Contacts with environmental biodiversity affect human health: links to allergies, physical and mental health revealed during the initial waves of the COVID-19 pandemic

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Between 2019 and 2022, public awareness of the threat of infectious diseases in humans was renewed by the global pandemic of a new type of a coronavirus, the SARS-COV-2. This public interest opened improved possibilities to test hypotheses on the factors associated with inter-individual variation in susceptibility to infectious and “modern” diseases. Based on the Hygiene hypothesis and Biodiversity hypothesis, we predicted that contacts with natural environment and wildlife in childhood and/or in adulthood can improve general health and decrease the risks of severe COVID-19 progression or prevalence of the “modern” diseases, namely the allergies. Here we report the results of an online, self-evaluating questionnaire survey conducted in the Czech Republic, where we contrasted selected health issues, and linked them to the living environment, including the level of contacts with biodiversity. In a sample of 1188 respondents, we revealed a significant effect of time spent in nature and contacts with biodiversity on physical and mental health, and incidence of allergies. This is unlike the COVID-19 progression, which was related to age, physical health, smoking, allergies, and interaction of age with smoking, but not to contacts with the natural environmental diversity. Our findings are in agreement with the Biodiversity hypothesis of allergy and, linking human and environmental health, they urge for One Health approach application. Earth and environmental sciences/Environmental sciences/Environmental impact Biological sciences/Ecology/Biodiversity Health sciences/Risk factors Health sciences/Diseases/Immunological disorders/Autoimmune diseases Biological sciences/Psychology/Human behaviour allergies biodiversity antigen richness civilization diseases contacts with nature infectious diseases wildlife Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Dramatic changes in the human lifestyle over the past century significantly shifted various physiological regulations from their optima earlier selected throughout evolution 1 . Recently, especially in high-income countries we have observed a massive increase in health disorders that can be linked to inflammation, such as increased susceptibility to immunopathologies and higher incidence of allergies 2 , 3 . These current health challenges are multifactorial, complex and global 4 . Although not yet clearly recognised, these issues may be related to decreased environmental health. Derived from the Hygiene hypothesis 5 , the Biodiversity hypothesis predicts the importance of contacts of individuals with heterogeneity of antigens derived from the natural environment, including pathogens and symbionts 6 . During ontogenetic development, immune system harnesses the richness of environmental antigens to set an optimal regulation of immune tolerance, balancing the affordable protection against the pathogens with costs resulting from immunopathology in a given environmental context 7 – 9 . Combined effects of the contacts with microbes and parasites naturally colonising host bodies during childhood and also later during life are expected to contribute to immunomodulation 10 . Absence of various immunomodulatory compounds in the modern urban environment can alter tolerogenic immune responses to common antigens into overreactive pro-inflammatory responses 11 . A shift has been suggested in the immune regulation balance from Treg/Th2-IgA-pruducing responses towards Th1 responses combined with IgE production responsible for exaggerated tissue damage in reaction to recognition of natural antigens 12 , 13 . Such changes in human-environment balance modulating immune regulation can also be tracked through the health trends indicated in population surveys 14 . Despite to certain level subjective, self-administered questionnaires used for epidemiologic surveys show good reproducibility 15 and offer important insights into the environmental associations with diseases 16 , although their ability to reveal direct causality is limited. Although proposed primarily for allergies, the impact of such regulation can be much wider and affect also other diseases, including infections, where pathology often results from the inflammatory over-responsiveness 17 . Similar to regulation of allergies, also regulation of immune responses to pathogens can be modulated by environmental changes that are associated with altered composition of the host’s symbiotic microbiota 18 , 19 . Current results show that different people responded differently to a novel coronavirus infection caused by the SARS-CoV-2 virus, assumingly dependent on their genetic background 20 , but also lifestyle and living environment 21 , 22 . Until recently, advances in medical care diminished the public awareness of the health threats resulting from infectious diseases 23 . However, the global pandemic of SARS-CoV-2 between 2019 and 2022, causing respiratory disease COVID-19, renewed the general interest in infectious diseases and facilitated public health questionnaire studies. Here we hypothesise that through decreased tolerogenic immune regulation, the lack of contacts with natural environmental diversity (biodiversity-related antigen richness) could increase the risk of COVID-19 infection and/or its severity, having in parallel analogous impact on selected “modern” diseases including allergies. We predict that controlling for age, sex, body mass, health, sport activities and socio-economic background, on a population level the self-reported COVID-19 disease progression will be milder, allergies less frequent and health improved in people experiencing increased direct contacts with wildlife, domestic animals, and plants that serve as sources of natural biodiversity of antigens. Methods Data structure and respondents This survey study was pre-registered on OSF (created: 2021-05-18; https://osf.io/x4zyv/?view_only=f22560412c55449daa22a6266b2cb842 ). We used the tool Qulatrics ( https://www.qualtrics.com/ ) to create an online questionnaire. This questionnaire was available from 27 May 2021 through our website ( https://web.natur.cuni.cz/zoology/eei/ ) and the site link was sent to various organisations involved in nature protection, animal and plant care (zoological and botanical gardens), schools and universities, and shared on social media used throughout the Czech Republic. Before commencing the questionnaire, participants received clear information that the study was performed for research purposes, and that the participation is voluntary and anonymous. To participate in the study, respondents had to provide informed consent by clicking the respective button. The questionnaire took approximately one hour to complete. The Institutional Review Board of the Faculty of Science, Charles University approved the project and the process of obtaining informed consent (No. 2020/25). The study was performed in accordance with relevant guidelines and regulations. In the questionnaire's anamnestic section, respondents were asked about their age, sex (assigned at birth), height, weight, and selection from multiple-choice lists on previous infections, vaccination, and allergies. They also answered three questions evaluating their current, usual and before-COVID physical health and three analogous questions on their mental health. Further, the respondents answered 10 questions regarding their living, work, and childhood environment (7-item scale from the countryside to metropolis), commuting, smoking, and daily hygiene. Next, the respondents were asked about their outdoor activities, contacts with plants and animals, as well as overall environmental diversity. Respondents used Likert scales for their answers, or they wrote in the exact number or chose an exact option. Crucially, they had to answer whether they were tested positively for SARS-CoV-2, which type of test they used (from options: PCR, antigenic or antibody test) and what was the disease progression (subjective severity assessment of the disease course on scale from asymptomatic to hospitalization on intensive care unit). The questionnaire containing the original questions and all answers obtained (in Czech) are available in Supplementary material 1. After seven months we closed the survey and downloaded the available data. We tested selected health parameters (physical and mental health, SARS-CoV-2 infection, COVID-19 progression and presence of allergies) as the variables dependent on selected environmental and lifestyle factors. All variables with multiple levels in scale were transformed to a numeral scale and all yes/no answers were treated as factors. Parameters indicating diversity, such as diversity of environmental activities, or animals and plants kept in households, or pathogen-borne diseases throughout life, were summed as the total number of realised options and further used as a continuous variables. All variables used for the statistical analysis are explained in detail in Table S2.1 in the Supplementary material 2. All pre-processed data used for the statistics are listed in Table S2.2. Original data are provided in Table S2.3. We used a correlation matrix and Principal Component Analysis (PCA) to reduce the number of individual variables adopted our statistical models (see Table S2.4). Importantly, the variable “contact with environmental diversity” was constructed as PC1 scores obtained from the PCA of all surveyed variables connected with activities conducted in nature or concerning animals, plants or wildlife. Dataset and Statistics In total, we collected 1811 survey responses which is comparable to datasets obtained from other similar questionnaire-based health surveys 24 , 25 . We first filtered out any answers from unfinished survey responses, retaining 1188 valid responses for the analysis. We created two datasets, first one with all the valid responses and a second one containing only the subset of self-reported SARS-CoV-2 positive