two claims make up the hygiene hypothesis

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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.

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MINI REVIEW article

The hygiene hypothesis and new perspectives—current challenges meeting an old postulate.

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

During its 30 years history, the Hygiene Hypothesis has shown itself to be adaptable whenever it has been challenged by new scientific developments and this is a still a continuously ongoing process. In this regard, the mini review aims to discuss some selected new developments in relation to their impact on further fine-tuning and expansion of the Hygiene Hypothesis. This will include the role of recently discovered classes of innate and adaptive immune cells that challenges the old Th1/Th2 paradigm, the applicability of the Hygiene Hypothesis to newly identified allergy/asthma phenotypes with diverse underlying pathomechanistic endotypes, and the increasing knowledge derived from epigenetic studies that leads to better understanding of mechanisms involved in the translation of environmental impacts on biological systems. Further, we discuss in brief the expansion of the Hygiene Hypothesis to other disease areas like psychiatric disorders and cancer and conclude that the continuously developing Hygiene Hypothesis may provide a more generalized explanation for health burden in highly industrialized countries also relation to global changes.

Introduction

Throughout its history, the Hygiene Hypothesis has shown itself to be adaptable and flexible whenever it has been challenged by innovation in science ( 1 ). A number of new findings need to be considered in this ongoing revisiting process: The originally proposed Th1/Th2 paradigm is challenged by currently elucidated new classes of effector and regulating immune cells pointing out to a more complex immune network involved in allergy development ( 2 ). Studies on biomarkers and deep phenotyping techniques changed our understanding of asthma as a uniform disease in favor of distinct phenotypes that are driven by different causations ( 3 ). The emerging field of epigenetics enables us to fill the black box of “gene-by-environment interactions” with conveying mechanisms ( 4 ). Currently recognized epigenetic pathways overlapping between chronic inflammatory diseases and other disorders such as psychiatric conditions or cancer might extend the Hygiene Hypothesis toward a model explaining in a broader sense the rise of health burdens in westernized societies ( 5 ). Finally, the world-wide challenge caused by the climate changes will not leave the consequences of Hygiene Hypothesis unaffected. Changing life-styles are closely related to measures implemented to slow down CO 2 emissions and to stabilize the world climate ( 6 ).

Challenges From Immunology – The Immune System Becomes More Complex

Parallel to the revisions that Hygiene Hypothesis has undergone over time ( 7 ), our perception of the mechanisms underlying cellular and humoral immune responses has changed fundamentally over the last decades. High-resolution flow cytometry and cell sorting and, most recently, single cell multiomics-based analyses provided a deeper insight into the phenotypic characterization, function, and development of diverse classes of hematopoietic cell types. The dichotomous model of divergent Th1 and Th2 responses was significantly expanded by the discovery that T lymphocytes represent a branched network of subsets, characterized by a high level of plasticity and adaptability ( 8 ). Namely, Sakaguchi’s discovery of regulatory T-cell (Treg) subsets provided a significant new impetus to researchers investigating the immunological origin of allergic and autoimmune diseases and their prevention under healthy conditions and pointed out new strategies to combat those maladies ( 9 , 10 ). Moreover, the discovery of new classes of effector cells and their cellular interactions added relevant evidence to the field. As one example, innate lymphoid cells (ILC) became of main interest as they have been shown to be both directly and indirectly associated with and involved in the development of allergic responses ( 11 ). This unique class of effector cells lacks a clonally distributed antigen receptor which thus resemble innate immune cells characterized by (antigen) unspecific activation, however, they exert T helper (Th)-like effector cell activities ( 12 ). According to their expression of effector cytokines and transcription factors ILC have been classified into three groups: ILC1, ILC2, and ILC3 ( 13 ). While ILC1 produce interferon-gamma (IFNγ) and tumor necrosis factor α (TNFα) and, similarly to Th1 cells, express T-bet, ILC2 are able to produce Th2 cytokines such as IL-5 and IL-13, like Th2 cells under the control of the transcription factor GATA-3. ILC3 are similar to Th17 cells and release IL-17A and IL-22 as well as granulocyte macrophage colony stimulating factor (GM-CSF). In animal models of allergic airway inflammation as well as in human allergic asthmatics ILC2 are present at elevated frequencies within the lung and airways epithelial compartments where they were found to produce high amounts of the type-2 cytokines IL-5 and IL-13 ( 14 ). Within the last years, ILC2 have been recognized as early promoters to establish and maintain allergic airway inflammatory responses but also as protectors promoting repair processes of the lung epithelium ( 15 , 16 ).

