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• Published: 16 October 2017

The hygiene hypothesis in autoimmunity: the role of pathogens and commensals

• Jean-François Bach 1 , 2 , 3  

Nature Reviews Immunology volume  18 ,  pages 105–120 ( 2018 ) Cite this article

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• Autoimmune diseases
• Toll-like receptors

The initial application of the hygiene hypothesis for autoimmune diseases proposed in the early 2000s has been confirmed and consolidated by a wealth of published data in both animal models and human autoimmune conditions.

The hygiene hypothesis probably explains the uneven geographical distribution of autoimmune diseases in the world. Individuals migrating from countries with low incidence of autoimmune diseases to countries with high incidence develop the disease with the frequency of the host country, provided that migration occurred at a young age and under a threshold that varies according to the disease.

Pathogenic bacteria, viruses and parasites are often endowed with strong protective effects on autoimmunity even when infection occurs late after birth.

Gut commensal bacteria may also have a protective role in autoimmunity when administered early in life.

Pathogens, parasites and commensals essentially act by stimulating immune regulatory pathways, implicating the innate and the adaptive immune system. Importantly, the effect is seen with both living organisms and their derivatives or purified extracts.

Both pathogens and commensals stimulate pattern recognition receptors, including Toll-like receptors (TLRs) to protect against autoimmunity. This effect may be mimicked by TLR agonists acting through pharmacological stimulation or desensitization of the target receptor.

The incidence of autoimmune diseases has been steadily rising. Concomitantly, the incidence of most infectious diseases has declined. This observation gave rise to the hygiene hypothesis, which postulates that a reduction in the frequency of infections contributes directly to the increase in the frequency of autoimmune and allergic diseases. This hypothesis is supported by robust epidemiological data, but the underlying mechanisms are unclear. Pathogens are known to be important, as autoimmune disease is prevented in various experimental models by infection with different bacteria, viruses and parasites. Gut commensal bacteria also play an important role: dysbiosis of the gut flora is observed in patients with autoimmune diseases, although the causal relationship with the occurrence of autoimmune diseases has not been established. Both pathogens and commensals act by stimulating immunoregulatory pathways. Here, I discuss the importance of innate immune receptors, in particular Toll-like receptors, in mediating the protective effect of pathogens and commensals on autoimmunity.

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Acknowledgements

The laboratory of the author was supported by an advanced grant from the European Research Council (ERC, Hygiene N°: 250290).

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PowerPoint slides

Powerpoint slide for fig. 1, powerpoint slide for fig. 2, powerpoint slide for table 1, powerpoint slide for table 2, powerpoint slide for table 3.

A genetic predisposition to the cumulative development of common allergies, for example, atopic dermatitis and allergic asthma. Atopy involves phenomena of cutaneous or general hypersensitivity to allergens.

A hypothesis that postulates that an increased frequency of infections contributes to a decrease in autoimmune and allergic diseases.

An inbred mouse line that spontaneously develops an autoimmune syndrome including insulin-dependent diabetes mellitus (IDDM or type 1 diabetes).

A digestive tract disorder provoked by eating contaminated food or drinking contaminated water. In the context of our discussion, it is a self-limited pathology that illustrates the presence of a basic health environment.

Autoantibodies to various β-cell-specific autoantigens that are markers of the destruction of insulin-producing β-cells, which is the hallmark of insulin-dependent diabetes mellitus (IDDM or type 1 diabetes).

An imbalance of the microbial flora that most frequently affects the digestive tract. Dysbiosis can also be detected in other 'barrier' organs such as the skin, the lungs or the vagina.

The metabolome consists of all signalling molecules (for example, metabolites and hormones) detected in a biological sample. The metabolome thus defines a given physiological or pathological state and is therefore dynamic.

Mice born by hysterectomy under sterile conditions and raised in isolators to guarantee an environment totally devoid of pathogenic and commensal germs.

(EAE). A demyelinating allergic encephalomyelitis produced by the injection of brain tissue or purified proteins of the nervous system or their derived peptides in the presence of an adjuvant.

Germ-free mice whose intestinal microflora is reconstituted by a single commensal bacterium (monocolonized mice).

Gut commensal bacteria available as single or combined species delivered orally and putatively endowed with a health benefit.

The competition for recognition of the cognate antigen for soluble factors (cytokines) driving the proliferation and differentiation of antigen-specific lymphocytes.

Islet transplants between syngeneic (genetically identical) donor and recipient individuals, which therefore does not give rise to allograft rejection. These grafts performed in diabetic non-obese diabetic mice provide a robust model to test for recurrence of the autoimmune disease.

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Bach, JF. The hygiene hypothesis in autoimmunity: the role of pathogens and commensals. Nat Rev Immunol 18 , 105–120 (2018). https://doi.org/10.1038/nri.2017.111

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MINI REVIEW article

The hygiene hypothesis – learning from but not living in the past.

• 1 Comprehensive Biobank Marburg, Medical Faculty, Philipps University of Marburg, Comprehensive Biobank Marburg, Marburg, Germany
• 2 German Center for Lung Research (DZL), Marburg, Germany
• 3 German Biobank Alliance, Marburg, Germany
• 4 Institute for Pathology, Medical Faculty, Institute for Pathology, Philipps University of Marburg, Marburg, Germany
• 5 Translational Inflammation Research Division & Core Facility for Single Cell Multiomics, Medical Faculty, Biochemical Pharmacological Center, Philipps University of Marburg, Marburg, Germany

Postulated by Strachan more than 30 years ago, the Hygiene Hypothesis has undergone many revisions and adaptations. This review journeys back to the beginnings of the Hygiene Hypothesis and describes the most important landmarks in its development considering the many aspects that have refined and generalized the Hygiene Hypothesis over time. From an epidemiological perspective, the Hygiene Hypothesis advanced to a comprehensive concept expanding beyond the initial focus on allergies. The Hygiene Hypothesis comprise immunological, microbiological and evolutionary aspects. Thus, the original postulate developed into a holistic model that explains the impact of post-modern life-style on humans, who initially evolved in close proximity to a more natural environment. Focusing on diet and the microbiome as the most prominent exogenous influences we describe these discrepancies and the resulting health outcomes and point to potential solutions to reestablish the immunological homeostasis that frequently have been lost in people living in developed societies.

Last year we celebrated the 30th anniversary of the Hygiene Hypothesis. Since Strachan framed the Hygiene Hypothesis in 1989 ( 1 ) his fundamental idea to explain the origins of allergic diseases development has survived the test of time. The basic idea of how humans, their microbiota, and a continuously modernizing environment have interacted to drive immune dysregulation has persisted and become part of the popular imagination. Here, we aim to provide an editorial overview on the history of the Hygiene Hypothesis and related topics to offer a framework for the articles collected in the special edition research topic “The Hygiene Hypothesis and its Immunological Implications.”

A Chronological Overview

The epidemiological basis for the Hygiene Hypothesis became apparent long before the Hygiene Hypothesis was postulated. Two simple observations were made in the 1960s and in the 1970s. First, a Swedish study described differences in the prevalence of asthma and socio-medical conditions between populations living in urban or rural sites ( 2 ). A few years later, in a population-based study conducted in Saskatchewan, Canada, showed that allergies were less frequent in native tribes living traditionally in rural sites compared to Caucasian Canadians living in urban habitats ( 3 ). Moreover, the authors postulated that frequent bacterial infections in childhood might be responsible for the inverse association with allergic diseases. Strachan's observations made in the late 80s in a British population corroborated these findings and he later named this concept “Hygiene Hypothesis” in 2000. Briefly, Strachan suggested that transfer of early childhood infections between siblings is associated with protection against allergies later in life ( 4 ).

The hypothesis was further substantiated and extended by studies that compared asthma and allergy prevalence directly after the “Fall of the Iron Curtain” between Western and Eastern Germany, a decade later ( 5 , 6 ). Interestingly, these studies triggered a paradigm shift in allergy research. Until then, environmental pollution was broadly regarded as the leading force for allergy development. Environmental data clearly indicated a higher level of pollution by industrial emissions in Eastern Germany compared to the Western part and the study team therefore hypothesized that the prevalence of allergic diseases was higher in children from Eastern Germany. Surprisingly, the researchers found their hypothesis disproved, as children in Western Germany showed a higher prevalence of allergies. Hence, it was postulated that other exposures than pollutants influence the development of atopic diseases. Socio-demographic and –economic factors, as well as household hygiene turned out to be further discriminatory factors between both parts of German population. Improved sanitation and hygiene were positively associated with atopic diseases. Another decade later a follow-up further validated this hypothesis and found life-style differences and the prevalence of atopic diseases began to equilibrate within 10 years after the reunification. In consequence, the Hygiene Hypothesis became the leading postulate to explain underlying relationships and mechanisms for the development of allergic diseases in a societal context ( 6 ).

