The main question remained, however. What is causing the inflammation in the first place? Why did the population seem ever more prone to airway inflammatory responses? In the Finnish young men, military conscripts, the rise of asthma and allergic rhinitis became apparent in the 1960s (21) (Figure 2, left panel). Many were allergic to pollen, house dust mite, animal danders, and small children were increasingly allergic to various food items. But also subjects without any signs of IgE-sensitization, i.e., atopic constitution, showed asthma and rhinitis, often provoked by respiratory viral infections (23).

Surprisingly, there was no difference in skin prick test positivity against house dust mite (Dermatophagoides pteronyssinus) between the Finnish and the Russian children. The latter were, however, much more frequently monosensitized, i.e. only to mite (5.2% vs. 1.4%) and without allergy symptoms while the Finns were polysensitized and symptomatic (31). Furthermore, mites tended to be abundant in Russian home dust (mean 125 mites/g dust), while being virtually absent in Finnish homes.

Mites are ectodermal parasites and the tropical mite (Blomia tropicalis), prevalent in houses of South America and Southeast Asia, even intrudes the skin. On the Russian side, the single IgE response to house dust mite, in those with low allergy prevalence, was probably a sign of a natural immune response in a mite-rich housing environment. Similar findings have been observed in rural and urban Ethiopia (32). Much of the biological role of IgE is to protect from parasite invasion and against various toxins (33). Although the relationship between parasites and allergy is still unclear, it was interesting, though not proving any causal relationship, that infection by Ascaris lumbricoides, the most common parasitic worm in humans, was associated with enhanced IgE responsiveness to common allergens in Russian children (34). This could be a triggering effect.

Overall, exposure to house dust mites did not explain any of the Finnish vs. Russian allergy disparity and was not causally related to the asthma and allergy epidemic (35).

Air pollution did not explain the Finnish/Russian allergy contrast. According to the WHO World Database in 2016, the amount of small particulate matter in the ambient air was lowest in Finland (36). Common environmental chemicals did not give an explanation either (37). Maybe the contrast was not the result of new risk factors but the consequence of losing protective factors along with the post-war Great Accleration (38). If so, what are the protective factors?

Originally, the hygiene hypothesis postulated that allergic diseases may be prevented by viral respiratory infections in early childhood (39). In adults, we measured antibodies against seven pathogens including hepatitis A virus, Helicobacter pylori, Toxoplasma gondii, herpes simplex virus, Chlamydia pneumoniae and the periodontal pathogens Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans. Indeed, seropositivity particularly to H. pylori and herpes simplex virus (40, 41), could partly explain the difference in allergy prevalence between Finland and Russia.

Did the result, however, rather indicate an overall microbial burden than any microbe-specific impact? Drinking water in Russian schools in Pitkäranta was much richer and more diverse regarding micro-organisms compared with the Finnish schools. The water in Pitkäranta schools was surface water from the lake Ladoga, not always chlorinated (Figure 3). The microbe-rich water had an independent allergy protective effect when confounding determinants were taken into account in the logistic regression analyses (42). The result was the same regarding house dust, which contained much more microbes on the Russian side compared with Finnish side (43).

In 2006, we discussed the role of environmental saprophytes and gut commensals, which might be major players in the immunological homeostasis (44). Graham A.W. Rook had called them old friends (45). Anecdotally, we also searched the data on asphalt use from 1960 to 1990 in Finland, as an indicator of built environment, and found a close correlation between asphalt use and the occurrence of asthma among Finnish young men (military conscripts). Furthermore, rapid decline in the number of farmers was associated with growing prevalence of allergic rhinitis. Both indicators reflect rapid urbanization, heavy changes in construction, land use, agriculture, forest management, and societal structures linked to them.

In 2009, interaction between human health and the environment was addressed in a commentary article of the butterfly theory, the showy insects being sensitive indicators of environmental changes (46). Although exact comparative data were missing, butterflies had a wider distribution on the Russian side while an isolation and island effect, i.e., habitat fragmentation threatened the Finnish fauna (47). It seemed that in areas with high butterfly numbers and diversity, allergies were rare. In such areas, humans are more closely connected with natural environment supporting immunocompetence. The conclusion was that preserving biodiversity might have a protective effect on allergy and other diseases resulting from modern civilization. At that time, the concept of biodiversity was not really applied to public health.

A field guide for Butterflies of Britain and Europe was completed in 2011 (48) and Ilkka Hanski, ecologist and father of the so called metapopulation theory (49) provided the foreword. He joined the Karelia study group to study biodiversity in relation to allergy and asthma.