individuals (327 responses). First, we tested if the self-reported usual physical health state was associated with incidence of allergies, number of infectious diseases during life, and selected lifestyle factors, including the contacts with various environmental diversity parameters (model structure shown in Table S2.5). In case of the significance of the composite variable contact with environmental diversity in a model, the statistics was repeated, using the original individual variables: intensity of the contacts with natural environment, intensity of the contacts with animals, diversity of animals in contact, diversity of plants in contact, time spent in nature, diversity of activities in nature at presence and diversity of activities in nature during childhood (Table S2.4). Then, using similar approach, we tested analogous associations also for the self-reported mental health, SARS-Cov-2 infection and COVID-19 progression, and incidence of allergies, adopted as response variables (see all the full models listed in Table S2.5). In all cases the relationships were tested using linear models (LMs) and in the case of a categorical variable (0/1) by the general linear models (GLM) in the ‘Ime4 package’ in R studio version 3.6.2 26 . Minimum adequate models (MAMs; here defined as models with all terms significant at p ≤ 0.05) were identified by backward elimination of non-significant terms from the full models. All backward elimination steps in the models were verified by changes in deviance with an accompanying change in degrees of freedom (ANOVA) and Akaike information criterion (AIC), using F-statistics. Results The analysed dataset contained 768 women (mean age = 37.99, sd = 12.80) and 420 men (mean age = 38.97, sd = 13.14). SARS-CoV-2 infection (codes: negative = 861, positive = 327) was reported by both women (205, i.e., 26.69% were positive) and men (122, i.e., 29.05% were positive). The effect of sex on self-reported SARS-CoV-2 positivity was not significant (OR = 0.889, C.I.95 = 0.683–1.160, p < 0.386). The feeling of self-reported physical healthiness (Physical health) was significantly negatively associated with the number of different infection diseases during life, (p < < 0.001, Figure S1) and positively with commuting (p = 0.010, Figure S2), sports (p = 0.009, Figure S3), number of hours of sleep (p = 0.033, Figure S4) and time spent in nature (p < < 0.001, MAM1, Table 1 ; Table S3.1; Fig. 1 ). Table 1 Complete list of the Minimum adequate models (MAMs). Df = degrees of freedom, MAM = minimal adequate model, SE = standard error. Minimum adequate model Estimate SE Df F P MAM1 : Physical health ~ number of different infection diseases + commuting + sport + sleep + time spent in nature 1/1058 3654.4 <<0.001 number of different infection diseases -3.127 0.572 1/1059 29.941 <<0.001 commuting 0.538 0.209 1/1059 6.610 0.010 sport 1.089 0.421 1/1059 6.687 0.009 number of hours of sleep 1.079 0.506 1/1059 4.541 0.033 time spent in nature 2.120 0.383 1/1059 30.652 <<0.001 MAM2 : Mental health ~ sex + age + number of different infection diseases + commuting + number of hours of sleep + intensity of contacts with natural environment + time spent in nature + diversity of activities in nature 1/1064 1466.5 <<0.001 sex (males) 4.071 6.751 1/1056 8.703 0.003 age 0.265 1.380 1/1056 23.146 <<0.001 number of different infection diseases -1.512 0.711 1/1056 4.530 0.034 commuting 1.793 0.262 1/1056 4.292 0.039 number of hours of sleep 3.331 0.632 1/1056 8.038 0.005 intensity of contacts with natural environment 3.027 1.336 1/1056 6.2143 0.013 time spent in nature 3.027 0.535 1/1056 32.006 <<0.001 diversity of activities in nature -1.294 0.560 1/1056 5.354 0.021 MAM3 : SARS-CoV-2 ~ physical health + number of different infection diseases + number of people in household + sport 5/1070 96.294 <<0.001 physical health -0.004 0.001 1/1066 30.635 <<0.001 number of people in household 0.030 0.009 1/1066 10.597 0.001 sport 0.022 0.010 1/1066 4.551 0.033 number of different infection diseases 0.029 0.015 1/1066 3.991 0.046 MAM4 : COVID progression ~ age + smoking + physical health + allergies + age:smoking 5/293 8.842 <<0.001 physical health -0.011 0.003 1/289 18.049 <<0.001 age 0.028 0.008 1/289 11.649 < 0.001 allergies 0.323 0.108 1/289 8.947 0.003 age : smoking -0.014 0.005 1/289 6.909 0.009 smoking 0.420 0.202 1/289 4.332 0.038 MAM5 : Allergies ~ number of different infection diseases + childhood environment + hygiene + contact with environmental diversity 5/1071 188.7 <<0.001 number of different infection diseases 0.0528 0.016 1/1060 10.722 0.001 childhood environment 0.023 0.008 1/1067 8.158 0.005 hygiene 0.042 0.015 1/1067 7.926 0.005 contact with environmental diversity -0.008 0.004 1/1067 4.974 0.026 Similar to Physical health, also the self-evaluated Mental health, that was sex-dependent (p = 0.003, Figure S5), was negatively associated with the number of different infections during life (p = 0.033, Figure S6). Surprisingly, we identified a weak negative association of the Mental health with the diversity of activities performed in nature (p = 0.021, Figure S7). This is contrasting the significant positive relationships of the Mental health with age (p < < 0.001, Figure S8), commuting (p = 0.039, Figure S9), number of hours of sleep (p = 0.005, Figure S10), time spent in nature (p < < 0.001, Figure S11) and intensity of the contacts with natural environment (p = 0.013, MAM2, Table 1 ; Table S3.2; Fig. 2 ). The infection of SARS-CoV-2 was in negative relationship with physical health (p < < 0.001, Fig. 3 ) and in positive relationship with number of people in the household (p = 0.001, Figure S12), and weakly also with the regular sport activities (p = 0.033, Figure S13) and number of infectious diseases during lifetime (p = 0.046, MAM3, Table 1 ; Table S3.3; Figure S14). Next, in the subset of the SARS-CoV-2-positive individuals (n = 327), we tested for the effect of the selected health and environmental parameters on the progression of the COVID-19 disease, expressed as occurrence of self-reported symptoms on a scale from no to severe. The results show negative association of the COVID-19 severity with physical health (p < < 0.001, Figure S15) and its positive association with smoking (p = 0.038, Figure S16), incidence of allergies (p = 0.003, Figure S17) and age (p < 0.001, Fig. 4 ). Furthermore, we detected significant interaction of age with smoking (p = 0.009). Our analysis did not show any link between the COVID-19 progression and contacts of the individual with natural environment or its diversity (MAM4, Table 1 ; Table S3.4). Finally, we focused on the relationship between the natural environment diversity and incidence of allergies. Our analysis revealed significant positive effects of the number of infectious diseases during life (p < < 0.001, Figure S18), childhood environment (scaled from countryside to metropolis, p = 0.005, Figure S19) and hygiene (p = 0.005, Figure S20) and significant negative effect of the contacts with natural environment diversity (p = 0.024, MAM 5, Table 1 ; Table S3.5; Fig. 5 ) on the incidence of allergies. Discussion Our results indicate that the general self-reported health status of an individual (including physical and mental health and allergies incidence), which further affects the outcomes of infectious diseases, including e.g., the COVID-19 progression, is linked with the time spent in nature, intensity of the contacts with nature and their diversity. We evidenced positive associations between the time spent in nature and physical health, and between the intensity of the contacts with natural environment and mental health. Furthermore, we reveal negative association between the diversity in the contacts with natural environment and incidence of allergies. Our data also show negative association of the SARS-CoV-2 infection with physical health and several lifestyle parameters and dependence of the COVID-19 progression on age, physical health, allergies, and smoking. However, in our dataset we were not able to directly link the SARS-CoV-2 infection or the COVID-19 severity with any parameter describing the level of contacts with nature or environmental diversity. During the last century, human population worldwide experienced important shifts in prevalence and effects of diseases of various types. While improved hygiene and medical care decreased mortality due to microbial infections, especially the modern societies in developed countries are experiencing a continuous increase in prevalence of allergies, autoimmune and chronic inflammatory diseases, as well as psychiatric and metabolic disorders 27 – 30 . Number of studies reported the importance of contacts with nature on health and condition 31 . The same pattern was observed in our current results. Multiple lines of evidence support the fact that living in an environment enriched with biodiversity is associated with decrease in overall early mortality in adults 32 . Apart to the effects on physical health, intensity of the contacts with natural environments and time spent in nature were also shown to positively affect mental health of children as well as adults 4 , 33 , 34 . Even early life exposure to nature has been repeatedly shown to provide positive effects on later mental health during life 35 . In line with that, our data suggest the link between intensity of the contacts with nature and natural environmental diversity with mental health. This relationship could result from psychological effects of natural environmental structures or from the variation in access to sunlight 36 – 38 . Surprisingly, we detected also the positive association between the commuting time and both physical and mental health. This might support the sunlight hypothesis 39 – 41 or alternatively, it has been previously suggested that commuting might represent a mild eustress which improves the physical and mental resilience of an organism 42 . Another possibility is a positive effect of mild pathogen exposure during commuting, consistent with the hygiene hypothesis 43 . Apart from the positive effects of exercise on body condition and psychological