Based on this paradigm shift, Rook published the “Old Friends-Hypothesis” which argues that infectious diseases have a long co-evolutionary history with human development, and appropriate levels of exposure to these microorganisms early in life might protect against immune deviation and allergic diseases. These early-life exposures to potential pathogens might educate the developing immune system from a type-2-dominated in utero -milieu toward a more defensive T helper (h)1 response ( 7 ).

The next milestone involved findings obtained from the so-called “Alpine farm studies” conducted at the turn of the millennium. Von Mutius and Braun-Fahrländer recognized the unique situation that the Alpine traditional farming environment represents a socio-cultural and ecological niche which significantly differs from the post-modern and urbanized life-style. In a number of epidemiological studies they identified traditional farming characteristics such as consumption of unprocessed farm milk and close contact with farm animals to act allergoprotective and found these parameters to be associated with a higher microbial load. These Alpine farm studies added substantial evidence to Strachan's basic idea and led to a broader view and understanding of the relationship between human health and (early life) exposure to microbes ( 8 , 9 ).

Further evidence was added by studies conducted in Northern Europe. In the late 1990s studies conducted in Scandinavian und Baltic children described microbial factors to be associated with a lower prevalence of allergic diseases in the Eastern countries ( 10 – 12 ). Next, the Karelia Study, conducted on both sides of the Finnish-Russian border, addressed the impact of the environmental microbial burden on the development of allergic diseases in Finnish and Russian Karelian children that share the same ethnic background but have different life-styles ( 13 ). These studies corroborated the Alpine farm studies and point to the microbial environment as a major factor in allergy development.

Furthermore, these studies demonstrate that the diversity and the richness of an immune-stimulating microbial world in human habitats is crucial to establish a competent, tolerogenic and defensive immune system configuration while absence or depletion of those stimuli as found in post-modern environments foster immune deviation and development of allergic diseases ( 14 ).

Moreover, two relevant studies [the cross-sectional study “Prevention of Allergy Risk factors for Sensitization In children related to Farming and Anthroposophic Lifestyle (PARSIFAL)” and the multi-center, pregnancy/birth cohort study “Protection against Allergy: Study in Rural Environments (PASTURE)”] support the idea that the “window of opportunity” in which the appropriate education of the immune system starts already in the mother's womb ( 15 – 17 ). The PARSIFAL Study demonstrated that maternal exposure to a farm environment rich in microbial compounds is inversely associated with the development of atopic sensitization and correlated with an upregulation of receptors of the innate immune system in the offspring at school age ( 15 ). Further, maternal farm activities during pregnancy were shown to modulate cord blood cytokines and allergen-specific immunoglobulin responses toward a Th1 pattern ( 16 , 17 ). These findings are in line with the Barker theory ( 18 ), postulating that pathological pathways occurring in adolescence and adulthood are paved already in prenatal life.

The Hygiene Hypothesis and the Bacterial World

Even before high-throughput sequencing techniques were established that allow a deeper view into the microbial world on our body surfaces, Noverr and Hufnagle proclaimed the “Microbiota Hypothesis” by which they claimed the microbiota to be indispensable for developing and maintaining a tolerogenic immune status ( 19 ). A similar idea concept was proposed earlier by Holt, Sly and Björkstén ( 20 ). The rediscovery of the microbiota and its powerful metabolic and immunologic interplay with the mucosal surfaces of the host underlined and complemented the principals of this basic idea ( 21 , 22 ). Microbiome research has made significant achievements over the past 15 years; here we can emphasize only a few aspects that might be relevant in the context of the Hygiene Hypothesis and the development of allergies.

Phylogenetic Impacts

An intriguing concept to better understand the complex symbiotic interplay at organ surfaces was suggested by McFall-Ngai in 2007. In her evolutionary perspective she shed light on findings made in invertebrates which not only lack an endoskeleton but also an adaptive immune system. Thus, invertebrates have to exclusively rely on their innate immune system, which to our current understanding, lacks an immunological memory. Analyses of the intestinal microbiota in such animals have shown—in contrast to vertebrates—a rather low diversity in the community of their microbial residents. Only a handful of strains could be identified as stable colonizers on the gastrointestinal surfaces while most bacteria travel through as transient visitors. Some invertebrates, like insects, separate bacterial colonies from epithelial host cells by a peritrophic matrix composed of chitin and other compounds ( 24 ). During the course of evolution, the microbial colonization of epithelia started to get more complex and in turn the host was challenged to develop new strategies to manage these diversifying communities. To permanently recognize a specific bacterium as beneficial or harmful, an adaptive immune response that provides an immunological memory over generations of immune cells was needed. Mutual adaption of both partners, the bacterial community, as well as the complex network of adaptive immune cells, led to a sophisticated metabolic and immunologic interplay with a highly digestive and defensive performance. This symbiosis is based on early education of the host's immune cells by a diverse microbial community to successfully discriminate dangerous pathogens from beneficial symbionts and own healthy cells. Finally McFall-Ngai stated, that complex systems might be prone to failure and allergies and autoimmune disorders might be a consequence of this ( 23 ).

Ontogenetic Impacts

A number of recently published reports substantiated the impact of the early life microbiota on immune maturation [recently reviewed in ( 25 )] and the development of allergic disorders in early infancy [recently reviewed in ( 26 )]. The developmental starting point of the infant gut microbiota is still unknown, but undoubtedly, the process of delivery seems to be a key point in the development of the neonatal microbiota ( 27 ). Meconium, the neonate's first intestinal discharge, was shown to contain various bacterial strains indicating that the perinatal gut is colonized by bacteria ( 28 , 29 ). In a landmark study, Dominguez-Bello et al. reported that the neonatal microbiota differs between vaginally born infants and neonates delivered by Caesarian (C)-section. The authors found a high abundance of Bacteroides, Bifidobacterium , and Lactobacillus spec . in meconium samples obtained from vaginally delivered newborns, while Staphylococcus, Streptococcus, Corynebacterium , and Propionibacterium spp . were found predominantly in meconium samples of C-section born neonates ( 30 ).

Colonization of the neonate's colon by Lactobacilli and Bifidobacteria transferred from the maternal vaginal compartment during vaginal passage might provide advantages for the newborn due to the metabolic properties of these bacteria that foster the adaptation to milk-based feeding. These bacteria are capable of metabolizing breast milk-derived lactose and human milk oligosaccharides (HMOS) ( 31 ) and were shown to provide immune-modulating short chain fatty acids (SCFAs) ( 32 ) and conjugated trans-linoleic acids (tCLAs) ( 33 ), which are shown to reduce pro-inflammatory eicosanoid production by regulating the transcription of cyclooxygenase 2 (COX-2) ( 34 ) and to induce anti-inflammatory M2-macrophage differentiation ( 35 ).

However, how sustainable and decisive are these mode of delivery-associated differences beyond the neonatal age? Chu et al. recently showed that function and composition of the microbiota significantly diversifies in all body sites within the first 6 weeks of life, resembling the corresponding maternal body site microbiota at this time point. Infant's mode of delivery or other prenatal factors seems to have no impact on this development ( 36 ). Data from the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC 2010 ) cohort underlined the importance of the maturation of the microbiota on the further development of the gut microbiome and the risk of asthma later in life. In that study, Stockholm et al. compared the gut microbiome of vaginally and C-section delivered infants from birth to 1 year of life in the context of asthma development at school age. Marked differences between C-section and vaginally delivered infants were observed by 1 week and by 1 month of life, but only minor differences between these groups were found by 1 year of age. An increased risk for school-age asthma was only observed in a subgroup of C-section-born infants that maintained the C-section-associated composition for at least 1 year. The authors conclude that vaginal delivery and/or subsequent maturation of the infant microbiota might support a more robust and stable microbiota in the offspring that is more adaptive to the challenges later in life ( 37 ). Further exposure to the maternal microbiota ( 38 ), as well as nutritional impacts (e.g., cessation of breastfeeding) ( 39 ) within the first month of life, might foster the maturation of the gut microbiome in early infancy.

Nutritional Impacts

How is the microbiota linked to the rising atopic epidemic observed in the recent decades? A recently published study conducted in indigenous tribes living in the Brazilian Amazonas-Orinoco Basin may help to answer this question ( 40 ). In this study the gut microbiome of the semi-nomadic gatherer/hunter people of the Yanomami who maintained a primitive close-to-nature life-style was compared to subjects representing populations that are characterized by a westernized or non-ancestral life-style in rural and urban settings. The Yanomami microbiota was significantly more diverse than those of the westernized counterparts. Moreover, an additional study comparing Venezuelan with Brazilian Yanomami indicated a high level of adaptability to specific environmental conditions of the microbiota in these peoples. While a high taxonomic diversity was found in both sub-tribes, the composition of microbiota was significantly different ( 41 ). These findings point to environmental and life-style factors that influence the composition of the microbiota the absence of which may thus foster the loss of taxonomic and metabolic diversity in westernized societies ( 42 ).