In the Finnish Karelia, the environmental biodiversity around the homes of adolescents, aged 14–18 years, was estimated by calculating the abundance of vascular plants in the yard and by characterizing the land use within a radius of three kilometer using the CORINE2000 land cover database (2). The data were correlated with skin microbiota, expression of an anti-inflammatory cytokine, IL-10, and the atopic status of the adolescents.

The results were straight forward: the higher the environmental biodiversity the richer the skin microbiota and the less atopic manifestations. A biodiverse environment is also a surrogate marker of housing and lifestyle, e.g., use of food substances in the diet, which was not specified. Nevertheless, the study showed, including only 118 subjects, strong correlations between the home environment, the microbiome, immune responses, and clinical status. The importance of green environment was further confirmed in two other cohorts of children, aged 3 and 6 years, from Finland and Estonia (50).

Especially, abundance of gammaproteabacteria, and on the species level, Acinetobacter, on the skin of the adolescents associated with allergy protection (51). The study also employed a mouse model, where intradermally applied Acinetobacter lwoffi induced anti-inflammatory and TH1- type gene expression and protected against allergen induced lung inflammation and increase of specific IgE.

The 7–11 year old Finnish and Russian children, originally surveyed in 2003, were re-examined in 2010–2012 at the age of 16–20 years (52). Allergic symptoms and allergen sensitization were still 3–10-fold more common in the Finnish subjects. The differences in allergic phenotypes, developed in early life, had remained between the two populations. In the Russian subjects, occurrence of hay fever and food allergy had remained low. Skin and nasal microbiota were highly contrasting between the populations. Especially, the genus Acinetobacter was abundant and diverse in Russia.

The allergy gap also called for genetic analyses. The disparity of innate immunity-related gene effects on asthma and allergy implied that living in contrasting environments associates with a different genetic profile (53). Surprisingly, in adult women (mothers of the schoolchildren), the risk allele for atopic phenotype in Finland ‒ in terms of CD14 and CC16 single nucleotide polymorphism ‒ was a protective allele in Russia (54). The opposite gene by environment interaction further emphasized the decisive role of environmental exposure and lifestyle on the allergy risk. Furthermore, the maternal genetic variants in IL-4/IL-13 pathways influenced IgE levels in the schoolchildren independently of the childrens´ own genetic effects (55). Obviously, these maternal effects were interacting with the contrasting environment and lifestyle, thereby influencing on the IgE producing capacity of the children.

Importantly, the transcriptomics analyses did not reveal any essential differences at the gene expression level that would explain the allergy disparity (56). Not unexpectedly, the function of the 261 differentially expressed genes of blood mononuclear cells (PBMC) was closely related to innate immunity, which was suppressed in the Russians compared to Finns. Moreover, long non-coding RNAs were expressed at significantly higher levels in the Russian subjects, indicating more robust gene regulation. Again, high Acinetobacter abundance on the skin seemed to play an important regulative role. In another comparison, the allergy gap between Finnish and Estonian children was best explained by disparate early exposure to environmental microbes, especially to the genus Acinetobacter (57).

Overall, the Russians had richer gene-microbe networks and interaction than the Finns, which could be linked to a more balanced innate immunity and related with lower allergy prevalence.

The genotype profiles are like computer “hardware”, preserving the individual information for life. Epigenetic programming, the “software”, regulates to what extent this information is open to translating genes to function (i.e., gene transcription followed by protein synthesis). Allergic disease is associated with epigenetics, i.e., chemical DNA modifications that regulate gene expression — and these modifications are induced by environmental exposures. Thus, epigenetics serves as environmental biomarkers linking our genes with exposure and disease. The epigenetic reading of the exposome (58) modulates gene-environment interaction and have a central role in immune homeostasis.

Methylation is one of the main epigenetic mechanisms. CD14 methylation, responding to endotoxins as markers of environmental microbial load, differed significantly between the Finnish and Russian subjects (59).

In the PBMCs, there were also marked differences in the expression of so called long non-coding RNAs (lncRNA, not coding protein synthesis) (60). The Russian subjects showed upregulation of 37 lncRNAs, which are part of the co-expression network with 20 genes known to be related to allergic disease. All these genes are also components of pathways corresponding to cellular response to bacteria. The upregulation of the lncRNAs was positively correlated with abundance of Acinetobacter and also associated with innate immune suppression in the Russian subjects, who showed less likely harmful response to common allergens. Thus, the function of lncRNAs seems essential in immune-microbiota crosstalk, although it is not fully understood.

