key: cord-0978127-n88x2uuz
authors: Prescott, Susan L.
title: A Butterfly Flaps its Wings: Extinction of Biological Experience and the Origins of Allergy
date: 2020-05-29
journal: Ann Allergy Asthma Immunol
DOI: 10.1016/j.anai.2020.05.025
sha: 9257e3c237b5839dd717d56c42f67252d9f3cf3d
doc_id: 978127
cord_uid: n88x2uuz

OBJECTIVE: The grand global challenges of the Anthropocene are interdependent with ample evidence that reduced early-life ‘experience’ of biodiversity primes for immune dysregulation and a higher propensity low-grade inflammation, increasing the risk of allergy many other later-onset NCDs —also now implicated in the susceptibility to acute inflammation in COVID-19 infection. The objective of this review is to explore links between biodiversity on all scales and allergic disease as a measure of immune dysregulation. DATA SOURCES: Were identified from PubMed and Web of Science using search terms pertaining to biodiversity, nature-relatedness, allergic disease, microbiome, NCDs, COVID-19 and associated terms. STUDY SELECTIONS: Studies were selected based on relevance to human health and biodiversity. RESULTS: Contact with natural environments enriches the human microbiome, promotes regulated immune responses, and protects from allergy and both acute and chronic inflammatory disorders. These important links to eco-psychological constructs of the ‘extinction of experience’ which indicates that loss of direct, personal contact with biodiversity—wildlife and the more visible elements of the natural world—might lead to emotional apathy and irresponsible behaviors toward the environment. CONCLUSION: The immune system is a useful early barometer of environmental impacts, and via the microbiome, a measure of the way in which our current experiences differ from our ancestral past. While we would benefit from further research, efforts to increase direct, personal contact with biodiversity have clear benefits for multiple aspect of physical and mental health, the skin and gut microbiome, immune function, food choices, sleep, physical activity, and promotes environmental responsibility.

Objective : The grand global challenges of the Anthropocene are interdependent with ample evidence that reduced early-life 'experience' of biodiversity primes for immune dysregulation and a higher propensity low-grade inflammation, increasing the risk of allergy many other lateronset NCDs -also now implicated in the susceptibility to acute inflammation in COVID-19 infection. The objective of this review is to explore links between biodiversity on all scales and allergic disease as a measure of immune dysregulation.

Data Sources : Were identified from PubMed and Web of Science using search terms pertaining to biodiversity, nature-relatedness, allergic disease, microbiome, NCDs, COVID-19 and associated terms.

Study Selections : Studies were selected based on relevance to human health and biodiversity.

Results : Contact with natural environments enriches the human microbiome, promotes regulated immune responses, and protects from allergy and both acute and chronic inflammatory disorders. These important links to eco-psychological constructs of the 'extinction of experience' which indicates that loss of direct, personal contact with biodiversity-wildlife and the more visible elements of the natural world-might lead to emotional apathy and irresponsible behaviors toward the environment.

Conclusion : The immune system is a useful early barometer of environmental impacts, and via the microbiome, a measure of the way in which our current experiences differ from our ancestral past. While we would benefit from further research, efforts to increase direct, personal contact with biodiversity have clear benefits for multiple aspect of physical and mental health, the skin and gut microbiome, immune function, food choices, sleep, physical activity, and promotes environmental responsibility.

interconnectivity between changing environments (at macro, meso, and micro scales) impacts 23 the human immune system from the first moments of development.

Indeed, it has been suggested that the allergy disease epidemic is a "canary in the coalmine" 25 that exposes the impact of modern environmental change, and in particular, the specific 26 vulnerability of the immune system-which wider significance for other aspects of health. 27 The early-life 'experience' of the immune system now appears to prime for a propensity for 28 low-grade inflammation and immune dysregulation, increasing the risk of many other later- 29 onset NCDs. In effect, the immune system is a useful early barometer of environmental 30 impacts, and via the microbiome (microorganisms, their genetic material and theatre of 31 activity), a measure of the way in which our current experiences in the Anthropocene differ 32 from our ancestral past 7 . We are also reminded that the smallest elements in our ecosystems, 33 microorganisms, are critical to large scale systems including climate change biology, as 34 highlighted in a recent warning by environmental scientists in Nature Reviews 8 .