Diet is one of the most prominent environmental factors that differ between modern and ancient life-styles. While dietary habits in indigenous people such as the Yanomami strongly depend on the sometimes limited food supply due to seasonal cycling, people living in developed societies have access to high in calories food ready at any time and in abundance. Moreover, diet in indigenous cultures is often based on high-fiber products derived from plants that are easy to culture such as plantain, manioc or sweet potatoes, all rich in inulin ( 43 ). High-fiber diet and, in particular inulin, is known as an effective enhancer of beneficial bacteria such as Bifidobacteria in the colon that stabilize gut homeostasis ( 44 ). Translating these findings into a clinical approach, McLoughlin et al. applied soluble inulin to asthmatics in a short-term placebo-controlled-trial and could report an array of beneficial effects in patients orally treated with inulin. In comparison to the placebo group, inulin-treated patients displayed a significantly reduced number of eosinophils in the sputum and, overall, reported a significantly improved asthma control. Inhibition of histone deacetylase 9 (HDAC9) in sputum cells upon a combined application of inulin and a multi-strain probiotic mixture of Lactobacillus acidophilus, Lactobacillus rhamnosus GG and Bifidobacterium animalis subspecies lactis indicated that epigenetic pathways are involved in the mechanisms by which lactic acid bacteria modulate host responses in combination with the prebiotic gavage ( 45 ).

A number of recently recognized metabolites released by beneficial symbiotic bacteria convey immunomodulatory effects, mainly in the gut but also on other mucosal surfaces ( 46 ).

In particular, SCFAs derived from dietary fibers and released in the lumen of the colon contribute to immune modulation and inhibition of pro-inflammatory cytokines when absorbed by gut epithelial cells ( 47 ). By binding to chemoattractant G protein 43 receptor, SCFAs are capable of regulating inflammatory responses ( 48 ) as shown for intestinal inflammation ( 49 ). Tryptophan, an amino acid produced by an array of beneficial microorganisms, is degraded to indole derivatives which may bind to the aryl hydrocarbon receptor (AHR) and by this regulate the activity of immune cells at the epithelial barrier. That involves AHR-dependent differentiation of regulatory T cells associated with anti-inflammatory IL-10 expression. Further, Th2-cells are inhibited on the transcription factor level in favor of a Th1 response ( 50 ).

A number of beneficial bacteria contribute to the orchestration of T cell subsets at the gut epithelial barrier. Bacteroides sp . and Clostridium clusters IV and XIVa colonizing the gut epithelium are known to stimulate intestinal epithelial cells to release thymic stromal lymphopoietin (TSLP), transforming growth factor (TGF)-ß and interleukin (IL)-25 which in combination may induce tolerogenic effects in dendritic cells (DCs) ( 51 ), e.g., by secretion of TGF-ß and retinoic acid. Both factors initiate differentiation of naïve T cells to regulatory T cells upon activation of the nuclear transcription factor forkhead box P (FoxP3) ( 52 ). These regulatory mechanisms are challenged by “pathobionts” or other damage factors. In presence of these stressors, overexpansion of Th1, Th2 and Th17 effector cell subsets might result in an inflammatory response in the infected organ or, by migration of these cells, at distant sites. Namely, Clostridium difficile , which is associated with wheezing and atopic sensitization, was shown to initially disturb the intestinal balance when acquired early in childhood ( 53 ).

Traveling from the gastrointestinal to the respiratory tract the microbiota established in the lung might also play a role in the development of allergic disorders, namely of allergic asthma. Though the gut is known to play a major role in establishing and regulating immune defense mechanisms, the “gut-lung axis” alone might not completely explain the rise of allergic asthma ( 54 ). As many studies focused on the lung microbiome, it has become clear that there is a strong relationship between frequently inhaled environmental microbes, microbial colonization of the respiratory tract, and the prevalence of allergic asthma ( 55 ). For example, results from the “Multidisciplinary Study to Identify the Genetic and Environmental Causes of Asthma in the European Community (GABRIEL) Advanced Studies (GABRIELA)” study suggested a transfer of built-environment-associated bacteria into the respiratory tract. Indoor dust samples from farm houses and nasal swabs from farm children displayed a higher bacterial diversity than those samples collected in rural non-farm children ( 56 ). New evidence was added recently by studies conducted in the Finnish part of the PASTURE-study. Kirjavainen et al. reported that the ecological diversity of the so-called “indoor microbiota” is inversely linked to the prevalence of allergic asthma. Substantiating former farm studies, this report further validated the hypothesis that microbial diversity and composition in the natural environment is linked to a reduced risk of early-onset allergic asthma and that traditional farming is a proxy for this effect ( 57 ).

But what are the cellular and molecular mechanisms associated with high microbial diversity? Interestingly, the farm studies consistently showed an inverse association between a highly diverse environmental microbiota and allergic asthma, but this did not account to other allergic manifestations such as hay fever or atopic sensitization. On the other hand, endotoxin exposure protects against atopy but fosters the risk of non-allergic asthma and early onset of wheeze when inhaled in higher concentrations. These findings derived from the farm studies still challenge the Hygiene Hypothesis and might point out that microbial colonization and exposure to microbial compounds have to be considered separately ( 58 ). Integration of beneficial environmental bacteria into the microbial community of the respiratory tract leads to a tolerogenic mucosal symbiosis that establishes a local T-cell balanced anti-inflammatory milieu at the epithelium, probably enhanced by a well-balanced gut microbiota. Endotoxins are potent activators of innate TLR-signaling and can attenuate B cell driven sensitization and formation of IgE-antibodies ( 59 ). Already in 2003, Vercelli postulated a switch from Th2-driven allergic responses at low endotoxin exposure to a pronounced Th1 response in the lung under high levels of environmental endotoxin. This might explain the elevated prevalence of non-allergic asthma in environments overloaded with endotoxin ( 60 ).

Conclusions

The many aspects and facets of the Hygiene Hypothesis have been supported by concepts and findings coming from a variety of scientific disciplines such as epidemiology, immunology, microbiology and anthropology. Within the last three decades we obtained a multiplicity of new insights into the complexity and plasticity of T cell networks which led us to recognize the complexity and significance of a powerful and well-regulated adaptive immune response in relation to exogenous factors ( 61 ). Early developmental findings characterizing pre and postnatal life events highlighted the initial role of the innate immune system as an early warning system that orchestrates, educates and shapes subsequent immune responses ( 62 , 63 ). Evidence from evolutionary biology and anthropology enabled us to understand how host-environment interactions are refined throughout evolutionary adaption ( 58 , 64 ). Microbiology added fundamental knowledge about the micro-ecosystem that is established throughout the human body as a unique symbiosis between humans and microbes. And finally, coming back to the introductory statement, epidemiological observations such as those initially made by Strachan and von Mutius about 30 years ago still challenge and refine the hypothesis.

Author Contributions

All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

This work was funded by the Library of the Philipps-University of Marburg.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Keywords: hygiene hypothesis, allergy, asthma, immune tolerance, T cell-response, microbiome

Citation: Pfefferle PI, Keber CU, Cohen RM and Garn H (2021) The Hygiene Hypothesis – Learning From but Not Living in the Past. Front. Immunol. 12:635935. doi: 10.3389/fimmu.2021.635935

Received: 30 November 2020; Accepted: 17 February 2021; Published: 16 March 2021.

Reviewed by:

Copyright © 2021 Pfefferle, Keber, Cohen and Garn. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Petra I. Pfefferle, petraina.pfefferle@uni-marburg.de

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The Hygiene Hypothesis - Learning From but Not Living in the Past

Affiliations.

• 1 Comprehensive Biobank Marburg, Medical Faculty, Philipps University of Marburg, Comprehensive Biobank Marburg, Marburg, Germany.
• 2 German Center for Lung Research (DZL), Marburg, Germany.
• 3 German Biobank Alliance, Marburg, Germany.
• 4 Institute for Pathology, Medical Faculty, Institute for Pathology, Philipps University of Marburg, Marburg, Germany.
• 5 Translational Inflammation Research Division & Core Facility for Single Cell Multiomics, Medical Faculty, Biochemical Pharmacological Center, Philipps University of Marburg, Marburg, Germany.
• PMID: 33796103
• PMCID: PMC8007786
• DOI: 10.3389/fimmu.2021.635935

Postulated by Strachan more than 30 years ago, the Hygiene Hypothesis has undergone many revisions and adaptations. This review journeys back to the beginnings of the Hygiene Hypothesis and describes the most important landmarks in its development considering the many aspects that have refined and generalized the Hygiene Hypothesis over time. From an epidemiological perspective, the Hygiene Hypothesis advanced to a comprehensive concept expanding beyond the initial focus on allergies. The Hygiene Hypothesis comprise immunological, microbiological and evolutionary aspects. Thus, the original postulate developed into a holistic model that explains the impact of post-modern life-style on humans, who initially evolved in close proximity to a more natural environment. Focusing on diet and the microbiome as the most prominent exogenous influences we describe these discrepancies and the resulting health outcomes and point to potential solutions to reestablish the immunological homeostasis that frequently have been lost in people living in developed societies.