balance, the association between the contacts with nature and health can be explained also on the basis of the Hygiene hypothesis of allergies 2 , 44 and the related Biodiversity hypothesis 6 . It has been suggested that human immune system is adapted to optimal regulatory balance with stimulation through the antigenic diversity of their original living environments 6 , 11 . Human immunity evolved in close contacts with diversified wildlife, but also many natural commensals and pathogens. Antigenic diversity presented to immune cells guides the immune system development and regulation 7 – 9 , 12 . Yet, it is a trend of modern human lifestyle to inhabit urban environments that are poor in antigenic diversity and providing diminished contacts with natural microbial communities 13 . The decrease in antigenic diversity can impair immunological tolerance and promote inflammatory pathways that eventually contribute to progression of diseases and health disorders 6 . The rate of smoking seems to be negatively associated with SARS-CoV-2 infection, however also protective effects of smoking on COVID-19 progression were recorded 45 , 46 . In our dataset, we were not able to directly link the SARS-CoV-2 infection or the COVID-19 severity with any parameter describing the level of contact with nature or environmental diversity. This could possibly result from the low number of respondents in our survey, namely between the COVID-positive individuals. However, an indirect connection can be still assumed through the links of the COVID progression to nature-associated physical health. The antigenic diversity loss is a multi-factorial process that includes excessive hygiene, life in artificial environment inside the buildings, and change in diet, further coupled with global biodiversity loss and stressful lifestyle disrupting the physiological balance 47 , 48 . It has been revealed that natural composition of microbiome sets tolerogenic immunity mediated though Treg/IgA responses. Shifts in microbial diversity can trigger pro-inflammatory responses against common natural antigens, activating Th1 cells and IgE production 12 . This may elicit chronic inflammation which acts as the causative agent in many “modern” diseases. This view is supported by evidence linking environmental variation to immune-related disorders. For example, children growing up on farms were reported to suffer less frequently from allergies 24 , 49 . In line with the assumed physiological mechanism, enrichment of the individual microbiome with commensal symbionts can attenuate chronic inflammatory disorders 9 , 50 . In our data, adults that grew up during their childhood in bigger cities suffered more commonly with allergies. Furthermore, individuals experiencing closer contacts with natural environments that are rich in biodiversity suffered less frequently from allergies than individuals lacking these contacts. Therefore, our results support the Hygiene hypothesis and Biodiversity hypothesis of allergies and highlight the adverse effects of biodiversity loss in the anthropogenic environments on human health. It has been suggested that the pattern linking the contacts with environmental diversity with health could be driven by the direct positive effects of sports-related physical training 51 . However, this is unlikely in our data because our analysis controlled for the direct effects of sports. Sports were revealed as positively contributing only to physical health and SARS-CoV-2 infection incidence which is in accordance with the previous study by Flegr et al. 46 . Yet, it has to be admitted that our research suffers from several limitations that might have caused decreased significance of the individual associations detected or impaired their interpretations. Among those we can include auto-selection of the respondents or subjective assessment of their own health or mental state that could mismatch with the objective clinical state. In addition to this, a persistent challenge in cross-sectional studies, including ours, is that they cannot answer the causality of the observed associations. Previous research has shown that in addition to correlative results, there is also causal, physiological and immunological, evidence supporting the beneficial effects of living in natural environments and having contacts with biodiversity 52 , 53 . Nevertheless, such evidence is still limited and conclusively addressing this question would require a different study design. Finally, it should be noted that a more detailed analysis of contribution of individual factors was hampered by a lower than expected number of respondents. We had anticipated the participation of approximately 10,000 subjects in the preregistration. However, this milestone was not achieved, possibly due to a prevailing weariness regarding COVID-related research within the Czech population during the latter stages of the pandemic. Nevertheless, the number of responses obtained was still sufficient for testing the main hypotheses and comparable to other similar questionnaire studies targeting public health 24 , 25 . Conclusions Our results suggest that self-reported health condition, including incidence of allergies, physical and mental health, is associated with intensity and diversity of the contacts with natural environmental diversity. While multiple explanations can be offered, these findings are in agreement with the Biodiversity hypothesis, linking environmental antigenic composition with modulation of immune function and resistance to immunopathologies. Modern lifestyle related to environmental biodiversity loss leads to disruption of the long-evolved homeostasis in physiological processes, allowing the outbreak of “modern” diseases including chronic inflammatory diseases, allergies, metabolic and psychiatric disorders. Our research thus indicates the value of the human contacts with nature and natural diversity of antigens in the environment. Since the frequency and quality of the human contacts with nature and wildlife are conditioned by the environmental health, this study aids to reveal the importance of biodiversity conservation in the human living environment for the good health maintenance, consistent with the concept of One Health. Declarations Acknowledgement We would like to thank all the survey respondents for their involvement. We are also grateful to Klára Klečková, Alžběta Kocábková and Nikol Míková for their help with the survey organisation. This study was supported by the Grant Schemes at Charles University (grant no. START/SCI/113 with reg. no. CZ.02.2.69/0.0/0.0/19_073/0016935). The study was further supported by the Institutional Research Support No. 260684/2023. Author contributions Conceptualization: DD, JT, JF, MV Data Curation: DD Formal Analysis: DD Funding Acquisition: DD Investigation: DD, MV Methodology: DD, JT, JF, MV Project Administration: DD, MV Resources: n/a Software: n/a Supervision: MV Validation: n/a Visualization: DD Writing – Original Draft Preparation: DD, MV Writing – Review and Editing: DD, JT, JF, MV Data Availability Data is provided within the manuscript or supplementary information files References Bosma-den Boer, M. M., van Wetten, M.-L. & Pruimboom, L. Chronic inflammatory diseases are stimulated by current lifestyle: how diet, stress levels and medication prevent our body from recovering. Nutr. Metab. 9, 32 (2012). Rook, G. A. W. Hygiene Hypothesis and Autoimmune Diseases. Clin. Rev. Allergy Immunol. 42, 5–15 (2012). Rook, G. A. W., Lowry, C. A. & Raison, C. L. Microbial ‘Old Friends’, immunoregulation and stress resilience. Evol. Med. Public Health 2013, 46–64 (2013). Laprise, C. 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Charoenngam, N. & Holick, M. F. Immunologic Effects of Vitamin D on Human Health and Disease. Nutrients 12, 2097 (2020). Bell, S. L., Audrey, S., Gunnell, D., Cooper, A. & Campbell, R. The relationship between physical activity, mental wellbeing and symptoms of mental health disorder in adolescents: a cohort study. Int. J. Behav. Nutr. Phys. Act. 16, 138 (2019). Stanhope, J., Breed, M. & Weinstein, P. Biodiversity, Microbiomes, and Human Health. in Evolution, Biodiversity and a Reassessment of the Hygiene Hypothesis (eds. Rook, G. A. W. & Lowry, C. A.) vol. 89 67–104 (Springer International Publishing, Cham, 2022). Bloomfield, S. F., Stanwell-Smith, R., Crevel, R. W. R. & Pickup, J. Too clean, or not too clean: the Hygiene Hypothesis and home hygiene. Clin. Htmlent Glyphamp Asciiamp Exp. Allergy 36, 402–425 (2006). Reddy, R. K. et al. The effect of smoking on COVID-19 severity: A systematic review and meta‐analysis. J. Med. Virol. 93, 1045–1056 (2021). Flegr, J., Flegr, P. & Příplatová, L. The effects of 105 biological, socioeconomic, behavioral, and environmental factors on the risk of SARS-CoV-2 infection and a severe course of COVID-19: a prospective, explorative cohort study. Biol. Methods Protoc. 7, bpac030 (2022). Aguilera, M., Vergara, P. & Martínez, V. Environment-Related Adaptive Changes of Gut Commensal Microbiota Do not Alter Colonic Toll-Like Receptors but Modulate the Local Expression of Sensory-Related Systems in Rats. Microb. Ecol. 66, 232–243 (2013). Vagnerová, K. et al. Interactions Between Gut Microbiota and Acute Restraint Stress in Peripheral Structures of the Hypothalamic–Pituitary–Adrenal Axis and the Intestine of Male Mice. Front. Immunol. 10, (2019). Ege, M. et al. Prenatal farm exposure is related to the expression of receptors of the innate immunity and to atopic sensitization in school-age children. J. Allergy Clin. Immunol. 117, 817–823 (2006). Fleming, J. et al. Probiotic helminth administration in relapsing–remitting multiple sclerosis: a phase 1 study. Mult. Scler. J. 17, 743–754 (2011). Rhodes, R. E., Janssen, I., Bredin, S. S. D., Warburton, D. E. R. & Bauman, A. Physical activity: Health impact, prevalence, correlates and interventions. Psychol. Health 32, 942–975 (2017). Bateson, M. & Matheson, S. Performance on a categorisation task suggests that removal of environmental enrichment induces ‘pessimism’ in captive European starlings (Sturnus vulgaris). undefined (2007). Aerts, R., Honnay, O. & Van Nieuwenhuyse, A. Biodiversity and human health: mechanisms and evidence of the positive health effects of diversity in nature and green spaces. Br. Med. Bull. 127, 5–22 (2018). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 30 Jul, 2024 Read the published version in Scientific Reports → Version 1 posted Reviews received at journal 26 May, 2024 Reviewers agreed at journal 17 May, 2024 Reviews received at journal 30 Apr, 2024 Reviewers agreed at journal 17 Apr, 2024 Reviewers invited by journal 29 Mar, 2024 Editor assigned by journal 29 Mar, 2024 Editor invited by journal 23 Mar, 2024 Submission checks completed at journal 23 Mar, 2024 First submitted to journal 12 Mar, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4085638","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":284220495,"identity":"1ccc92b9-72cc-44e3-8409-3d86512a0b04","order_by":0,"name":"Daniel Divín","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCklEQVRIie2RsWoCQRCGZ1nQZk/bWQ7zDAPXJJDkWRRbDSkDAaMIk8Zoa4qQ17Dc5QqbTWyFlIFUBg7SJJAinho0sJ5tiv1YWBj+j52ZBQgE/iMmP5cgGEQXsm0dDyi0VsR4Gy1WIFe6y0uqwuiGyvTJmoygNsQmv55Nzjv0YsRHNDmG6sh4Fe0u6nZMkDA2bpO2ayI912UcOQQ0foVMi1JF0GBlOW6zRHJQkhEj0KpZjzJbUPr9q5zwzY4i/bPQfPkK5Eq5x7HgdEcp+RU9X5AdECa5ou94qu+d6OsHRoVuz8ZmrST7vDqtPfbLb/jF19WKkzZ7587Rvo1t+PMb67FVUT4QCAQCxfwAPBhWFSZyZW0AAAAASUVORK5CYII=","orcid":"","institution":"Charles University","correspondingAuthor":true,"prefix":"","firstName":"Daniel","middleName":"","lastName":"Divín","suffix":""},{"id":284220497,"identity":"c2023423-3fd4-407f-8e07-991975088880","order_by":1,"name":"Jan Toman","email":"","orcid":"","institution":"Charles University","correspondingAuthor":false,"prefix":"","firstName":"Jan","middleName":"","lastName":"Toman","suffix":""},{"id":284220498,"identity":"85d257e0-2b0a-4b89-9b3a-68d60670c137","order_by":2,"name":"Jaroslav Flegr","email":"","orcid":"","institution":"Charles University","correspondingAuthor":false,"prefix":"","firstName":"Jaroslav","middleName":"","lastName":"Flegr","suffix":""},{"id":284220502,"identity":"058f8827-3995-4c6c-b2b2-ab281d155147","order_by":3,"name":"Michal Vinkler","email":"","orcid":"","institution":"Charles University","correspondingAuthor":false,"prefix":"","firstName":"Michal","middleName":"","lastName":"Vinkler","suffix":""}],"badges":[],"createdAt":"2024-03-12 16:16:59","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4085638/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4085638/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-024-67489-6","type":"published","date":"2024-07-30T15:57:45+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":53583354,"identity":"c2e80948-fc70-4bc3-aeb9-62298a78493c","added_by":"auto","created_at":"2024-03-27 17:47:03","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":10227,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePositive association between the physical health and time spent in nature. \u003c/strong\u003ePhysical health is scaled from 0 (worst physical health), to 100 (best physical health). Time spent in nature is scaled from 1 (no regular time spent in nature), to 6 (every day activity in nature). The graph was created using the \u003cem\u003evisreg\u003c/em\u003e function, which visualises the response variable treated on the effects of other significant variables represented in the minimum adequate model (MAM 1, Table 1).\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4085638/v1/6639cf8e4cf6d877576ac3aa.png"},{"id":53583356,"identity":"40f49601-3dce-4e73-a28c-00c2a031536e","added_by":"auto","created_at":"2024-03-27 17:47:03","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":9473,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePositive association of mental health and contact with nature. \u003c/strong\u003eMental health is scaled from 0 (bad mental health) to 100 (best mental health). Contact with nature is scaled from 0 (minimal or no contact) to 3 (intensive contact). The graph was created using the \u003cem\u003evisreg\u003c/em\u003e function which visualises the response variable treated on the effects of other significant variables in the minimum adequate model (MAM 2, Table 1).\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-4085638/v1/752f9d63877c73fa617f89b2.png"},{"id":53583355,"identity":"540dbe85-7419-4f92-aecb-05ff938670a6","added_by":"auto","created_at":"2024-03-27 17:47:03","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":24165,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eNegative association of SARS-Cov-2 infection with physical health. \u003c/strong\u003eSelf-reported physical health is expressed on a scale from 0 (worst physical health) to 100 (best physical health). The graph was created using the \u003cem\u003evisreg\u003c/em\u003e function which visualises the response variable treated on the effects of other significant variables in the minimum adequate model (MAM 3, Table 1).\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-4085638/v1/48c8fdd1bcb2891e56a3365d.png"},{"id":53583357,"identity":"c6e6446b-b172-45c3-b8d8-ae41effbc92d","added_by":"auto","created_at":"2024-03-27 17:47:03","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":9831,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePositive association of the COVID-19 progression symptoms with age (years). \u003c/strong\u003eSelf-reported COVID-19 infection symptoms on a scale from 0 (no symptoms) to 5 (very severe symptoms) were more severe progression was reported in individuals of advanced age. The graph was created using the \u003cem\u003evisreg\u003c/em\u003efunction which visualises the response variable treated on the effects of other significant variables in the minimum adequate model (MAM 4, Table 1).\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-4085638/v1/069bd1cfc022fd156e980e13.png"},{"id":53583358,"identity":"5e0d01b9-ec38-4f31-bb74-b1a7d2a9a8e5","added_by":"auto","created_at":"2024-03-27 17:47:03","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":13345,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eNegative association of the incidence of allergies and contact with environmental diversity. \u003c/strong\u003eThe variable “Contact with environmental diversity” represents PC1 score obtained from the PCA of variables: intensity of the contacts with natural environment, intensity of the contacts with animals, diversity of animals in contact, diversity of plants in contact, time spent in nature, diversity of activities in nature now and diversity of activities in nature during childhood. The graph was created using the \u003cem\u003evisreg\u003c/em\u003e function which visualises the response variable treated on the effects of other significant variables in the minimum adequate model (MAM 5, Table 1).\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-4085638/v1/82e0c083b2d5dfc32e12255b.png"},{"id":61793969,"identity":"b6706a8a-1140-440f-9525-75d32540d72c","added_by":"auto","created_at":"2024-08-05 16:17:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":669492,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4085638/v1/e61348b0-bd71-431c-b0ee-136903129f44.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Contacts with environmental biodiversity affect human health: links to allergies, physical and mental health revealed during the initial waves of the COVID-19 pandemic","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDramatic changes in the human lifestyle over the past century significantly shifted various physiological regulations from their optima earlier selected throughout evolution \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Recently, especially in high-income countries we have observed a massive increase in health disorders that can be linked to inflammation, such as increased susceptibility to immunopathologies and higher incidence of allergies \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. These current health challenges are multifactorial, complex and global \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Although not yet clearly recognised, these issues may be related to decreased environmental health.\u003c/p\u003e \u003cp\u003eDerived from the Hygiene hypothesis \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e, the Biodiversity hypothesis predicts the importance of contacts of individuals with heterogeneity of antigens derived from the natural environment, including pathogens and symbionts \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. During ontogenetic development, immune system harnesses the richness of environmental antigens to set an optimal regulation of immune tolerance, balancing the affordable protection against the pathogens with costs resulting from immunopathology in a given environmental context \u003csup\u003e\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Combined effects of the contacts with microbes and parasites naturally colonising host bodies during childhood and also later during life are expected to contribute to immunomodulation \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Absence of various immunomodulatory compounds in the modern urban environment can alter tolerogenic immune responses to common antigens into overreactive pro-inflammatory responses \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. A shift has been suggested in the immune regulation balance from Treg/Th2-IgA-pruducing responses towards Th1 responses combined with IgE production responsible for exaggerated tissue damage in reaction to recognition of natural antigens \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Such changes in human-environment balance modulating immune regulation can also be tracked through the health trends indicated in population surveys \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Despite to certain level subjective, self-administered questionnaires used for epidemiologic surveys show good reproducibility \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e and offer important insights into the environmental associations with diseases \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e, although their ability to reveal direct causality is limited.