A potential link between the Hygiene Hypothesis and the function of ILC lineages comes from the gut. The symbiotic interaction between immune cells and the microbiota in the gut is principally decisive for the development of tolerance or pathogenicity. The ILC3 lineage is essential in the development of lymphoid follicles and Peyer’s patches in the gut and was shown to be crucial for the maintenance of a well-balanced symbiosis with the microbiota ( 17 ). The host microbiota itself might play an important role in determining ILC subsets specificity as indicated by results coming from experimental approaches. Sepahi et al. very recently reported that short chain fatty acids (SCFA) arising from dietary fibers by microbial fermentation in the intestine induced expansion of prevailing ILC subsets. By triggering ILC subset expansion via G-protein-coupled receptors (GPCR) those dietary metabolites contribute to the homeostasis in the local compartment ( 18 ). Another mechanism to induce repair and homeostatic conditions at epithelial surfaces is mediated via IL-22-producing ILC3 in response to the microbiota. In interaction with IL-18 produced by the epithelial cells, IL-22 is involved in the promotion of repair and remodeling processes as well as in the maintenance of the gut homeostasis ( 19 ). By acting as mediators between the microbiota and the host ILC are recognized as crucial in the early host response to microbial stimuli.

Challenges From Changing Environments – Can Epigenetics Provide the Missing Link to Explain “Gene-by-Environment Interactions”?

Very recently, damaging factors that jeopardize the normal development or disturb the balance of an established immune system have come into the focus of research on allergic diseases. Environmental changes caused by in- and outdoor pollution ( 20 , 21 ) and the global warming impact the atopic epidemic and some attempts were undertaken recently to integrate these scenarios into the concept of the Hygiene Hypothesis on the basis of epigenetic changes driven by gene-by-environment interactions ( 22 ).

In contrast to our ancestors who spent most of their life time outdoors and thus close to a natural environment, post-modern and mainly urban life-styles are characterized by a significantly higher proportion of indoor activities. These changing habits underline the potential importance of indoor air composition on the development of allergic diseases and further emphasize the role of the environmental microbiota ( 23 ). Indoor air in urban homes is often burdened with elevated levels of molds which are found to be harmful to the airways and favor the development of airway inflammation and asthma ( 24 ). Against the background of growing climate awareness and the resulting increased efforts to reduce energy consumption and CO 2 emissions, current research on these indoor exposures in homes with improved house insulation points out to an up-coming health problem. Enrichment of volatile organic compounds released from furniture or brought in by tobacco smoke as well perennial allergens and molds will jeopardize mainly infants as the developing immune system and the growing lung are highly susceptible to these damage factors ( 25 ). Already the fetus might become affected by these components ( 26 ). This was exemplarily shown for tobacco smoke in a transgenerational case control study conducted to assess the risk for asthma by prenatal smoking. Grandmothers and mothers of asthmatic and non-asthmatic children were asked about smoking habits during their own pregnancy. The study reported an odds ratio twice as high for children to develop asthma in families where grandmothers frequently smoked during the mother’s fetal period ( 27 ).

At that point the Hygiene Hypothesis was in line with an upcoming general idea that non-inherited/non communicable diseases like allergies and asthma develop on the background of an inappropriate interaction between environmental exposures and a given genotype to shape a specific (disease) phenotype. Though based on the concept of a so-called epigenetic landscape postulated by Waddington already in the 50ties of the last century, the underlying molecular mechanisms of epigenetic programming had still been the “missing link” in the scenario of gene-by-environment-interactions ( 28 ). By discovering mechanisms such as DNA methylation, diverse histone modifications and microRNA regulation as molecular mechanisms underlying epigenetic regulation of gene expression, an exciting new field of research was opened that currently has a strong impact on research aiming to unravel the still existing mysteries of allergy development and prevention ( 29 – 31 ).