Keywords: T cell-response; allergy; asthma; hygiene hypothesis; immune tolerance; microbiome.

Copyright © 2021 Pfefferle, Keber, Cohen and Garn.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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The Hygiene Hypothesis

• First Online: 04 February 2016

Cite this chapter

• Caroline Roduit 2 , 3 ,
• Remo Frei 4 , 5 ,
• Erika von Mutius 6 &
• Roger Lauener 4 , 7  

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Over the past decades, an increase of the prevalence of allergic diseases has been observed in Western countries. The hygiene hypothesis proposes that viral, bacterial, or helminth infections; environments with high levels of microbial components, such as farms; and the nutrition are preventive against the development of allergies despite the same genetic predisposition. The timing of these exposures is crucial. The critical window of time starts already in utero and ends in school age depending on the kind of exposure. The underlying immunological mechanism of such exposures seems rather to include the induction of regulatory processes to control the allergic reaction than to prevent the production of IgE.

In this chapter, we review the best understood exposures together with the timing and the immunological mechanisms they induce to get the most preventive effect on the development of allergic diseases.

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Molecular Immunology, Swiss Institute of Allergy and Asthma Research, University of Zurich, Zurich, Switzerland

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Roduit, C., Frei, R., von Mutius, E., Lauener, R. (2016). The Hygiene Hypothesis. In: Esser, C. (eds) Environmental Influences on the Immune System. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1890-0_4

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Is the Hygiene Hypothesis True?

Did Covid shutdowns stunt kids' immune systems?

Caitlin Rivers

The hygiene hypothesis is the idea that kids need to be exposed to germs in order to develop healthy immune systems. We know that many common viruses did not circulate as widely during the pandemic, thanks to social distancing, masking, and other COVID mitigation measures. Are there downsides to those missed infections? 

In this Q&A, Caitlin Rivers speaks with Marsha Wills-Karp, PhD, MHS , professor and chair of Environmental Health and Engineering , about the role of household microbiomes, birth, and vaccines in the development of kids’ immune systems—and whether early exposure really is the best medicine.

This Q&A is adapted from Rivers’ Substack blog, Force of Infection .

I think there’s some concern among parents who have heard about the hygiene hypothesis that there is a downside to all those stuffy noses that didn’t happen [during the COVID-19 pandemic]. Are there any upsides to viral infections? Do they help the immune system in some meaningful way?

I don’t think so.

You mentioned the hygiene hypothesis, which was postulated back in the ‘80s. German scientists noticed that families with fewer children tended to have more allergic disease. This was interpreted [to mean] that allergic disease was linked to experiencing fewer infections. I have explored this idea in my research for a couple of decades now.

This phenomenon has helped us to understand the immune system, but our interpretation of it has grown and expanded—particularly with respect to viruses. Almost no virus is protective against allergic disease or other immune diseases. In fact, infections with viruses mostly either contribute to the development of those diseases or worsen them.

The opposite is true of bacteria. There are good bacteria and there are bad bacteria. The good bacteria we call commensals . Our bodies actually have more bacterial cells than human cells. What we’ve learned over the years is that the association with family life and the environment probably has more to do with the microbiome. So one thing I would say is sanitizing every surface in your home to an extreme is probably not a good thing. Our research team showed in animals that sterile environments don’t allow the immune system to develop at all. We don’t want that.

What does contribute to the development of the immune system, if not exposure to viruses?

There are a number of factors that we’ve associated with the hygiene hypothesis over the last 20 years, and these exposures start very early in life. Cesarean sections, which do not allow the baby to travel through the birth canal and get exposed to the mother’s really healthy bacterial content, is a risk factor for many different immune diseases. Getting that early seeding with good bacteria is critical for setting up the child going forward. Breastfeeding also contributes to the development of a healthy immune system.

There are other factors. Our diets have changed dramatically over the years. We eat a lot of processed food that doesn’t have the normal components of a healthy microbiome, like fiber. These healthy bacteria in our gut need that fiber to maintain themselves. They not only are important for our immune system but they’re absolutely critical to us deriving calories and nutrients from our food. All these things contribute to a healthy child.

We’ve also noticed that people who live on farms have fewer of these diseases because they’re exposed to—for lack of a better term—the fecal material of animals. And what we have found is that it’s due to these commensal bacteria. That is one of the components that help us keep a healthy immune system. Most of us will probably not adopt farm life. But we can have a pet, we can have a dog.

I think all the pet lovers out there will be pleased to hear that.

There’s a lot of evidence that owning a pet in early childhood is very protective.

What about the idea that you need to be exposed to viruses in early life because if you get them as an adult, you’ll get more severely ill? We know that’s true for chickenpox, for example. Do you have any concerns about that?

We should rely on vaccines for those exposures because we can never predict who is going to be susceptible to severe illness, even in early childhood. If we look back before vaccines, children under 4 often succumbed to infections. I don’t think we want to return to that time in history.

Let me just give you one example. There’s a virus called RSV, it’s a respiratory virus. Almost all infants are positive for it by the age of 2. But those who get severe disease are more likely to develop allergic disease and other problems. So this idea that we must become infected with a pathogenic virus to be healthy is not a good one.

Even rhinovirus, which is the common cold, most people recover fine. But there’s a lot of evidence that for somebody who is allergic, rhinovirus exposures make them much worse. In fact, most allergic or asthmatic kids suffer through the winter months when these viruses are more common.

And that’s particularly salient because there is a lot of rhinovirus and enterovirus circulating right now.

From my point of view, right now, avoiding flu and COVID-19 is a priority. Those are not going to help you develop a healthy immune response, and in fact, they can do a lot of damage to the lungs during that critical developmental time. Data [show] that children that have more infections in the first 6 months to a year of life go on to have more problems.

It’s always surprising to me when I look at the data of the fraction of time that young children spend with these common colds—and this is pre-pandemic—it’s not uncommon for kids to be sick 50% of the time. That feels right as a parent, but it’s startling.

The other thing people don’t know is that the GI tract is where you get tolerized to all of your foods, allergens and things. Without those healthy bacteria in your gut, you can’t tolerate common allergens.

How does that relate to the guidance that’s changed over the years—that you should withhold peanuts in early life and now you’re supposed to offer them in early life?

The guidance to delay exposure to peanuts didn’t consider the fact that oral exposure to peanuts was not the only exposure kids were getting. There were peanut oils in all kinds of skin creams and other things. So kids got exposed through their skin, but they had no gut protection—and the GI tract is important for a tolerant system. If you have a healthy immune response, you get tolerized in early life.

This concept is a little bit different for those families who may already have a predisposition to allergies. But for the general public, exposure is key to protecting them in early life.

I think some parents look at the guidance that you should now offer peanuts in early life and say, “Are we not doing that with rhinovirus by masking kids or improving ventilation?” How should people think about the development of the immune system for food allergies compared to infections?

The thing about rhinoviruses is that after recovering, you’re not protected from the next infection. There is no real immune protection there. Most of us suffer from colds throughout our whole life. Like I said, bacterial exposure is what’s key to priming the immune response. 

Also, we forget that a lot of kids die from the flu. Unlike COVID-19, where younger kids are not quite as susceptible to severe illness, that’s not true for flu. RSV, too, can be quite severe in young children and older adults.

Caitlin Rivers, PhD, MPH , is a senior scholar at the Johns Hopkins Center for Health Security and an assistant professor in Environmental Health and Engineering at the Johns Hopkins Bloomberg School of Public Health.

RELATED: 

• Study Finds That Children’s Antibody Responses to COVID-19 Are Stronger Than Adults’
• Back to School: COVID, CDC Guidance, Monkeypox, and More
• A New Shot Prevents Serious Illness from RSV

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• A-Z Publications

Annual Review of Anthropology

Volume 51, 2022, review article, the ecoimmunology of health and disease: the hygiene hypothesis and plasticity in human immune function.

