They surmised that having more siblings increased their exposure to infections, which, in turn, protected them from asthma and allergies.

A growing body of research suggests that a variety of environmental and lifestyle factors converge to disrupt the body's natural community of microbes. These disruptions prevent valuable crosstalk between microbiota and innate immune cells that helps to establish immune tolerance. In essence, microbial exposures during the first year of life, especially in the first few months and even in utero, train the body not to react against allergens and other harmless substances.

"Early exposure to good microbes -- microbes that our immune system most likely evolved to deal with -- is what protects [farm children] from asthma and allergies," said Donata Vercelli, MD, in an interview with Medscape. This evolution took place over hundreds of thousands of years, and our immune system has not yet adapted to modern urban conditions, which are "very recent in evolutionary times," she noted. Farming environments are "much closer to that initial setup that our immune system evolved to deal with."

From an early age, farm children inhale a range of substances that city kids rarely encounter: microbial products from livestock and other animals.

In the 2016 analysis of farm children,^[3] median levels of endotoxins (bacterial toxins) were 6.8 times higher in dust samples from Amish homes. Perhaps even more remarkable, the researchers showed they could prevent airway hyperreactivity in mice by treating them intranasally with dust from Amish homes -- but not from Hutterite homes; however, the Amish dust offered no such benefit to mice that were genetically deficient in 2 innate immune molecules (MyD88 and Trif), suggesting that farm-related protection from atopic disease requires an effective innate immune system.

"We don't yet know about all the pathways involved, but we know that ultimately, they converge on the basic signaling of innate immunity," said Vercelli, who helped lead the 2016 study.

A 2014 study^[5] of urban US children found that homes of children with atopy or atopic wheeze had less bacterial richness: reflecting reduced numbers of bacterial taxa per dust sample. Interestingly, these health conditions were associated with reduced exposure to specific Firmicutes and Bacteriodetes bacteria present in house dust during the first year of life. The findings suggest that "the type of environmental factors are also important," said Roduit. "It's not just diversity but what kind of diversity."

Diet seems to be another key factor. Children raised on farms often drink raw cow's milk, whereas urban children typically drink pasteurized milk.

"If it's more processed, maybe you reduce certain good bacteria," Roduit said. "Fiber is also removed during processing."

Carina Venter, PhD, RD, associate professor in allergy and immunology at the University of Colorado in Denver, and her colleagues investigated whether having a diverse diet during infancy had an impact on the development of food allergies. They analyzed a cohort of 969 children who were born in the Isle of Wight, in the United Kingdom, from 2001 to 2002. The investigators followed the children prospectively for a decade.

The decade-long study, published in 2020,^[6] found that for each additional food introduced by 6 months of age, the child's risk of developing food allergies by age 10 dropped about 10%. Additional allergenic food consumed by 1 year reduced the risk for food allergies by 30%. Studies from China^[7] and Europe^[8] support that trend: Food diversity in the first few years of life protects against development of allergic diseases.

Vercelli's team initiated efforts to translate the findings from the 2016 study of Amish and Hutterite children for children who do not have the benefit of growing up on a farm. They launched the ORBEX study^[11] to test whether giving a daily capsule of Broncho-Vaxom, an oral extract containing 8 kinds of bacteria involved in respiratory infections, can prevent or delay the development of asthma in young children. The study is underway, although it was set back somewhat by the COVID pandemic, Vercelli said.

A study by Pivniouk and colleagues^[12] that was conducted in mice showed that administering these microbial products into the airway protected the animals from experimental allergic asthma. Eventually the team would like to test intranasal application of the microbial extracts in people.

Leveraging the effects of microbes is a promising area of ongoing investigation; however, "the microbiome is a very dynamic entity," Vercelli said. "If you give something, you have to ask what it does to the other microbes that are present. It's not simple."

Carina Venter has received grants from Reckitt Benckiser, Food Allergy Research and Education, and the National Peanut Board; and personal fees from Reckitt Benckiser, the Nestle Nutrition Institute, Danone, Abbott Nutrition, Else Nutrition, and Before Brands. Donata Vercelli is an inventor in PCT/US2021/016918, entitled "Therapeutic Fractions and Proteins from Asthma-Protective Farm Dust"; PCT/EP2019/085016, entitled "Barn Dust Extract for the Prevention and Treatment of Diseases"; and PCT/EP2019/074562, entitled, "Method of Treating and/or Preventing Asthma, Asthma Exacerbations, Allergic Asthma and/or Associated Conditions with Microbiota Related to Respiratory Disorders." Vercelli was supported by grants from the National Institutes of Health. Her lab was funded in part by a research grant from OM Pharma SA to the University of Arizona. Frei and Roduit have no relevant financial relationships.

Clinical Implications

• The first atopic illness diagnosed among infants and toddlers is atopic dermatitis. In addition, food allergies frequently develop during the first 2 years of life. The prevalence of asthma among children in industrialized countries is 10% to 20%, and the respective prevalence of allergic rhinitis is 30% to 40%.
• Exposure to animals and silage during early childhood appears to reduce the risk for incident asthma and allergic rhinitis, as does the consumption of unprocessed milk. Greater food diversity during the first 2 years of life reduces the risk for atopic disease.
• Implications for the healthcare team: The healthcare team may advise parents and caregivers regarding the potential benefits of farm living during childhood when it comes to the prevention of atopic disease.

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