Whatever label we use for the current global burden of allergic diseases and asthma- 36 epidemic, crisis, scourge-we can all agree that the rates are intolerably excessive. Moreover, 37 there is consensus that genetics cannot explain the rapid shift in the burden of disease and 38 that environmental change has play a primary role, interacting with genetic susceptibilities 39 over time. With good reason, the initial scientific search for causation has largely focused on 40 environmental toxins-the increasing presence of detrimental exposures. However, it is 41 equally important to consider that the absence of protective factors could have commensurate 42 impacts on health. 43 In this context, this Commentary focuses on the consequences of "biological extinction of 44 experience" considering the evidence that the current burden of allergic disease may be, at 45 least partially, driven by the absence of immune system "experience" with biodiversity. The 46 "canary in the coalmine" was a useful metaphor for illuminating the once subtle concept that the rise in allergic diseases fifty years ago was a forewarning of a larger crisis of NCDs-that 48 allergy may be an "indicator species" for the effects of ill-defined toxins on the risk of inflammatory disease 7 . But now, there is nothing subtle about environmental change, nor the 50 impact on human health. Indeed, the avian metaphor has become a terrible reality, with 51 concomitant stunning real-world losses of a multitude of bird species over the same period 9 .

It is time to understand the direct links between these phenomena, namely the links between 53 biodiversity losses, on all scales, and the current rates of allergic diseases and immune 54 dysregulation. The butterfly effect is another oft-used a metaphor to explain how the most minute change in 62 local conditions can lead to massive differences in the state of wider systems-through ripple 63 effects across a complex inter-connected web. As first postulated by Edward Lorenz as part 64 of chaos theory, if a butterfly flaps its wings in one location, this tiny change in the 65 atmosphere could, at least theoretically, influence weather at distant, future sites. It's rare for 66 mathematical theories to penetrate the discourse of popular culture, but the butterfly effect 67 has captured the imagination of the public. Perhaps because humans love both metaphors and 68 butterflies. 69 Finnish physician-scientist Tari Haahtela has dedicated his career to the study of allergic Research conducted by Dr Haatela's group and others has indicated that westernized urban 78 environments appear to lack essential elements, which otherwise provide necessary exposures 79 for the "optimal" development of tolerance against foreign proteins. Notably, these 80 observations came to light with striking differences between immune disease between 81 Finland and neighboring Russian Karelia. Although situated in close geographic proximity, 82 Dr Haatela's group had discovered strikingly different allergy prevalence in the borderlands 83 of Finnish and Russian Karelia. The higher microbial quantity and diversity in the drinking 84 water and house dust were among the implicated factors associated with a reduced risk of 85 allergic disease in Russian Karelia 11, 12 . 86 From his broader vantage, Dr Haahtela also noted that allergic diseases appeared to be rarer 87 in regions where butterfly populations enjoy rich diversity. It was a generalized observation, 88 and although it lacked detailed investigation on butterfly populations per se, the plausibility 89 matched evolving knowledge derived from the 'hygiene hypothesis'; the overarching idea of 90 the original hypothesis 13 , and its related variants 14 , that the global rise in allergic disease 91 could be related to diminished opportunity for early life exposure to microbial diversity via 92 antibiotic overuse, smaller family sizes, excessive use of personal and household cleaning 93 products (including detergents), lower exposure to non-pathogenic bacteria in foods (e.g. 94 lowered consumption of fermented foods). According to the hypothesis, the mediator 95 between these environmental changes and immune system training was proposed to be an 96 'abnormally stable microflora' 14 . In essence, a "new normal" microbiome may characterize the lived experience in urbanized, western industrial nations-reflecting a more generalized 98 decline in biodiversity. In essence, a manifestation of wider "dysbiotic drift" 15 (Figure 2) . 99 Dr. Haatela's Commentary served to underscore the potential relevancy of biodiversity at all 100 scales to the work of both clinicians and scientists working in the field of allergy and 101 immunology. More than ten years on, the global collapse of insect species is far more 102 devastating than even imagined. In 2019, Australian researchers reported shocking declines 103 in flying insect populations, and projections indicating extinction of as many as 40% of the 104 world's insect species over the next few decades 16 . Butterflies are among the species 105 experiencing devastating declines 17, 18 . While some insect species are resilient, urbanization 106 is detrimental to both abundance and species richness 19 . If these declines continue, the water, plant and animal-associated microbiota, and an inner layer including the microbiota of the skin, lungs and alimentary canal. The outer layer plays a large role in the colonization of 122 the inner layer, and by extension, the operations of the immune system 21, 22 ; given the recent 123 discoveries on the immune-nervous system interface, the natural environment and its outer 124 mantle of biodiversity can potentially extend its reach to the brain through microbe-mediated 125 non-sensory pathways 15, 23 .