• Aaron D. Blackwell 1
• View Affiliations Hide Affiliations Affiliations: Department of Anthropology, Washington State University, Pullman, Washington, USA; email: [email protected]
• Vol. 51:401-418 (Volume publication date October 2022) https://doi.org/10.1146/annurev-anthro-101819-110236
• First published as a Review in Advance on July 27, 2022
• Copyright © 2022 by Annual Reviews. All rights reserved This article is part of a special theme on Global Health. For a list of other articles in this theme, see https://www.annualreviews.org/toc/anthro/51/1

The original hygiene hypothesis proposed that certain diseases derive from low levels of early-life microbial exposure. Since then, the hypothesis has been applied to numerous inflammatory, autoimmune, and allergic conditions. The changes in hygiene linked to these diseases include numerous changes in biotic exposure and lifestyle. To this end, some scholars have called for abandonment of the term or have suggested alternate labels, e.g., the old friends hypothesis. However, neither of these terms encompasses the complexity of plasticity in immune response and host–parasite/commensal interactions that influence these conditions. Here, I review this complexity, with particular regard to the factors affecting immunological strategies, the development of tolerance, immune dysfunction, and ecological interactions among organisms. I discuss the biotic factors that affect immune plasticity and how these interact with abiotic factors such as nutrition, as well as how transgenerational exposures may affect immune plasticity. Finally, I review the general features of diseases linked to biotic exposures.

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Time to abandon the hygiene hypothesis: new perspectives on allergic disease, the human microbiome, infectious disease prevention and the role of targeted hygiene

Sally f bloomfield.

London School of Hygiene & Tropical Medicine and International Scientific Forum on Home Hygiene, The Old Dairy Cottage, Montacute, Somerset TA15 6XL, UK

Graham AW Rook

Centre for Clinical Microbiology, Department of Infection, University College London (UCL), London, UK

Elizabeth A Scott

Center for Hygiene and Health, Department of Biology, Simmons College, Boston, MA, USA

Fergus Shanahan

APC Microbiome Institute, University College Cork – National University of Ireland, Cork, Ireland

Rosalind Stanwell-Smith

London School of Hygiene & Tropical Medicine, London, UK

Paul Turner

Section of Paediatrics (Allergy & Infectious Diseases) and MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, UK; Discipline of Paediatrics and Child Health, The University of Sydney, Sydney, NSW, Australia

To review the burden of allergic and infectious diseases and the evidence for a link to microbial exposure, the human microbiome and immune system, and to assess whether we could develop lifestyles which reconnect us with exposures which could reduce the risk of allergic disease while also protecting against infectious disease.

Using methodology based on the Delphi technique, six experts in infectious and allergic disease were surveyed to allow for elicitation of group judgement and consensus view on issues pertinent to the aim.

Key themes emerged where evidence shows that interaction with microbes that inhabit the natural environment and human microbiome plays an essential role in immune regulation. Changes in lifestyle and environmental exposure, rapid urbanisation, altered diet and antibiotic use have had profound effects on the human microbiome, leading to failure of immunotolerance and increased risk of allergic disease. Although evidence supports the concept of immune regulation driven by microbe–host interactions, the term ‘hygiene hypothesis’ is a misleading misnomer. There is no good evidence that hygiene, as the public understands, is responsible for the clinically relevant changes to microbial exposures.

Conclusion:

Evidence suggests a combination of strategies, including natural childbirth, breast feeding, increased social exposure through sport, other outdoor activities, less time spent indoors, diet and appropriate antibiotic use, may help restore the microbiome and perhaps reduce risks of allergic disease. Preventive efforts must focus on early life. The term ‘hygiene hypothesis’ must be abandoned. Promotion of a risk assessment approach (targeted hygiene) provides a framework for maximising protection against pathogen exposure while allowing spread of essential microbes between family members. To build on these findings, we must change public, public health and professional perceptions about the microbiome and about hygiene. We need to restore public understanding of hygiene as a means to prevent infectious disease.

Introduction

Allergic diseases including asthma, hay fever, eczema and food allergies have dramatically increased over the last century, initially in high-income communities but now elsewhere. At the same time, threats of infectious disease pandemics, antibiotic resistance and numbers of immune-compromised people living in the community have increased. Taken together, these diseases are a significant burden on health and prosperity.

The idea that there might be a link between the rise in allergic disease and reduced microbial exposure as a result of measures introduced to protect against infection was first proposed in 1989. 1 , 2 This so-called hygiene hypothesis, as outlined by Dr David Strachan, proposed that a lower incidence of infection in early childhood could be an explanation for the 20 th century rise in atopic diseases. Although a simple idea in itself, it raised the thought that rising allergies may be an inevitable price to be paid for freedom from the burden of killer infectious diseases. Although evidence still supports the concept that immune regulation is driven by microbe–host interactions, the term ‘hygiene hypothesis’ is now being seen by many as a misleading misnomer for a concept with far-reaching consequences for public health and an issue which needs to be addressed. 3 , 4

Humans are ecosystems, where the microbes that live on and within us (the human microbiome) constitute an organ at least as essential to health as our liver or kidneys. 5 The immune system is a learning device, and at birth it resembles a computer with hardware and software but few data. Additional data must be supplied during the first years of life, through contact with microorganisms from other humans and the natural environment. If these inputs are inadequate or inappropriate, the regulatory mechanisms of the immune system can fail. As a result, the system attacks not only harmful organisms which cause infections but also innocuous targets such as pollen, house dust and food allergens resulting in allergic diseases.

Despite this new understanding, the hygiene hypothesis concept – that we have become too clean – still persists in the minds of the public. As a result, the public has lost confidence in hygiene. This is happening at a time when infectious disease issues mean that hygiene is becoming more, rather than less, important.

The aim of this study is to review the burden of allergic and infectious diseases and the evidence for a link to microbial exposure, the human microbiome and immune system. Also, it is to assess whether and to what extent we could develop lifestyles which reconnect us with exposures and thereby reduce the risks of allergic disease while also protecting against infectious disease.

Using methodology based on the Delphi technique, 6 – 9 six experts in infectious and allergic disease were surveyed to allow for elicitation of group judgement in order to arrive at a consensus view on issues pertinent to the aim of the study.

Key themes emerged: first, the extent of the health burden of allergic and hygiene-related diseases; second, the most recent evidence regarding the nature of the link between reduced microbial exposure and its impact on the human microbiome and the immune regulatory system; third, the question of relationship between lifestyles and protection against infectious diseases. The Delphi technique is a qualitative research method that relies on the judgement of individuals presumed to be knowledgeable and expert at what they do. When a sufficient degree of consensus is achieved, the Delphi process is curtailed and the resulting judgement is published. Six experts in infectious diseases and allergies were invited to participate, and the issues to be addressed were agreed via online communication. The authors participated in a conference in which each presented evidence related to their area of expertise. Following this, authors submitted a written contribution. These were analysed and key themes were integrated into a paper which was made available online to all authors for review. This included further questions soliciting the author’s views. After further rounds of questions and revision, a consensus position was obtained.

Why hygiene is important in the 21 st century

In the 1950s and 1960s, there was optimism that, with vaccination and antibiotics freely available, conquest of most infections would follow. During the last four decades, this opinion has been reversed. Infectious disease continues to exert a heavy burden on health and prosperity. The various infectious disease issues are most often considered in isolation, but when viewed together, they represent a powerful argument for renewed emphasis on hygiene, which alongside vaccination strategies remain key to containing infectious disease. 10

During the 1980s, there was a rapid increase in reported cases of food poisoning in the United Kingdom, particularly related to Salmonella and Campylobacter. 11 Although reported cases have somewhat declined, food, waterborne, and non-food-related infectious intestinal diseases (IIDs) remain at unacceptable levels. The latest study of IID (food and non-foodborne IID) reported that the true incidence in the community is 43% higher than in the mid-1990s: this study estimated 17 million cases a year in the United Kingdom. 12 The estimated cost of food-related IID is £1.5 billion a year, including resource and welfare losses. 12 Norovirus, mainly spread from person-to-person, is the most significant cause of intestinal infections in the developed world, including 3 million cases per year in the United Kingdom. 12

Evidence shows that respiratory hygiene involving hands and surfaces can limit spread of respiratory infections, particularly colds, and also influenza. 13 – 15 Since respiratory and intestinal viral infections are not treatable by antibiotics, prevention through hygiene is key.

In developed countries, about 7% of inpatients acquire an infection in hospital. 16 Recent figures show a decline in health-care-associated infection (HCAI), in the United Kingdom, particularly of Clostridium difficile and MRSA (methicillin-resistant Staphylococcus aureus ), 17 , 18 while other causes of HCAI have emerged, including new epidemic strains of Escherichia coli, Pseudomonas spp. and viruses.