\u003c/p\u003e \u003cp\u003eAlthough proposed primarily for allergies, the impact of such regulation can be much wider and affect also other diseases, including infections, where pathology often results from the inflammatory over-responsiveness \u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Similar to regulation of allergies, also regulation of immune responses to pathogens can be modulated by environmental changes that are associated with altered composition of the host\u0026rsquo;s symbiotic microbiota \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Current results show that different people responded differently to a novel coronavirus infection caused by the SARS-CoV-2 virus, assumingly dependent on their genetic background \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e, but also lifestyle and living environment \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eUntil recently, advances in medical care diminished the public awareness of the health threats resulting from infectious diseases \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. However, the global pandemic of SARS-CoV-2 between 2019 and 2022, causing respiratory disease COVID-19, renewed the general interest in infectious diseases and facilitated public health questionnaire studies. Here we hypothesise that through decreased tolerogenic immune regulation, the lack of contacts with natural environmental diversity (biodiversity-related antigen richness) could increase the risk of COVID-19 infection and/or its severity, having in parallel analogous impact on selected \u0026ldquo;modern\u0026rdquo; diseases including allergies. We predict that controlling for age, sex, body mass, health, sport activities and socio-economic background, on a population level the self-reported COVID-19 disease progression will be milder, allergies less frequent and health improved in people experiencing increased direct contacts with wildlife, domestic animals, and plants that serve as sources of natural biodiversity of antigens.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData structure and respondents\u003c/h2\u003e \u003cp\u003eThis survey study was pre-registered on OSF (created: 2021-05-18; \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://osf.io/x4zyv/?view_only=f22560412c55449daa22a6266b2cb842\u003c/span\u003e\u003cspan address=\"https://osf.io/x4zyv/?view_only=f22560412c55449daa22a6266b2cb842\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). We used the tool Qulatrics (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.qualtrics.com/\u003c/span\u003e\u003cspan address=\"https://www.qualtrics.com/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) to create an online questionnaire. This questionnaire was available from 27 May 2021 through our website (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://web.natur.cuni.cz/zoology/eei/\u003c/span\u003e\u003cspan address=\"https://web.natur.cuni.cz/zoology/eei/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) and the site link was sent to various organisations involved in nature protection, animal and plant care (zoological and botanical gardens), schools and universities, and shared on social media used throughout the Czech Republic. Before commencing the questionnaire, participants received clear information that the study was performed for research purposes, and that the participation is voluntary and anonymous. To participate in the study, respondents had to provide informed consent by clicking the respective button. The questionnaire took approximately one hour to complete. The Institutional Review Board of the Faculty of Science, Charles University approved the project and the process of obtaining informed consent (No. 2020/25). The study was performed in accordance with relevant guidelines and regulations.\u003c/p\u003e \u003cp\u003eIn the questionnaire's anamnestic section, respondents were asked about their age, sex (assigned at birth), height, weight, and selection from multiple-choice lists on previous infections, vaccination, and allergies. They also answered three questions evaluating their current, usual and before-COVID physical health and three analogous questions on their mental health. Further, the respondents answered 10 questions regarding their living, work, and childhood environment (7-item scale from the countryside to metropolis), commuting, smoking, and daily hygiene. Next, the respondents were asked about their outdoor activities, contacts with plants and animals, as well as overall environmental diversity. Respondents used Likert scales for their answers, or they wrote in the exact number or chose an exact option. Crucially, they had to answer whether they were tested positively for SARS-CoV-2, which type of test they used (from options: PCR, antigenic or antibody test) and what was the disease progression (subjective severity assessment of the disease course on scale from asymptomatic to hospitalization on intensive care unit). The questionnaire containing the original questions and all answers obtained (in Czech) are available in Supplementary material 1. After seven months we closed the survey and downloaded the available data. We tested selected health parameters (physical and mental health, SARS-CoV-2 infection, COVID-19 progression and presence of allergies) as the variables dependent on selected environmental and lifestyle factors. All variables with multiple levels in scale were transformed to a numeral scale and all yes/no answers were treated as factors. Parameters indicating diversity, such as diversity of environmental activities, or animals and plants kept in households, or pathogen-borne diseases throughout life, were summed as the total number of realised options and further used as a continuous variables. All variables used for the statistical analysis are explained in detail in Table S2.1 in the Supplementary material 2. All pre-processed data used for the statistics are listed in Table S2.2. Original data are provided in Table S2.3. We used a correlation matrix and Principal Component Analysis (PCA) to reduce the number of individual variables adopted our statistical models (see Table S2.4). Importantly, the variable \u0026ldquo;contact with environmental diversity\u0026rdquo; was constructed as PC1 scores obtained from the PCA of all surveyed variables connected with activities conducted in nature or concerning animals, plants or wildlife.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eDataset and Statistics\u003c/h2\u003e \u003cp\u003eIn total, we collected 1811 survey responses which is comparable to datasets obtained from other similar questionnaire-based health surveys \u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. We first filtered out any answers from unfinished survey responses, retaining 1188 valid responses for the analysis. We created two datasets, first one with all the valid responses and a second one containing only the subset of self-reported SARS-CoV-2 positive individuals (327 responses).\u003c/p\u003e \u003cp\u003eFirst, we tested if the self-reported usual physical health state was associated with incidence of allergies, number of infectious diseases during life, and selected lifestyle factors, including the contacts with various environmental diversity parameters (model structure shown in Table S2.5). In case of the significance of the composite variable contact with environmental diversity in a model, the statistics was repeated, using the original individual variables: intensity of the contacts with natural environment, intensity of the contacts with animals, diversity of animals in contact, diversity of plants in contact, time spent in nature, diversity of activities in nature at presence and diversity of activities in nature during childhood (Table S2.4). Then, using similar approach, we tested analogous associations also for the self-reported mental health, SARS-Cov-2 infection and COVID-19 progression, and incidence of allergies, adopted as response variables (see all the full models listed in Table S2.5). In all cases the relationships were tested using linear models (LMs) and in the case of a categorical variable (0/1) by the general linear models (GLM) in the \u0026lsquo;Ime4 package\u0026rsquo; in R studio version 3.6.2 \u003csup\u003e26\u003c/sup\u003e. Minimum adequate models (MAMs; here defined as models with all terms significant at p\u0026thinsp;\u0026le;\u0026thinsp;0.05) were identified by backward elimination of non-significant terms from the full models. All backward elimination steps in the models were verified by changes in deviance with an accompanying change in degrees of freedom (ANOVA) and Akaike information criterion (AIC), using F-statistics.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe analysed dataset contained 768 women (mean age\u0026thinsp;=\u0026thinsp;37.99, sd\u0026thinsp;=\u0026thinsp;12.80) and 420 men (mean age\u0026thinsp;=\u0026thinsp;38.97, sd\u0026thinsp;=\u0026thinsp;13.14). SARS-CoV-2 infection (codes: negative\u0026thinsp;=\u0026thinsp;861, positive\u0026thinsp;=\u0026thinsp;327) was reported by both women (205, i.e., 26.69% were positive) and men (122, i.e., 29.05% were positive). The effect of sex on self-reported SARS-CoV-2 positivity was not significant (OR\u0026thinsp;=\u0026thinsp;0.889, C.I.95\u0026thinsp;=\u0026thinsp;0.683\u0026ndash;1.160, p\u0026thinsp;\u0026lt;\u0026thinsp;0.386).\u003c/p\u003e \u003cp\u003eThe feeling of self-reported physical healthiness (Physical health) was significantly negatively associated with the number of different infection diseases during life, (p\u0026thinsp;\u0026lt;\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Figure S1) and positively with commuting (p\u0026thinsp;=\u0026thinsp;0.010, Figure S2), sports (p\u0026thinsp;=\u0026thinsp;0.009, Figure S3), number of hours of sleep (p\u0026thinsp;=\u0026thinsp;0.033, Figure S4) and time spent in nature (p\u0026thinsp;\u0026lt;\u0026thinsp;\u0026lt;\u0026thinsp;0.001, MAM1, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e; Table S3.1; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eComplete list of the Minimum adequate models (MAMs).