The farm-like effect: Rural exposures in early life, the microbiome, and asthma

Abstract

Big things have small beginnings. In 1989, the epidemiologist David Strachan published a concise report (612 words, which is less than half the length of this editorial) observing decreased hay fever among British youths with more siblings.1Strachan D.P. Hay fever, hygiene and household size.Br Med J. 1989; 299: 1259-1260Crossref PubMed Scopus (3686) Google Scholar Strachan commented that his findings could be explained “if allergic diseases were prevented by infection in early childhood.” This original conception of the “hygiene hypothesis” proved hugely influential and has been cited, on average, twice per week since it was published. In the ensuing 31 years, simultaneous advances in the epidemiology of asthma and in gene sequencing and bioinformatics led to a reduced emphasis on infections and a greater recognition of the benefits of a diverse commensal microbiome. Host-microbiome relationships are complex and ancient in their origins, and microbes are not necessarily or always pathogenic. The hygiene hypothesis has given rise to several updated theories decreasing the emphasis on infections and highlighting the health benefits of a diverse microbiota: the “biodiversity hypothesis,” the “old friends hypothesis,” and the “biome depletion theory” among them. Accordingly, evidence connecting a longer list of microbiome-modifying exposures, including mode of delivery, breast-feeding, dog ownership, day care attendance, and antibiotic treatment, to development of asthma and atopy, has accumulated.2Lynch S.V. Boushey H.A. The microbiome and development of allergic disease.Curr Opin Allergy Clin Immunol. 2016; 16: 165-171Crossref PubMed Scopus (64) Google Scholar It is now established that microbial exposures when individuals are very young yield big effects on later risk of asthma and allergic inflammation. In several human observational studies, perturbations to the microbiome during infancy have been linked to subsequent asthma and atopy.2Lynch S.V. Boushey H.A. The microbiome and development of allergic disease.Curr Opin Allergy Clin Immunol. 2016; 16: 165-171Crossref PubMed Scopus (64) Google Scholar The “farm effect” is one of the most compelling observations to arise from investigations of the microbiome in asthma development, and it is one of the key phenomena that has maintained the relevance of the hygiene hypothesis. Worldwide, observational studies have documented reduced asthma and atopy among individuals who grew up on a farm.3Von Mutius E. The microbial environment and its influence on asthma prevention in early life.J Allergy Clin Immunol. 2016; 137: 680-689Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar Differential microbial exposures, including ingestion of unpasteurized milk and proximity to cattle- and other animal-associated microbes, have been proposed to mediate the farm effect. A more recent study, conducted in Finland and Germany, suggested that the farm effect extends beyond a simple dichotomy and that among nonfarm homes, there is a spectrum of environments that vary in their similarity to farms.4Kirjavainen P.V. Karvonen A.M. Adams R.I. Täubel M. Roponen M. Tuoresmäki P. et al.Farm-like indoor microbiota in non-farm homes protects children from asthma development.Nat Med. 2019; 25: 1089-1095Crossref PubMed Scopus (109) Google Scholar Microbiomes of living room dust collected from the homes (including from rural farm homes, rural nonfarm homes and suburban homes) of 2-month-olds were compared. The house dust microbiome compositions of some nonfarm homes were similar to those of farm homes, and infants from these homes had reduced rates of asthma at age 6 years. A study in this issue of the Journal of Allergy and Clinical Immunology by Lehtimäki et al lends additional credence to the concept of early-life environmental exposures existing on a continuum.5Lehtimäki J. Thorsen J. Rasmussen M.A. Hjelmø M. Shah S. Mortensen M.S. et al.Urbanized microbiota in infants, immune constitution, and later risk of atopic diseases.J Allergy Clin Immunol. 2021; 148: 234-243Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Data from 700 participants in the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) 2010 study, who spent their infancies in a Westernized, densely populated area in Zealand, Denmark, were analyzed. Although few of the subjects lived on farms, their living areas ranged from urban to rural. The authors used a European land cover database to characterize the area surrounding each subject’s home address at birth. The first axis in a principal coordinates analysis of these data correlated well with urban-rural differences, with higher values corresponding to “artificial surfaces,” including urban structures and transport networks, and lower values corresponding to wetlands, forested areas, and agricultural areas. This principal coordinates analysis axis was used to define an “urbanization gradient,” and subjects were additionally categorized as living in either a rural (n = 314) or urban (n = 372) environment. At age 6 years, children who had spent their infancies in more urban areas were more likely to have asthma (odds ratio = 2.31; 95% CI = 1.47-3.68; P < .01) and aeroallergen sensitization (odds ratio = 1.77; 95% CI = 1.05-3.02; P =.03). Unlike in the majority of studies of the environmental microbiome in asthma development, data on the infant microbiome were also analyzed, including via 16S rRNA bacterial microbiome profiling of airway (hypopharyngeal) samples collected from subjects aged 1 week, 1 month, and 3 months and stool samples collected from