Governments, looking at prevention as a means to reduce health spending, have introduced shorter hospital stays and increased homecare. This requires new policies to prevent HCAIs in community settings 19 where there is no evidence of a decline. Until recently, most episodes of C. difficile infection were believed to result from acquisition in health-care settings. There is now increasing evidence of multiple other potential sources, including asymptomatic patients, and sources in the wider environment, such as water, farm animals or pets, and food. 20 The contribution of cases acquired from these sources to the overall burden of disease is unclear, particularly with concerns about increased community-associated C. difficile infection. 21

Societal changes mean that people with greater susceptibility to infectious disease make up an increasing proportion of the population, up to 20% or more. 10 The largest proportion comprises the elderly who have reduced immunity, often exacerbated by other illnesses. It also includes the very young and family members with invasive devices such as catheters and people whose immuno-competence is impaired as a result of chronic and degenerative illness (including HIV/AIDS) or drug therapies such as cancer chemotherapy.

Emerging pathogens and new strains are a significant concern. It is remarkable that norovirus, Campylobacter and Legionella were largely unknown as human pathogens before the 1970s, with others such as E. coli O157 and O104 emerging in subsequent decades. It is now thought likely that we shall identify many more, the latest being Zika virus. 22 Agencies worldwide recognise that for threats such as new influenza strains, SARS (severe acute respiratory syndrome) and Ebola, hygiene is a first line of defence during the early critical period before mass measures such as vaccination become available. 23 The low infectious dose observed for several of the emerging pathogens, such as E. coli O157:H7 and norovirus, is an additional concern that emphasises the role that hygiene can play in prevention. 24 , 25

Antibiotic resistance is a global priority. 26 Hygiene addresses this problem by reducing the need for antibiotic prescribing and reducing ‘silent’ spread of antibiotic resistant strains in the community and hospitals. 27 As persistent nasal or bowel carriage of these strains spreads in the healthy population, this increases the risk of infection with resistant strains in both hospitals and the community. 27

Infections can act as co-factors in diseases, such as cancer and chronic degenerative diseases. Syndromes such as Guillain–Barré 28 and triggering of allergy by viral infections 29 add to the burden of hygiene-related infection.

The rise of allergies in the 20 th century

While infectious disease and hygiene have been key public health issues for centuries, 30 allergic diseases have only relatively recently been regarded as a significant health burden. The marked increase in prevalence of allergic diseases, such as eczema, 31 allergic rhinitis 32 and food allergy, 32 has been a prominent trend over the past century in all regions of the world, but most characterised in Western countries. 33 While this is frequently presented as an ‘epidemic’, epidemiological data indicate the situation is more complex. As highlighted by Platts-Mills 34 ( Figure 1 ), the ‘spikes’ in prevalence of allergic rhinitis, asthma and food allergy have occurred at different times in the past 120 years, and thus different atopic diseases may have different contributing factors. Indeed, there are emerging data that in some areas (mostly in ‘Western’ countries) these increases may have plateaued and even begun to subside. 34 A further issue is that at least for food allergy, prevalence may have been overestimated, depending on the methodology used. Venter et al. 35 assessed the rate of challenge-positive food allergy in three birth cohorts on the Isle of Wight (UK) between 1989 and 2002. A major finding of this study, confirmed in other reports, is that rates of parent-reported allergy were significantly higher (33%) than those confirmed by placebo-controlled food challenge (6%) (the accepted gold standard for diagnosis). For peanut allergy, the same study reported a rate of 1 in 200 children aged 3–4 years in 1989, increasing to 1 in 70 in the mid-1990s, but plateauing thereafter. A 2016 UK intervention study, in children breast-fed to at least 6 months of age, reported a rate of 1 in 40. 36 Of note, the development of an inappropriate immune response to foods (‘sensitisation’), which occurs before onset of clinical disease, is an early event often occurring in the first few months of life. 36

Trends in allergic disease

Reprinted from Platts-Mills, 34 Copyright (2015), with permission from American Academy of Allergy, Asthma & Immunology and Elsevier

Perhaps the relatively late appearance of food allergy over the past few decades is a consequence of a progression from allergic airways disease (hay fever, asthma) in parents to a more severe clinical phenotype (food allergy) in their offspring. 37 However, a compelling alternative is the interaction between genetic predisposition and environmental influences, particularly for food allergy, where immune sensitisation to foods may originate with exposure to food allergens in the environment through the skin, a situation exacerbated by eczema and reduced skin barrier function. 36 At the same time, there have been changes in how foods are consumed (e.g. roasted peanut, as consumed in Europe and North America, is more allergenic than raw or other forms of processed peanut).

From Hygiene Hypothesis to Old Friends Mechanism

Building on the significant amount of research published since 1989, a number of refinements to the original hygiene hypothesis now seem to offer more plausible explanations. The Old Friends (OF) Mechanism was proposed by Rook in 2003 and argues that the vital microbial exposures are not colds, measles and other childhood infections (the crowd infections), but rather microbes already present during primate evolution and in hunter-gatherer times when the human immune system was evolving. 38 – 40 OF microbes include environmental species which inhabit indoor and outdoor environments, and the largely non-harmful commensal microbes acquired from the skin, gut and respiratory tract of other humans. In evolving humans, before the advent of modern medicine, the OF also included organisms such as helminths, Helicobacter pylori , and hepatitis A virus that could persist for life in hunter-gatherer groups and that needed to be tolerated. They all therefore activated immunoregulatory mechanisms, 38 but few experts believe that they need to be replaced or even that there is any feasible way of doing so.

Whereas the hygiene hypothesis implicated childhood virus infections as the vital exposures, from an evolutionary point of view this was never likely. Crowd infections were not part of human evolutionary experience because they either kill or induce solid immunity, so could not persist in small hunter-gatherer groups. 41 Epidemiological studies carried out in Finland, Denmark and the United Kingdom now confirm that childhood infections do not protect against allergic disorders. 42 – 44

Studies show how OF exposures are vital because they interact with the regulatory systems that keep the immune system in balance and prevent overreaction, which is an underlying cause of allergies. Diversity of microbial exposure is key. First, a large experience of harmless bacteria and archaea during infancy, when immunoregulatory systems are being established, increases the repertoire of organisms that can be tolerated. Second, since all life-forms are ultimately constructed from similar building blocks, exposed individuals acquire some memory lymphocytes that recognise novel pathogens or even novel viruses. 45

What are the likely causes of reduced or altered microbial exposures

In order to look for strategies which might restore the necessary microbial exposures, it is first necessary to understand the underlying causes of the loss of exposure. Since allergic diseases are largely conditions of the last 100 years, an obvious assumption is that the sanitary revolution is a root cause. The latter part of the 19 th century saw radical improvements in sanitation, cleaner food and water, clean-up of cities, and rapid decline in infectious diseases. 46 However, it is likely that these changes also inadvertently reduced exposure to OF microbes which occupy the same habitats. Since the major changes in water, sanitation and hygiene had occurred by 1920, it is difficult to ascribe the massive changes in the asthma prevalence from 1960 onwards to these changes. 34

It is now clear that the most important times for OF exposure are early in development, during pregnancy, delivery, and the first few days or months of infancy. 47 , 48 A 2008 review of epidemiological studies show that Caesarean section is linked to increased risk of allergy. 49 C-sections have become increasingly common since 1950 and now account for 25% of UK births. 50 Furthermore, transfer of microbiota occurs via the mother’s milk, which is not sterile. 51 Breast versus bottle feeding has a large influence on gut microbiome, 52 , 53 but further studies are needed to confirm any association with allergic disease. In high-income settings, there is likely to be a trans-generational effect where each generation receives a more impoverished microbiota, and essential microbiota are lost from the community. 54

Continuing early-life exposure from the mother and siblings is also important. 55 , 56 Studies show that children from large families are at lower risk of developing allergies. 52 , 57 Exposure to pets protects against allergies, 58 , 59 although domestic animals in the home have increased rather than decreased. 60 People seem to share their microbiota via dogs, 61 which greatly increase the microbial biodiversity of the home. 62 , 63

There is good evidence that contact with microbial diversity from the natural environment is crucial. Numerous studies now show that exposure to farm environments during the first 2–3 years of life protects against allergic disorders 64 – 66 and correlates with microbial biodiversity in the air 67 and the home. 68 Animal models show candidate organisms from these environments protect against allergic disorders. 69 Studies in Finland show that living close to green space and agriculture rather than close to a town increases biodiversity of the skin microbiota and correlates with reduced allergic sensitisation. 70 Urbanisation has accelerated loss of exposure to the natural environment. In the United Kingdom, 82% of the population now live in urban areas, 71 with up to 90% of our time spent indoors. 72