\u003c/b\u003e Df\u0026thinsp;=\u0026thinsp;degrees of freedom, MAM\u0026thinsp;=\u0026thinsp;minimal adequate model, SE\u0026thinsp;=\u0026thinsp;standard error.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMinimum adequate model\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEstimate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSE\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDf\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMAM1\u003c/b\u003e: Physical health\u0026thinsp;~\u0026thinsp;number of different infection diseases\u0026thinsp;+\u0026thinsp;commuting\u0026thinsp;+\u0026thinsp;sport\u0026thinsp;+\u0026thinsp;sleep\u0026thinsp;+\u0026thinsp;time spent in nature\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/1058\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3654.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003enumber of different infection diseases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-3.127\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.572\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/1059\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e29.941\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecommuting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.538\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.209\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/1059\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.610\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003esport\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.089\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.421\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/1059\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.687\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003enumber of hours of sleep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.079\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.506\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/1059\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.541\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.033\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003etime spent in nature\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.120\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.383\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/1059\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e30.652\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMAM2\u003c/b\u003e: Mental health\u0026thinsp;~\u0026thinsp;sex\u0026thinsp;+\u0026thinsp;age\u0026thinsp;+\u0026thinsp;number of different infection diseases\u0026thinsp;+\u0026thinsp;commuting\u0026thinsp;+\u0026thinsp;number of hours of sleep\u0026thinsp;+\u0026thinsp;intensity of contacts with natural environment\u0026thinsp;+\u0026thinsp;time spent in nature\u0026thinsp;+\u0026thinsp;diversity of activities in nature\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/1064\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1466.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003esex (males)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.071\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6.751\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/1056\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8.703\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.265\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.380\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/1056\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e23.146\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003enumber of different infection diseases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-1.512\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.711\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/1056\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.530\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.034\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecommuting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.793\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.262\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/1056\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.292\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.039\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003enumber of hours of sleep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.331\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.632\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/1056\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8.038\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eintensity of contacts with natural environment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.027\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.336\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/1056\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.2143\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.013\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003etime spent in nature\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.027\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.535\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/1056\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e32.006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ediversity of activities in nature\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-1.294\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.560\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/1056\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5.354\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.021\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMAM3\u003c/b\u003e: SARS-CoV-2\u0026thinsp;~\u0026thinsp;physical health\u0026thinsp;+\u0026thinsp;number of different infection diseases\u0026thinsp;+\u0026thinsp;number of people in household\u0026thinsp;+\u0026thinsp;sport\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5/1070\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e96.294\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ephysical health\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/1066\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e30.635\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003enumber of people in household\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.030\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/1066\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10.597\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003esport\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/1066\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.551\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.033\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003enumber of different infection diseases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.029\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/1066\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.991\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.046\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMAM4\u003c/b\u003e: COVID progression\u0026thinsp;~\u0026thinsp;age\u0026thinsp;+\u0026thinsp;smoking\u0026thinsp;+\u0026thinsp;physical health\u0026thinsp;+\u0026thinsp;allergies\u0026thinsp;+\u0026thinsp;age:smoking\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5/293\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8.842\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ephysical health\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/289\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e18.049\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.028\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/289\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e11.649\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eallergies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.323\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.108\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/289\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8.947\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eage : smoking\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/289\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.909\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003esmoking\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.420\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.202\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/289\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.332\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.038\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMAM5\u003c/b\u003e: Allergies\u0026thinsp;~\u0026thinsp;number of different infection diseases\u0026thinsp;+\u0026thinsp;childhood environment\u0026thinsp;+\u0026thinsp;hygiene\u0026thinsp;+\u0026thinsp;contact with environmental diversity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5/1071\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e188.