subjects aged 1 week, 1 month, and 1 year. The airway microbiome composition at all 3 time points differed between infants living in more urban versus rural areas, with infants from urban areas exhibiting more homogeneous airway microbiota. In contrast, gut microbiome composition differed by urban-rural environment of the subjects at age 1 year but not earlier in infancy. The observed microbiome variation was leveraged to estimate “bacterial scores” for each subject, with higher values reflecting a more urbanized microbiome. Bacterial scores were generally higher among subjects who developed asthma, although this association was not seen during examination of the gut microbiome at age 1 week (the earliest time point) or the airway microbiome at age 3 months (the latest time point). Overall, the findings provide modest evidence in favor of a pathway whereby the environmental microbiome affects the gut and/or airway microbiome, thereby modulating asthma risk. However, whether gut and/or airway microbiome changes are critical to the farm effect on asthma remains nebulous, and it is likely that the environmental microbiome has effects on asthma risk independent of the host internal microbiome. In general, replication in other cohorts will be critical to support these findings, especially given those features of the COPSAC 2010 cohort that could limit generalizability, such as being a predominantly white cohort and embedded study interventions, including prenatal omega-3 fatty acid and/or vitamin D supplementation and postnatal azithromycin for troublesome lung symptoms. This article draws attention to several unanswered questions. The mechanisms behind the farm effect and related phenomena remain undefined. Lehtimäki et al5Lehtimäki J. Thorsen J. Rasmussen M.A. Hjelmø M. Shah S. Mortensen M.S. et al.Urbanized microbiota in infants, immune constitution, and later risk of atopic diseases.J Allergy Clin Immunol. 2021; 148: 234-243Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar found that in COPSAC 2010 participants, the levels of several cytokines and chemokines measured in nasal mucosal samples from subjects aged 1 month and plasma from subjects aged 6 months differed by rural-urban living area gradient, although these differences were complex and did not fall neatly into orchestrated type 2 or type 1 inflammation patterns. Additional human studies integrating microbiome and immunophenotyping data and functional studies are needed to clarify the immune effects of rural versus urban living environments. The specific exposures that contribute most to the protective effect of residing in a farm-like home also remain elusive (Fig 1). In this COPSAC 2010 study, a portion of the observed microbiome differences appeared to be driven by more numerous older siblings and pets in rural homes. The Finnish and German study also pointed toward a protective effect of having more numerous children in the home, as well as toward wearing outdoor shoes inside the home and residing in an older home.4Kirjavainen P.V. Karvonen A.M. Adams R.I. Täubel M. Roponen M. Tuoresmäki P. et al.Farm-like indoor microbiota in non-farm homes protects children from asthma development.Nat Med. 2019; 25: 1089-1095Crossref PubMed Scopus (109) Google Scholar Although their findings dovetail nicely, both studies were observational and we cannot rule out that their results could be attributable to other factors, such as differential exposure to air pollution, allergens, or differences in diet or physical activity. The weight of evidence favors the concept that at least some of the protective effect of spending infancy in a rural home is due to microbial exposures. It may be that there are discrete “windows of opportunity” during which microbial communities at different body sites affect risk of asthma and atopy. Alternatively, recent findings, including from COPSAC 2010,6Stokholm J. Blaser M.J. Thorsen J. Rasmussen M.A. Waage J. Vinding R.K. et al.Maturation of the gut microbiome and risk of asthma in childhood.Nat Commun. 2018; 9: 141Crossref PubMed Scopus (206) Google Scholar suggest that microbiome maturation over infancy is an orchestrated event and is delayed in 1-year-olds at risk of subsequent asthma. Intriguingly, delayed gut microbial maturation was associated with having fewer siblings in the home in COPSAC 2010,6Stokholm J. Blaser M.J. Thorsen J. Rasmussen M.A. Waage J. Vinding R.K. et al.Maturation of the gut microbiome and risk of asthma in childhood.Nat Commun. 2018; 9: 141Crossref PubMed Scopus (206) Google Scholar and in the PASTURE study7Depner M. Taft D.H. Kirjavainen P.V. Kalanetra K.M. Karvonen A.M. Peschel S. et al.Maturation of the gut microbiome during the first year of life contributes to the protective farm effect on childhood asthma.Nat Med. 2020; 26: 1766-1775Crossref PubMed Scopus (53) Google Scholar microbial maturation was recently reported to be accelerated by growing up on a farm, thus supporting the concept that microbial maturation could be a critical link between farm or farm-like exposures and asthma protection. These puzzle pieces are coming together, one at a time, to produce a fuller picture of how rural and farm environments may protect against development of asthma and allergies. Urbanized microbiota in infants, immune constitution, and later risk of atopic diseasesJournal of Allergy and Clinical ImmunologyVol. 148Issue 1PreviewUrbanization is linked with an increased burden of asthma and atopic traits. A putative mechanism is insufficient exposure to beneficial microbes early in life, leading to immune dysregulation, as was previously shown for indoor microbial exposures. Full-Text PDF