Although research has tended to focus on the gut microbiome, it seems likely that the microbiome of skin and airways is also involved. 73 – 75 Much of the exposure obtained from outdoor environments is likely to be via the airways. The air contains bacteria, archaea, viruses, fungi, spores, pollen, plant biomass and dust. Depending on the environment and on degree of exertion, the number of bacteria/archaea breathed in could vary between about 10 6 and 10 10 in 24 h. A proportion of these will be retained in the airways, and recent work reveals that exposure to bacterial components causes increased expression of a protein that inhibits inflammation. 73 , 74 Gut exposure is also mediated via the airways where ciliary action brings about transfer to the gut. The likelihood that skin microbiota are OF microbes is indicated by studies showing that Acinetobacter species in skin protect against allergy. 75

Factors that maintain the gut microbiota

Once the microbiome has been acquired and evolved during childhood, 48 the critical question becomes what factors maintain optimum composition and biodiversity, because loss of biodiversity is strongly associated with disease states, inflammation and decline. 76 – 78

Increasingly, the answer appears to be that the optimal composition of the microbiota is maintained by diet, 79 which needs to be diverse, and contain fibre (polysaccharides digested by the microbiota rather than the human host), 80 and polyphenols found in plant products. 81 – 83 A diet deficient in fibre can lead to progressive extinctions of important groups of organisms, 54 which are cumulative and increasingly difficult to reverse in subsequent generations. 42 Polyphenols and also fish oils also appear to modulate the composition of the microbiota. 84 , 85

Citizens of high-income countries have less diverse microbiota than do hunter-gatherers. 77 – 79 Other studies show that the elderly living in the community with healthy diets 78 have higher gut microbiota diversity than those in long-stay residential care who have a less diverse diet. Studies in Sweden and Denmark show that reduced gut microbiota diversity in infants is associated with increased risk of allergic disease in childhood. 86 – 88

Introduction of antibiotics in the 1950s and subsequent prescribing trends, show a compelling temporal fit with rising allergies since the 1970s. A 2014 review of evidence from over 50 epidemiological studies shows a reasonably consistent relationship between excessive antibiotic use, particularly in early childhood, and increased risk of allergic disease. 89 Evidence showing that exposure to antibiotics during pregnancy increases the risk of allergic disorders in infants 90 , 91 has been further confirmed in recent studies. 92 , 93 Antibiotics, particularly macrolides, have lasting effects on the microbiota of young children and increase risks of asthma. 92 This mirrors effects documented in animal models, where early disruption of gut microbiota causes long-term damage to metabolic regulation. 94

Disruptions of maternal microbiota diversity by antibiotics or inadequate diet are found to be transmitted to future generations. 54

Domestic and personal hygiene

Of all the trends that might explain declining OF exposure, one of the weakest is the popular notion of ‘being too clean in our own homes’. If this factor contributes, its role is likely to be small relative to other factors. An explosion of data, obtained using high-throughput RNA sequencing of samples from US homes, suggests that modern homes are ‘teeming with microbes’. It also suggests that the bacterial communities found in the home relate to the people and domestic animals living there and the food they eat, together with input from the local outdoor environment. 63 , 95

Microbiological studies in westernised homes indicate that routine daily or weekly cleaning habits (even involving use of antibacterial cleaners) have no sustained effect on levels of microbes in our homes. 96 – 98 The idea that we could create ‘sterile’ homes through excessive cleanliness is implausible; as fast as microbes are removed, they are replaced, via dust and air from the outdoor environment, and commensal microbes shed from the human body and our pets, and contaminated foods brought into the homes. Strachan’s 1 1989 proposition that ‘ higher standards of personal cleanliness ’ could also contribute to reduced exposure to essential microbes may be compatible with increased bathing/showering/shampooing since around 1950s, 46 but although bathing and so on removes large numbers of microbes from the skin, these are rapidly replaced.

Although data from westernised homes suggest that more diverse communities can be found on less-cleaned surfaces (TV screen, door trims, floors) than regularly cleaned surfaces (cutting board, kitchen surface, toilet seat), 63 , 95 to date, there is no confirmed evidence of a link between personal or home cleanliness and increased risk of allergic disease. In a German birth cohort study of 399 families, personal cleanliness (e.g. handwashing and showering) was associated with lower levels of endotoxin and muramic acid (bacterial markers) in bedding and floor dust. In comparison, household cleanliness (e.g. cleaning floors and bathrooms, dusting, and changing towels) was associated with less dust but not with lower microbial marker levels. Endotoxin in infancy was associated with less allergic sensitisation and less asthma when these children reached school age, whereas muramic acid exposure at school age, but not infancy, was associated with less school-age asthma and eczema. 99 It might seem surprising that neither personal nor home cleanliness activities were directly associated with allergy outcomes, but Liu 100 suggests that this may reflect the importance of early-life timing of microbial exposures and not cleanliness behaviours, with the influence of endotoxin exposure being in infancy. A 2002 data analysis of UK children born in 1991/1992 found association between parent-reported frequency of hand and face washing, showering and bathing at 15 months and wheezing and atopic eczema at 30–42 months, but this association was not reported in other studies. 101 , 102

The key point may be that the microbial content of modern urban homes has altered relative to earlier generations, not because of home and personal cleanliness but because, prior to the 1800s, people lived in predominantly rural surroundings. Also, although human gut and skin microbiota are constantly shed from family members, it is likely that exposure has altered reflecting the reduced diversity of the human microbiota due to factors described above. This means we now interact with an altogether different and less diverse mix of microbes.

Other factors also argue against the role of hygiene. Hygiene is irrelevant to microbiome disruption through altered diet and antibiotics. Also, if contact with the natural environment and microbial components of house dust occurs mostly via the airways, hygiene and cleanliness is unlikely to be responsible for reduced inputs from this key source.

Communicating Microbiome Science to Society – Prelude to Reversing Immunoallergic Disorders

Although evidence suggests that strategies such as promoting natural childbirth and breast feeding, increased social exposure through sport, other outdoor activities, less time spent indoors, diet and appropriate antibiotic use could help restore the microbiome and perhaps reduce risks of allergic disease, clinical and other evaluations are required to establish whether and to what extent this might occur and when intervention is most beneficial.

There is a window of time when the developing microbiome is critical for the education of the maturing immune system. Disruption or delay in acquisition of the microbiome in the first few years of life may predispose to later immune dysfunction. It follows that preventive efforts against immuno-allergic disorders must be focussed on early life events. Attempts to correct abnormal host–microbe interactions, once immunological events which lead to allergic disease are established, may be too late. These issues are further discussed by Shanahan and colleagues. 103 – 105 Gaps in understanding host–microbe interactions will be addressed as research continues, and one can anticipate a time, when optimal conditions for colonisation of the newborn are understood and can be controlled by strategies ensuring neonates begin life with a robust and diverse microbiota. In the interim, there is much that can be achieved by education and behaviour change, based on current information.

Several factors seem to conspire to limit effective communication of microbiome science to society ( Table 1 ). Some elements within the popular media do disservice to their readership. Examples include mis-representation of the role of hygiene and cleanliness, failure to clarify that probiotics are not all the same, and failure to probe unsubstantiated health claims or address seemingly complex concepts in detail. Fault also lies elsewhere ( Table 1 ). In contrast to policy makers and public health officials, clinicians deal with individual patients, not populations. Unless concerns about antibiotic usage are brought to an individual level, with emphasis on the consumer rather than the prescriber, reform initiatives will have limited impact. Patients are less likely to demand antibiotics if provided with information on the impact of such agents on the microbiota and the risk of immune disorders in later life. 106

Science and society – communication barriers

Promotion of breast feeding is lacking in precise rationale for modern women. Breast-feeding mothers need to know they are promoting a lifelong healthy microbiota for their offspring. Since the neonate acquires its microbiome primarily from its mother, greater attention needs to be paid to the mother’s diet, faecal and vaginal microbiome. Increasing awareness of the importance of the microbiome and the factors which sustain or disrupt it should be part of antenatal education.

Microbiome science already provides a glimpse of how the microbiota may be preserved or restored, including development of smart antibiotics, 107 non-antibiotic anti-microbials, microbial transplants, microbial consortia or single strains, and use of personalised biomarkers of disease risk prediction. 108 , 109 Restoration of the microbiome by vaginal microbiota transplants in C-section infants has been demonstrated, 110 albeit of unproven long-term benefit and controversial. 111 In addition, the molecular basis by which bifidobacteria engage with the host immune system is emerging; 112 , 113 this is important because such organisms are a predominant component of the microbiota in neonates.