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003enumber of different infection diseases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.0528\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/1060\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10.722\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003echildhood environment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/1067\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8.158\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ehygiene\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.042\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/1067\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7.926\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003econtact with environmental diversity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/1067\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.974\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.026\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eSimilar to Physical health, also the self-evaluated Mental health, that was sex-dependent (p\u0026thinsp;=\u0026thinsp;0.003, Figure S5), was negatively associated with the number of different infections during life (p\u0026thinsp;=\u0026thinsp;0.033, Figure S6). Surprisingly, we identified a weak negative association of the Mental health with the diversity of activities performed in nature (p\u0026thinsp;=\u0026thinsp;0.021, Figure S7). This is contrasting the significant positive relationships of the Mental health with age (p\u0026thinsp;\u0026lt;\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Figure S8), commuting (p\u0026thinsp;=\u0026thinsp;0.039, Figure S9), number of hours of sleep (p\u0026thinsp;=\u0026thinsp;0.005, Figure S10), time spent in nature (p\u0026thinsp;\u0026lt;\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Figure S11) and intensity of the contacts with natural environment (p\u0026thinsp;=\u0026thinsp;0.013, MAM2, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e; Table S3.2; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe infection of SARS-CoV-2 was in negative relationship with physical health (p\u0026thinsp;\u0026lt;\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) and in positive relationship with number of people in the household (p\u0026thinsp;=\u0026thinsp;0.001, Figure S12), and weakly also with the regular sport activities (p\u0026thinsp;=\u0026thinsp;0.033, Figure S13) and number of infectious diseases during lifetime (p\u0026thinsp;=\u0026thinsp;0.046, MAM3, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e; Table S3.3; Figure S14).\u003c/p\u003e \u003cp\u003eNext, in the subset of the SARS-CoV-2-positive individuals (n\u0026thinsp;=\u0026thinsp;327), we tested for the effect of the selected health and environmental parameters on the progression of the COVID-19 disease, expressed as occurrence of self-reported symptoms on a scale from no to severe. The results show negative association of the COVID-19 severity with physical health (p\u0026thinsp;\u0026lt;\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Figure S15) and its positive association with smoking (p\u0026thinsp;=\u0026thinsp;0.038, Figure S16), incidence of allergies (p\u0026thinsp;=\u0026thinsp;0.003, Figure S17) and age (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Furthermore, we detected significant interaction of age with smoking (p\u0026thinsp;=\u0026thinsp;0.009). Our analysis did not show any link between the COVID-19 progression and contacts of the individual with natural environment or its diversity (MAM4, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e; Table S3.4).\u003c/p\u003e \u003cp\u003eFinally, we focused on the relationship between the natural environment diversity and incidence of allergies. Our analysis revealed significant positive effects of the number of infectious diseases during life (p\u0026thinsp;\u0026lt;\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Figure S18), childhood environment (scaled from countryside to metropolis, p\u0026thinsp;=\u0026thinsp;0.005, Figure S19) and hygiene (p\u0026thinsp;=\u0026thinsp;0.005, Figure S20) and significant negative effect of the contacts with natural environment diversity (p\u0026thinsp;=\u0026thinsp;0.024, MAM 5, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e; Table S3.5; Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e) on the incidence of allergies.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur results indicate that the general self-reported health status of an individual (including physical and mental health and allergies incidence), which further affects the outcomes of infectious diseases, including e.g., the COVID-19 progression, is linked with the time spent in nature, intensity of the contacts with nature and their diversity. We evidenced positive associations between the time spent in nature and physical health, and between the intensity of the contacts with natural environment and mental health. Furthermore, we reveal negative association between the diversity in the contacts with natural environment and incidence of allergies. Our data also show negative association of the SARS-CoV-2 infection with physical health and several lifestyle parameters and dependence of the COVID-19 progression on age, physical health, allergies, and smoking. However, in our dataset we were not able to directly link the SARS-CoV-2 infection or the COVID-19 severity with any parameter describing the level of contacts with nature or environmental diversity.\u003c/p\u003e \u003cp\u003eDuring the last century, human population worldwide experienced important shifts in prevalence and effects of diseases of various types. While improved hygiene and medical care decreased mortality due to microbial infections, especially the modern societies in developed countries are experiencing a continuous increase in prevalence of allergies, autoimmune and chronic inflammatory diseases, as well as psychiatric and metabolic disorders \u003csup\u003e\u003cspan additionalcitationids=\"CR28 CR29\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. Number of studies reported the importance of contacts with nature on health and condition \u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. The same pattern was observed in our current results. Multiple lines of evidence support the fact that living in an environment enriched with biodiversity is associated with decrease in overall early mortality in adults \u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. Apart to the effects on physical health, intensity of the contacts with natural environments and time spent in nature were also shown to positively affect mental health of children as well as adults \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. Even early life exposure to nature has been repeatedly shown to provide positive effects on later mental health during life \u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. In line with that, our data suggest the link between intensity of the contacts with nature and natural environmental diversity with mental health. This relationship could result from psychological effects of natural environmental structures or from the variation in access to sunlight \u003csup\u003e\u003cspan additionalcitationids=\"CR37\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. Surprisingly, we detected also the positive association between the commuting time and both physical and mental health. This might support the sunlight hypothesis \u003csup\u003e\u003cspan additionalcitationids=\"CR40\" citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e or alternatively, it has been previously suggested that commuting might represent a mild eustress which improves the physical and mental resilience of an organism \u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e. Another possibility is a positive effect of mild pathogen exposure during commuting, consistent with the hygiene hypothesis \u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eApart from the positive effects of exercise on body condition and psychological balance, the association between the contacts with nature and health can be explained also on the basis of the Hygiene hypothesis of allergies \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e and the related Biodiversity hypothesis \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. It has been suggested that human immune system is adapted to optimal regulatory balance with stimulation through the antigenic diversity of their original living environments \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Human immunity evolved in close contacts with diversified wildlife, but also many natural commensals and pathogens. Antigenic diversity presented to immune cells guides the immune system development and regulation \u003csup\u003e\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Yet, it is a trend of modern human lifestyle to inhabit urban environments that are poor in antigenic diversity and providing diminished contacts with natural microbial communities \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. The decrease in antigenic diversity can impair immunological tolerance and promote inflammatory pathways that eventually contribute to progression of diseases and health disorders \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. The rate of smoking seems to be negatively associated with SARS-CoV-2 infection, however also protective effects of smoking on COVID-19 progression were recorded \u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e,\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e. In our dataset, we were not able to directly link the SARS-CoV-2 infection or the COVID-19 severity with any parameter describing the level of contact with nature or environmental diversity. This could possibly result from the low number of respondents in our survey, namely between the COVID-positive individuals. However, an indirect connection can be still assumed through the links of the COVID progression to nature-associated physical health.\u003c/p\u003e \u003cp\u003eThe antigenic diversity loss is a multi-factorial process that includes excessive hygiene, life in artificial environment inside the buildings, and change in diet, further coupled with global biodiversity loss and stressful lifestyle disrupting the physiological balance \u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e,\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e. It has been revealed that natural composition of microbiome sets tolerogenic immunity mediated though Treg/IgA responses. Shifts in microbial diversity can trigger pro-inflammatory responses against common natural antigens, activating Th1 cells and IgE production \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. This may elicit chronic inflammation which acts as the causative agent in many \u0026ldquo;modern\u0026rdquo; diseases. This view is supported by evidence linking environmental variation to immune-related disorders. For example, children growing up on farms were reported to suffer less frequently from allergies \u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e. In line with the assumed physiological mechanism, enrichment of the individual microbiome with commensal symbionts can attenuate chronic inflammatory disorders \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e. In our data, adults that grew up during their childhood in bigger cities suffered more commonly with allergies. Furthermore, individuals experiencing closer contacts with natural environments that are rich in biodiversity suffered less frequently from allergies than individuals lacking these contacts. Therefore, our results support the Hygiene hypothesis and Biodiversity hypothesis of allergies and highlight the adverse effects of biodiversity loss in the anthropogenic environments on human health.