Indeed, epigenetic mechanisms have meanwhile clearly been demonstrated to be involved in mediating the effects of environmental factors increasing or decreasing the risk of allergy development ( 4 ). Pro-allergic environmental influences can be exemplified by pollution. For instance, higher in utero exposure to polycyclic aromatic hydrocarbons (PAH) has been shown to be associated with increased cord blood leukocyte DNA methylation at the promoter of the IFNγ-encoding gene ( 32 , 33 ). Moreover, in Treg isolated from peripheral blood mononuclear cells, higher PAH exposure has been correlated with elevated DNA methylation at the promoter of the gene encoding FOXP3, a master regulator of Treg development and activities, with the effect being stronger in asthmatic than in non-asthmatic children ( 34 ).

After epidemiological studies had demonstrated an association between spending early life time in specific agricultural environments and protection against the development of allergies in childhood ( 35 , 36 ), functional investigations of various types started to clarify which elements of farming, such as contact with farm animals, consumption of raw cow’s milk, exposure to so-called farm-dust, and others, mechanistically underlie this observation. DNA demethylation at the FOXP3-encoding locus related to higher expression of the gene and activation of Treg ( 37 ) has been associated in cord blood with maternal consumption of raw cow’s milk ( 38 ) and in children’s whole blood with early-life ingestion of raw cow’s milk ( 39 ). Compared to processed shop milk, pretreatment with raw cow’s milk reduced features of the disease in mice subjected to a model of food allergy and this effect was mediated by changes in histone acetylation patterns at crucial T cell-related genes ( 40 , 41 ). Interestingly enough, unprocessed cow’s milk has been shown to contain miRNAs potentially affecting the expression of important allergy-related immune genes, which might contribute to its protective effects against asthma ( 42 ). Several bacteria have been isolated from the farming environment, for instance Acinetobacter lwoffii ( A. lwoffii ), which were demonstrated to diminish the development of allergic symptoms in murine models ( 43 ). A. lwoffii -mediated protection against allergic airway inflammation has been observed in mouse models also transmaternally and shown to be IFNγ−dependent, with this effect being at least partly mediated by preservation of histone H4 acetylation at the promoter of the IFNγ-encoding gene as observed in CD4 + T cells isolated from spleens of the offspring ( 44 , 45 ).

Challenges From the Clinics and Lessons From Animal Models – Asthma Phenotypes and the Hygiene Hypothesis

A recurrent debate flared up in the field of asthma research excellently summarized at the time being in a review by Wenzel in 2012 ( 46 ). Coming from clinical heterogeneity of asthma patients she highlighted that basic inflammation patterns differ in asthma patients which in turn determines the success of the applied therapeutic strategy. As an early diagnosis and adequate treatment may prevent the development of a severe asthma phenotype later on, novel strategies to discriminate children at risk from those who will not develop asthma are required ( 47 ). Following the clinical definition of a phenotype as a result of an interaction between a given genotype and the environment Wenzel and colleagues expressed the strong medical need for novel molecular and genetic biomarkers indicative for the characterization of such phenotypes and defining the specific requirements for stratified therapies. Based on differences between Th2-driven atopic asthma and non-atopic asthma a number of subtypes were defined that evolve and differ with age and respond differentially to standard drug treatment regimes. It quickly became clear that the search for a specific biomarker that clearly identifies a respective phenotype would not be successful. Rather, the synopsis of all data collected from a subject known as “deep phenotyping” may lead to better understanding of complex asthmatic conditions ( 48 ). Deep phenotyping in the era of OMICS goes along with a tremendous increase in data that needs to be analyzed. To handle these big data-sets new approaches become increasingly employed involving models of statistical data dimension reduction and machine-learning strategies ( 49 , 50 ). The idea behind these data-driven approaches is to mine data collections and classify them based on so far hidden patterns behind the data. The hypothesis-free latent class analysis (LCA) approach represent one of the most promising tools to identify new or verify proposed asthma (and other allergic disease) phenotypes. A first LCA approach was carried out in two cohorts of adult asthmatics. Based on clinical and personal characteristics Siroux et al. described two distinct phenotypes in two independent cohorts, a severe phenotype in which asthma is already established in childhood and a second type that starts in adulthood with milder outcomes ( 51 ). In line with the Hygiene Hypothesis, these results pointed out specific preconditions in infant age which pave the pathway to severe asthma later in life. LCA analyses in children substantiated the link between early onset and later disease since early clinical signs such as current unremitting wheezing episodes are ascribed to indicate a higher risk for asthma development later in life while transient wheezing seems to have no pathological consequences ( 52 ).