"What is the extinction the condor to a child who has never seen a wren?" Relatedness have been linked with general health and mental wellbeing 33, 34 , as well as 149 higher concern for the sustainability of the natural environment 35, 36 . Intervention research 150 involving children exposed to biodiversity-rich environments indicates that psychological killer cells), blood pressure, and heart rate variability 44 (Figure 3) . 171 These 'shinrin-yoku' studies are limited by small sample sizes and short duration; moreover, 172 given that potential allergens are among the "components emitted" from trees and flowering and allergic diseases 53, 54 . Several studies have found relationships between residential 192 proximity to farms, arable lands, exposure to farm-associated microbiota, and protection against allergic diseases and asthma 55, 56 . Yet, all farms cannot be painted with the same 194 brush, and efforts to bring protective soil/farm-associated microbiota to clinicians and 195 patients awaits lengthy translation 57 . In the meantime, it may be helpful to know more about 196 the psychological antecedents (beyond the oft-discussed term 'stress') that might influence prescriptions, also known as also known as nature-based solutions, may have significant co-214 benefits for individuals, community and the wider environment 64 (Figure 3) . Similarly, 215 microbiome-inspired green infrastructure provide ecological solutions that promote personal 216 biodiversity through healthier, more biodiverse cities and urban environments 65 . These place-based environmental strategies will also provide opportunities to study the impact on 218 immune function, especially in children.

In sum, the psychological constructs of extinction of experience and nature relatedness are 220 highly relevant to the work of professionals in our field of allergic diseases; it can be argued 221 that up to now, work within the Biodiversity Hypothesis rubric has involved searching for 222 clues in the 'immunological extinction of experience' (e.g. missing microbes) and that such 223 work will be bolstered by looking more deeply at the upstream drivers of behaviors that 224 otherwise put us in contact with biodiversity. Anthropocene-associated 'dis-ease' 83 . This cannot be achieved without also addressing the 276 value systems that drive the attitudes and actions of individuals and whole societies 84, 85 .

There is little doubt that in the Anthropocene, conversations concerning medicine, science, 278 and health (at all scales) are political discussions. There is ample evidence that 279 authoritarianism is detrimental to health at all scales. Hence, experts in planetary health have 280 advocated for a broad introduction of political science into medical and health-related 281 graduate programs. This is described in detail elsewhere, but a part of this must be in 282 understanding the corporate and commercial determinants of health [86] [87] [88] . pandemic has occurred on a much slower time frame and seemingly more insidious, the 307 devastated large scale personal, economic and societal impact of these chronic diseases is 308 arguably far more significant and long-lasting-and no less important. Without the same 309 coordinated large-scale efforts to address these conditions, the burden on our societies and 310 our health care systems is unsustainable. This is also ultimately rooted in the way we live-311 our behaviours, our attitudes and our relationship with the environment that sustains us.

Experts working in the field of allergy should be proud of a progressive legacy of scientific 314 research into the effects of the total environment on human health. Many of our early 315 findings on environmental toxins and microbes have influenced virtually every branch of 316 science and medicine; for example, research in the early days of 'microflora' and the immune 317 system/allergy set the table for the burgeoning gut-brain-microbiome field 94 .

However, the interrelated challenges of the Anthropocene, including those directly and 319 indirectly associated with allergic disease, demand interdisciplinary work; in order to truly 320 explore the merits of the Biodiversity Hypothesis, the closed silo system is untenable; our 321 colleagues in psychology, ecology and other fields can help us with a more fine-grained 322 understanding of how the disappearance of the Monarch butterfly might be connected, not 323 only to allergic disease, but the myriad of noncommunicable and communicable threats that 324 we face today.

As we reflect on the "butterfly effect" we are again reminded that small changes can have 326 large effects (Figure 4) , and that we should not underestimate the importance of our 327 contribution as individuals to much-needed global change for greater good. We can apply the same principles to affect positive change.

Key Messages:

1. The once subtle effects of urbanisation have escalated into large-scale biodiversity loss which is echoed on the micro-ecological scale with changes in personal and environmental microbial ecosystems. This is directly implicated in the epidemic of allergy and many other noncommunicable diseases (NCDs) 2. Modernity has also been associated with human behavioural changes, with significantly more time indoors, progressively less contact with biodiversity in natural environments, and evidence that reduced early-life 'experience' of biodiversity primes for immune dysregulation and a higher propensity low-grade inflammation 3. Efforts to increase direct, personal contact with biodiversity have clear benefits for multiple aspect of physical and mental health, the skin and gut microbiome and immune function. There are also beneficial effects on health behaviours-such as food choices, sleep, and physical activity-that also favourably impact immune function.

4. Increasing nature connectedness is also important for promoting environmental responsibility and value systems that are geared to restoring and preserving biodiversity. Decades of research show health benefits across all domains including mental health (improved mood and sleep, reduce depression, anxiety, PTSD), performance (improved concentration, cognitive performance), reduced inflammation, reduced cortisol/stress responses, reduced asthma and allergies, lower BP, HR, oxidative stress, reduces and buffers NCDs. There is also evidence that increasing urban greenspaces can reduce health inequalities due to social disadvantage. (Artwork created by Dr. Susan Prescott). 

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