\u003c/p\u003e \u003cp\u003eIt has been suggested that the pattern linking the contacts with environmental diversity with health could be driven by the direct positive effects of sports-related physical training \u003csup\u003e\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e. However, this is unlikely in our data because our analysis controlled for the direct effects of sports. Sports were revealed as positively contributing only to physical health and SARS-CoV-2 infection incidence which is in accordance with the previous study by Flegr et al. \u003csup\u003e\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e. Yet, it has to be admitted that our research suffers from several limitations that might have caused decreased significance of the individual associations detected or impaired their interpretations. Among those we can include auto-selection of the respondents or subjective assessment of their own health or mental state that could mismatch with the objective clinical state. In addition to this, a persistent challenge in cross-sectional studies, including ours, is that they cannot answer the causality of the observed associations. Previous research has shown that in addition to correlative results, there is also causal, physiological and immunological, evidence supporting the beneficial effects of living in natural environments and having contacts with biodiversity \u003csup\u003e\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e,\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003e. Nevertheless, such evidence is still limited and conclusively addressing this question would require a different study design. Finally, it should be noted that a more detailed analysis of contribution of individual factors was hampered by a lower than expected number of respondents. We had anticipated the participation of approximately 10,000 subjects in the preregistration. However, this milestone was not achieved, possibly due to a prevailing weariness regarding COVID-related research within the Czech population during the latter stages of the pandemic. Nevertheless, the number of responses obtained was still sufficient for testing the main hypotheses and comparable to other similar questionnaire studies targeting public health \u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eOur results suggest that self-reported health condition, including incidence of allergies, physical and mental health, is associated with intensity and diversity of the contacts with natural environmental diversity. While multiple explanations can be offered, these findings are in agreement with the Biodiversity hypothesis, linking environmental antigenic composition with modulation of immune function and resistance to immunopathologies. Modern lifestyle related to environmental biodiversity loss leads to disruption of the long-evolved homeostasis in physiological processes, allowing the outbreak of \u0026ldquo;modern\u0026rdquo; diseases including chronic inflammatory diseases, allergies, metabolic and psychiatric disorders. Our research thus indicates the value of the human contacts with nature and natural diversity of antigens in the environment. Since the frequency and quality of the human contacts with nature and wildlife are conditioned by the environmental health, this study aids to reveal the importance of biodiversity conservation in the human living environment for the good health maintenance, consistent with the concept of One Health.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank all the survey respondents for their involvement. We are also grateful to Kl\u0026aacute;ra Klečkov\u0026aacute;, Alžběta Koc\u0026aacute;bkov\u0026aacute; and Nikol M\u0026iacute;kov\u0026aacute; for their help with the survey organisation. This study was supported by the Grant Schemes at Charles University (grant no. START/SCI/113 with reg. no. CZ.02.2.69/0.0/0.0/19_073/0016935). The study was further supported by the Institutional Research Support No. 260684/2023.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization: DD, JT, JF, MV\u003c/p\u003e\n\u003cp\u003eData Curation: DD\u003c/p\u003e\n\u003cp\u003eFormal Analysis: DD\u003c/p\u003e\n\u003cp\u003eFunding Acquisition: DD\u003c/p\u003e\n\u003cp\u003eInvestigation: DD, MV\u003c/p\u003e\n\u003cp\u003eMethodology: DD, JT, JF, MV\u003c/p\u003e\n\u003cp\u003eProject Administration: DD, MV\u003c/p\u003e\n\u003cp\u003eResources: n/a\u003c/p\u003e\n\u003cp\u003eSoftware: n/a\u003c/p\u003e\n\u003cp\u003eSupervision: MV\u003c/p\u003e\n\u003cp\u003eValidation: n/a\u003c/p\u003e\n\u003cp\u003eVisualization: DD\u003c/p\u003e\n\u003cp\u003eWriting \u0026ndash; Original Draft Preparation: DD, MV\u003c/p\u003e\n\u003cp\u003eWriting \u0026ndash; Review and Editing: DD, JT, JF, MV\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData is provided within the manuscript or supplementary information files\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBosma-den Boer, M. 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Bull. 127, 5\u0026ndash;22 (2018).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"allergies, biodiversity antigen richness, civilization diseases, contacts with nature, infectious diseases, wildlife","lastPublishedDoi":"10.21203/rs.3.rs-4085638/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4085638/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe gradual decrease in the prevalence of serious infectious diseases over the last century has been followed by increase in so called \u0026ldquo;modern\u0026rdquo; diseases, including allergies, chronic inflammatory conditions, psychiatric, and metabolic disorders. Between 2019 and 2022, public awareness of the threat of infectious diseases in humans was renewed by the global pandemic of a new type of a coronavirus, the SARS-COV-2. This public interest opened improved possibilities to test hypotheses on the factors associated with inter-individual variation in susceptibility to infectious and \u0026ldquo;modern\u0026rdquo; diseases. Based on the Hygiene hypothesis and Biodiversity hypothesis, we predicted that contacts with natural environment and wildlife in childhood and/or in adulthood can improve general health and decrease the risks of severe COVID-19 progression or prevalence of the \u0026ldquo;modern\u0026rdquo; diseases, namely the allergies. Here we report the results of an online, self-evaluating questionnaire survey conducted in the Czech Republic, where we contrasted selected health issues, and linked them to the living environment, including the level of contacts with biodiversity. In a sample of 1188 respondents, we revealed a significant effect of time spent in nature and contacts with biodiversity on physical and mental health, and incidence of allergies. This is unlike the COVID-19 progression, which was related to age, physical health, smoking, allergies, and interaction of age with smoking, but not to contacts with the natural environmental diversity. Our findings are in agreement with the Biodiversity hypothesis of allergy and, linking human and environmental health, they urge for One Health approach application.\u003c/p\u003e","manuscriptTitle":"Contacts with environmental biodiversity affect human health: links to allergies, physical and mental health revealed during the initial waves of the COVID-19 pandemic","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-27 17:46:58","doi":"10.21203/rs.3.rs-4085638/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2024-05-26T13:29:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"158377922663137835518564573700378321985","date":"2024-05-17T13:37:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-04-30T07:22:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"ee5ba6a4-d31e-4e3a-9e3a-b0d670078b7b","date":"2024-04-17T13:04:28+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-03-29T11:11:53+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-03-29T11:08:43+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-03-23T18:01:31+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-03-23T18:00:23+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-03-12T14:28:54+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5befc37e-b9f6-451b-b493-556920647457","owner":[],"postedDate":"March 27th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":29921326,"name":"Earth and environmental sciences/Environmental sciences/Environmental impact"},{"id":29921327,"name":"Biological sciences/Ecology/Biodiversity"},{"id":29921328,"name":"Health sciences/Risk factors"},{"id":29921329,"name":"Health sciences/Diseases/Immunological disorders/Autoimmune diseases"},{"id":29921330,"name":"Biological sciences/Psychology/Human behaviour"}],"tags":[],"updatedAt":"2024-08-05T16:09:44+00:00","versionOfRecord":{"articleIdentity":"rs-4085638","link":"https://doi.org/10.1038/s41598-024-67489-6","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2024-07-30 15:57:45","publishedOnDateReadable":"July 30th, 2024"},"versionCreatedAt":"2024-03-27 17:46:58","video":"","vorDoi":"10.1038/s41598-024-67489-6","vorDoiUrl":"https://doi.org/10.1038/s41598-024-67489-6","workflowStages":[]},"version":"v1","identity":"rs-4085638","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4085638","identity":"rs-4085638","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}