LCA approaches using data from patient studies elucidated that there might be phenotypic asthmatic manifestations that could be explained by the Hygiene Hypothesis while other phenotypes that might have different pathomechanistic origins failed to be covered by this supposition ( 53 ). Among others, this discrepancy led to new approaches in pre-clinical animal-based experimental set-ups as well as investigations based on human data. New animal models were employed to prove the postulate of such phenotypes that can be discriminated on the immunological and histological levels. By switching from the well-established Ovalbumin (OVA) model, where the sensitization was mainly achieved by a rather artificial intraperitoneal allergen sensitization in the presence of the type-2 driving adjuvant alum, to a more flexible administration of standardized house dust mite extracts (HDM) via the nasal route, it was feasible to induce a more natural and broader spectrum of inflammatory phenotypes ranging from typical allergic eosinophil-dominated respiratory inflammation to airway inflammatory conditions almost exclusively dominated by the influx of neutrophils ( 54 – 56 ). Such more flexible model systems allow deeper and more precise investigations of the mechanisms underlying the development of different phenotypes and a much better characterization of the orchestration of different regulatory and effector T cell subsets in dependence of allergen administration on a continuum between Th2 and Th1/Th17-driven inflammation. In addition, these mouse models mimic the natural situation more closely by using common allergens and a potential natural route of sensitization and thus became helpful for understanding the diverse clinical phenotypes of allergic and non-allergic as well as mild and severe asthma ( 57 , 58 ). By switching between different effector T cell responses in these experimental set-ups substantial knowledge is currently added to our understanding of clinical manifestations in asthma. In combination with LCA helping to elucidate clinical phenotypes these recent research developments strongly boosted a better discrimination between transient and persistent pediatric allergic conditions as well as allergic and non-allergic asthma later in life. This new evidence might lead us to the current limits of the Hygiene Hypothesis. While IgE-driven allergic asthma undoubtedly fits to the Hygiene Hypothesis, it is still unclear whether this holds true also for non-atopic asthma phenotypes the development of which is much more strongly determined by factors different from a missing (microbial) education of the immune system. Thus and to further fine-tune the Hygiene Hypothesis, continuous efforts are required to distinguish between environmental conditions (such as early life infection with pathogenic viruses) that are either associated with the induction of a disease phenotype and/or just contribute to a shift between distinct inflammatory manifestations of allergic disease phenotypes ( 59 , 60 ) and those that really result in a general or a phenotype/endotype-specific prevention of disease in line with the Hygiene Hypothesis ( 43 , 61 ).

Challenges From a View Over the Fence – The Hygiene Hypothesis in Psychiatric Disorders and Cancer

The French scientist Bach was the first who made the principal observation of a general inverse correlation in the prevalences of infectious versus non-communicable chronic inflammatory diseases within the last seven decades ( 62 ). Meanwhile we know that abundant exposure to a high diversity of infectious or even harmless microbes resulting in repeated, low-grade acute inflammatory episodes in early life, associates with lower prevalence of chronic inflammatory disorders accompanied by low levels of inflammatory markers in adulthood. Conversely, high levels of hygiene during perinatal and early childhood developmental periods characteristic for Western countries corresponds to higher levels of inflammatory markers correlating with a higher prevalence of chronic inflammatory disorders later in life. Based on these facts, it has been hypothesized that frequent episodes of low-grade, in most cases clinically symptom-free inflammation in infancy may balance responses to inflammatory stimuli and thus reduce the rate of continuation of chronic inflammation into adulthood, most probably by adequately shaping the adaptive immunity-dependent regulation ( 23 ).