Because of the multiplicity of factors involved, strategies to preserve or manipulate the microbiota will probably require a personalised approach tailored to individual genetics and lifestyle factors. 109

Developing and Promoting A Targeted Approach to Hygiene in Home and Everyday Life

Over the last 20 years or so, for reasons outlined above, there has not only been a revival of concern about infection and the role of hygiene 10 , 114 but also a realisation that the ‘scrupulous cleanliness’ approach advocated by Florence Nightingale 115 is no longer appropriate. If, as this review suggests, allergic diseases are not the price we have to pay for protection against infection, this is good news for hygiene. However, if we are to maximise protection against infection while at the same time sustaining exposure to essential microbes, we need a revised approach to hygiene based on current scientific evidence.

The International Scientific Forum on Home Hygiene (IFH) ( http://www.ifh-homehygiene.org ) was established in 1997 with the aim of developing and promoting a more effective approach to hygiene, based on scientific principles and the growing database of evidence about pathogen transmission. 116 To achieve this, IFH adopted the principle of targeted hygiene. 117 Targeted Hygiene is based on a four-step risk assessment requiring identification of the sources and reservoirs of pathogens, the routes of transmission, the critical control points, and appropriate hygiene interventions.

Targeted hygiene is based on the chain of infection transmission ( Figure 2 ) which shows that pathogenic organisms are continually shed into the environment from sources such as human occupants, pets and raw foods. 118

The chain of infection transmission in the home

To get from an infected source to another individual, pathogens use well defined routes. Sampling studies record the presence of non-pathogenic bacteria and bacteria and viruses of medical interest on environmental surfaces in home and community settings, and laboratory and field studies have evaluated the rates of transfer of viral and bacterial pathogens via hands and common touch surfaces. 116 These demonstrate that the critical control points for transmission of infection are the hands, hand contact surfaces, food contact surfaces, and cleaning utensils and that these present the highest risk of transmission ( Figure 3 ).

Ranking of sites and surfaces based on risk of transmission of infection

Equally important considerations are the interventions used to eliminate pathogens from critical control points before they spread further. This is important since inadequate procedures can increase transmission. 119 – 123 Hygienic (as opposed to visible) cleaning of hands, surfaces, fabrics and so on can be achieved by the following:

• Physical removal of pathogens from inanimate or skin surfaces using soap or detergent-based cleaning. To be effective as a hygiene measure, this should be accompanied with thorough rinsing under running water, such that pathogens are not further disseminated.
• Using an antimicrobial product (disinfectants or alcohol hand sanitisers) or processes (heat) that inactivate pathogens in situ . Antimicrobials are required where adequate removal is not possible by wiping/cleaning and/or rinsing alone, or in situations of higher risk. 124
• Combined action, for example, laundering, where physical removal is combined with inactivation by heat together with an oxygen bleach–based laundry product.

While it is difficult to quantify the impact, evidence suggests that targeted hygiene reduces spread of infection. A review of evidence published between 1980 and 2001 concluded that the strength of the association between hygiene in the community and infections, as measured by the relative reduction in risk of illness by one or more hygiene measures (including handwashing), was generally greater than 20%. 125 A meta-analysis of community studies showed that improvements in hand hygiene alone resulted in reductions in gastrointestinal and respiratory illness of 31% and 21%, respectively. 126

Changing hygiene behaviour, however, requires changing public perceptions about hygiene, most particularly that hygiene is different from cleanliness, that is, more than just absence of dirt. Hygiene is what we do in the places and at the times that matter (hand, food, toilet and respiratory hygiene, health care, etc.) to protect against infection.

Communication and social marketing campaigns are now being evaluated and used as a means to achieve behaviour change mainly (but not exclusively) in relation to food and respiratory hygiene. These campaigns, however, focus on changing behaviours rather than changing understanding and dispelling misconceptions. 13 , 127 – 130 The e-bug project is a Europe-wide initiative aimed at ensuring all children leave school with an understanding of targeted hygiene. 131 An important feature of this teaching resource is that it is based on understanding infection and how it is transmitted.

The evidence reviewed in this study reflects the significant shift in thinking in the last 25 years. It shows that the interaction of the OF microbes which inhabit the natural environment and human microbiome with our immune system plays an essential role in immune regulation, promoting a tolerising milieu for the immune system which may impact against the development of allergic disease. Changes in lifestyle and environment, along with rapid urbanisation, have all contributed to changes in our exposure to essential microbes. 132 In addition, altered diet and excessive antibiotic use have also sustained detrimental effects on the content and diversity of the human microbiome. Together, these factors have had profound effects on the immune system, which are likely to have contributed to the onset of allergic disease.

By contrast, the public idea that obsessive hygiene and cleanliness is the root cause of the rise in allergies is no longer supported. Data show that relevant microbial exposures are almost entirely unrelated to hygiene as the public understands it. This is partly because sustaining the human microbiome through diet and avoiding excessive antibiotic usage are factors entirely unrelated to hygiene.

As far as understanding strategies which may reduce the risk of allergic disease, work is progressing fast, but there is still a long way to go. The multiple factors involved (including those not directly associated with microbiome interactions (allergen exposure, genetic, pollution, etc.)) make it impossible to assess the contribution of each factor. It is likely that success will only be achieved through combined effects of lifestyle changes, together with improved diet and reduced antibiotic prescribing. Nevertheless, data are now strong enough to encourage changes, such as encouraging natural childbirth, physical interaction between siblings and non-siblings, more sport and other outdoor activities (including babies in prams), and less time spent indoors, and reduced antibiotic consumption.

This review further supports the view that the term ‘hygiene hypothesis’ is a misleading and dangerous misnomer which needs to be abandoned in favour of a more appropriate term such as the OF Mechanism. However, in order to tackle both allergy and infection issues we also need to develop a smarter approach to hygiene. Although targeted hygiene was developed to optimise protection against infection, it provides a framework for maximising protection against pathogen exposure but, at the same time, minimising disturbance of the indoor microbiome and spread of essential microbes between family members.

As summarised in Table 1 , if we want to take advantage of these new findings, we first have to change public, public health and professional perceptions about the microbiome and about hygiene. Unstructured and conflicting advice and vague health warnings in the consumer and professional media must be replaced with simple clear mechanistic explanations and consistent messages using consistent terminology which avoids the use of the term ‘hygiene hypothesis’ to define the concept of a link between microbial exposure and allergies. Recent media articles which promote unsubstantiated suggestions that reduced handwashing could be a means to build and sustain a diverse gut microbiome are in direct conflict with public health agency advice on handwashing which is identified as probably the most important ‘critical control point’ for preventing spread of infection in all settings. 133 , 134

An underlying problem that needs addressing is that, both nationally and internationally there are no lead agencies which take ownership of hygiene promotion, looking at it from the point of view of the public at large and what they need to understand and know. Campaigns targeting food or respiratory, pet or health-care hygiene are developed by different agencies, often with conflicting messages. They also do little to address public misunderstandings about how infections are transmitted, the difference between hygiene, cleanliness and dirt, the widespread misuse of the term ‘germs’, and the hygiene hypothesis misnomer. 135

The imperative to understand and reverse the epidemiologic trends in allergic and immune-mediated disorders relates not solely to the personal suffering and health-care burden in the developed world. Without urgent effective intervention, such trends will be replicated around the globe as societies undergo socio-economic development. 105

Funding: P.J.T. holds a Clinician Scientist Award from the UK Medical Research Council (reference MR/K010468/1) and is supported through the National Institute for Health Research (NIHR)/Imperial Biomedical Research Centre. F.S. is a founder shareholder in Atlantia Food Clinical Trials, Tucana Health, and Alimentary Health Ltd. He is director of the APC Microbiome Institute, a research centre funded in part by Science Foundation Ireland (APC/SFI/12/RC/2273) and which has recently been in receipt of research grants from the following companies: Abbvie, Alimentary Health Ltd, Cremo, Danone, General Mills, Friesland Campina, Janssen, Kerry, MeadJohnson, Nutricia, 4D Pharma plc, Second Genome, and Sigmoid pharma. The authors received an honorarium from the International Scientific Forum on Home Hygiene for their time in preparation of this manuscript.

Contributor Information

Sally F Bloomfield, London School of Hygiene & Tropical Medicine and International Scientific Forum on Home Hygiene, The Old Dairy Cottage, Montacute, Somerset TA15 6XL, UK.

Graham AW Rook, Centre for Clinical Microbiology, Department of Infection, University College London (UCL), London, UK.

Elizabeth A Scott, Center for Hygiene and Health, Department of Biology, Simmons College, Boston, MA, USA.

Fergus Shanahan, APC Microbiome Institute, University College Cork – National University of Ireland, Cork, Ireland.

Rosalind Stanwell-Smith, London School of Hygiene & Tropical Medicine, London, UK.

Paul Turner, Section of Paediatrics (Allergy & Infectious Diseases) and MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, UK; Discipline of Paediatrics and Child Health, The University of Sydney, Sydney, NSW, Australia.