In the birch-pollen-allergic individuals, the activated innate immunity networks during in vitro allergen stimulation mimicked those activated during viral infections (61). It looked like the immune system of the allergic subjects misread the birch-pollen proteins as potential viruses.

Many other comparisons exploring allergy disparities among populations have been carried out in Europe and elsewhere. In Karelia, another Finnish-Russian Study Group made surveys for type 1 diabetes and found it sixfold more common on the Finnish side (62). They also looked for allergy among schoolchildren and found less sensitization and more microbial load on the Russian side (63).

Already in 1992, the lower prevalence of allergic disorders in former Eastern Germany, Leipzig, compared with Munich, was speculated to associate with Western lifestyle and living conditions (64). This was in accordance with the observations from children in Eastern Europe having less atopy-related disorders than those living in Scandinavia (65). Especially, the composition of intestinal microflora during the first year of life seemed to modify the allergy risk (66).

A population-based study in Mongolia showed that rural lifestyle protected from allergic rhinitis and sensitization (67). In US, the traditional farming practices protected the Amish children from asthma by shaping their microbial load and innate immune response, compared with the Hutterites with more industrialized type of agriculture (68).

Does the biodiversity hypothesis work in practice? The burden of allergic disease and asthma has been growing for decades in Finland and elsewhere, which implies that prevention strategies at the population level have failed. The Finnish 10-year, nationwide action plan to mitigate the allergy burden was based on clinical experience and the Karelia study results (69, 70). It was also a continuum of the Asthma Programme 1994–2004 (17).

The real-world intervention aimed to improve immunological tolerance, encourage nature contacts, and promote allergy health, i.e., wellbeing even with allergic disease (Table 1). Jean Bousquet wrote: “In allergy, a new day has begun” (71). A major effort was taken to educate healthcare workers and to inform patients, families, and lay-public.

The Programme reached most of its quantitative goals, e.g., food allergy diets, work-related allergies and asthma hospital days halved (72, 73). Prevalence of asthma, rhinitis and eczema levelled off (74, 75). In 10 years, about €2 million were invested in education and public information, not including the major voluntary work by healthcare professionals. The cumulative savings were €1.2 billion in direct healthcare and indirect disability costs (76).

The Finnish Allergy Programme was an open, non-controlled public health intervention including all citizens and employing real-world data and questionnaire surveys to evaluate outcomes. We cannot be sure whether the favourable result would have emerged even without the Programme. Thus, controlled studies to show benefits of improved nature relatedness are necessary.

In a controlled intervention study, daycare yards were enriched by soil blocks and other natural elements (77). In four weeks, the skin microbiota of the intervention group was enriched with immunomodulatory effects. Importantly, continuing the biodiversity intervention up to two years sustained the enriched microbiota in children (78).

The daycare study was continued with a placebo-controlled, double-blinded intervention where the playground sand was enriched with microbially diverse soil (79). Visually similar, but microbially poor sand was used in the placebo group. At two and four weeks, skin bacterial richness and diversity were higher in the intervention than placebo group with immunomodulatory effects. The result supported the biodiversity hypothesis of immune-mediated diseases.

The City of Lahti in Southern Finland with 120 000 inhabitants was nominated the EU Green Capital 2021 for its long-term work for sustainable environment. Nature Step to Health is a 10-year Health and Environment Programme in the Lahti region to combine public health promotion with stopping nature loss and mitigating climate change (Figure 4) (80, 81).

The non-communicable diseases chosen as specific indicators for the Lahti Programme are asthma, diabetes, obesity, and depression, but data for cardiovascular and autoimmune diseases are also followed. The asthma preventive effect of farming environment has been convincingly shown (82). Altered microbiome precedes or associates with types 1 and 2 diabetes (83, 84), cardiovascular disease (85) or autoimmune diseases (86). The risk of type 1 diabetes is decreased in children with disease associated HL-DQ alleles, who are exposed to an agricultural environment early in life (87). A protective effect of residential greenness on major depressive disorder (88) and obesity (89) has come up in observational studies. Recently, the risk of early-onset cancers (adults <50 years) has been linked to early-life environmental exposures and microbiome (90).

The practical actions concern all citizens to favor healthy diet, increase physical activity and mobility, improve housing environment, and encourage nature contacts. These actions are also prescriptions for planetary health (7, 91). A new kind of educational effort for healthcare and information for lay public is taking place. The Päijät-Häme Joint Authority for Health and Wellbeing implements the Programme together with the City of Lahti and Lahti University Campus. Real-world data are employed from official registers, and questionnaire surveys are carried out. Cross-sectional research, new services and nature-based solutions for environmental sustainability are promoted.