Interestingly, this observation considers a broader spectrum of chronic inflammatory conditions beyond allergies that might fit under the umbrella of the Hygiene Hypothesis such as multiple sclerosis, irritable bowel disease or diabetes type 1 ( 63 ). Moreover, within the last years a similar approach emerged to explain the tremendous increase in psychiatric disorders in westernized countries. Mainly affective disorders such as major depression and bipolar disorder are increasingly diagnosed in the westernized world. Patients suffering from affective and anxiety disorders depict an array of features that mirror inflammatory conditions such as pro-inflammatory cytokines in the blood and the central nervous system accompanied by elevated levels of circulating C-reactive protein (CRP), activation of lymphocytes and inflammatory cellular signaling pathways (MAPK and NF-κB), with the question of causality remaining a chicken or egg problem ( 64 ). Nevertheless, based on genetic predispositions and epigenetic modifications in the brain (nervous system) and the periphery (immune system), both kinds of pathologies, mood and inflammatory disorders, might become established on the basis of a disturbed homeostasis of otherwise tightly balanced adaptive systems of the body. Interestingly but fitting to the hypothesis, the microbiota of the gut seems to play a critical role also in the development of psychiatric disorders as shown by recently conducted studies ( 65 ). Based on an interplay between the gut and the central nervous system, persistent stress and maltreatment modifies the nervous system and thereby the endocrine hypothalamic pituitary axis (HPA) which in turn alters gut microbiota by cortisol release ( 66 ). Dysbiosis in the gut might lead to a compromised cytokine balance in the blood followed by an activation of the microglia in the brain after transfer of inflammatory mediators/cytokines through the blood-brain barrier ( 67 ). Further, degradation of beneficial bacteria in the gut microbiota might result in a loss of microbiota-derived products such as butyrate which directly results in the downregulation of γ-aminobutyrate, serotonin and dopamine, all factors directly involved in the neurological regulation circuits and thus in the genesis of neuropsychiatric disorders when dysregulated ( 68 ).

Finally, to add another example to this collection, there is increasing evidence that similar mechanisms as involved in the protection from allergies might also play a role in the prevention of oncologic diseases ( 69 ). There is no doubt that preceding infections with certain pathogens may favor initiation and further development of several tumor disease entities. However, a variety of recent studies also demonstrated positive effects of pathogen-induced “benign” inflammatory processes on cancer development, even though the underlying mechanisms of this dichotomous influence of microbial exposure-mediated immune modulation on carcinogenesis are not well understood so far ( 70 ). As one example, the origins of childhood leukemia have long been discussed in the context of microbial stimuli in early childhood. Already at the end of 20 th century the question emerged whether early infections in childhood may act protectively against childhood acute leukemia by eliminating expanding aberrant leukocyte clones through well-trained and established immune mechanisms. In concordance with the Hygiene Hypothesis, Greaves propagated the “Delayed Infection Hypothesis” as an explanation for the development of childhood acute (lymphoblastic/myeloid) leukemia (ALL/AML) that peaks at the age of 2-5 years of life in affluent countries ( 71 , 72 ). In his two hit model, Greaves proposed that based on a prenatally occurred chromosomal translocation or hyperdiploidy a pre-leukemic clone is already established around birth (first hit). A second hit event beyond the toddler age then leads to gene deletion or mutation and subsequent transformation to ALL/AML. While children suffering from infections and/or exposed to a rich microbial environment early in life might be ready to prevent that second aberration, predisposed children with an insufficiently educated immune system due to missing “old friends” contacts in the early postnatal life might not be able to eliminate expanding malignant cell clones ( 72 ). A number of studies aimed to prove this hypothesis by exploiting “day care attendance” before the third year of life as a proxy for infection. This concept is still a matter of debate. While the vast majority of these studies could add evidence to the Greaves hypothesis, some well-conducted studies could not support his assumptions ( 73 , 74 ). Recently, a meta-analysis investigated the farm effect with regard to childhood leukemia and confirmed that contact to livestock provides protection not only against allergies but also against childhood leukemia ( 75 ). This study might point out to microbiota as a crucial player in both prevention of allergies and childhood cancer.

The challenges outlined in this mini review are intended to stimulate further exciting debates that might result in continuing revisions and adaptations of the Hygiene Hypothesis. We are aware that the examples reported in this review may only describe a limited subjective selection of the scientific topics currently discussed in context of the Hygiene Hypothesis. However, it is common to all topics that the explanations to unravel the underlying mechanisms refer to the close and beneficial relationship between man and microbes as established on the mucosal surfaces of our body. These interactions result in adequate shaping of adaptive systems of the body (mainly the immune system) that enables the whole organisms to appropriately handle diverse adverse influences. Without exaggeration, this finding might be considered one of the most fundamental insights of the life sciences within the last thirty years.

Author Contributions

All authors contributed by writing and editing of the manuscript. All authors contributed to the article and approved the submitted version.

Funded by the German Center for Lung Research (DZL). Open Access was funded by the Library of the Philipps University Marburg, Germany.

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, non-communicable inflammatory diseases, chronic inflammation

Citation: Garn H, Potaczek DP and Pfefferle PI (2021) The Hygiene Hypothesis and New Perspectives—Current Challenges Meeting an Old Postulate. Front. Immunol. 12:637087. doi: 10.3389/fimmu.2021.637087

Received: 02 December 2020; Accepted: 04 March 2021; Published: 18 March 2021.

Reviewed by:

Copyright © 2021 Garn, Potaczek and Pfefferle. 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: Holger Garn, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Is Being Too Clean Bad for Your Health?

From taking a shower to brushing your teeth to washing your hands, you practice good personal hygiene on the daily. And it’s not just because you like the way your new shampoo smells, either. You know these habits keep you clean and, in some cases, can even help prevent you from getting sick.

But after all that lathering, rinsing and scrubbing, can you actually be too clean for your own good?

That’s what supporters of the so-called hygiene hypothesis think, saying that the rising rates of allergies, asthma and other autoimmune disorders in children is linked to our increasingly hygienic surroundings. And while statistics appear to back this up, experts in the fields of immunology and infectious disease say, not so fast.

“To say that being clean means you’re at a higher risk of allergies or asthma is not quite right,” agrees Dr. John Lynch , an associate microbiology professor at the University of Washington School of Medicine and medical director of Harborview Medical Center’s Infection Control, Antibiotic Stewardship and Employee Health programs.

The problem, he says, is that the hygiene hypothesis doesn’t tell the full story.

What is the hygiene hypothesis?

Largely popularized by British epidemiologist David Strachan in 1989, the hygiene hypothesis theorizes that because modern parents are able to clean their children and households more effectively, kids these days just aren’t exposed to the same level of germs as previous generations.

That excessively sterile upbringing — hand sanitizer, anyone? — means children’s immune systems aren’t able to develop properly and, as a result, malfunction.

When you look at the statistics, they seem to support this idea. In developed countries, the number of kids who have asthma and allergies has been going up.

Washington state has some of the highest incidences of asthma in the nation, and it’s only increasing. More than 600,000 Washingtonians have asthma, and nearly 120,000 of them are children.

Research from the Centers for Disease Control and Prevention shows that the same trend applies to kids who have food allergies. Now 1 in 13 children in the United States has a food allergy, a 50% increase between 1997 and 2011. To put it in perspective, that means in every American classroom, there are two kids who may have a food-related allergic reaction.

Is the hygiene hypothesis true?

Don’t toss out your hand soap or quit bathing your kids just yet. Remember, while data appears to back up the hygiene hypothesis, it’s not a complete picture.

“There was no randomized control study to determine the hygiene hypothesis,” Lynch explains. “It ends up being observations of populations, biased by our ability to detect diseases. You have less likelihood of being diagnosed with asthma or even diabetes in a developing country versus a developed country.”

What Lynch means is that as the field of medicine has advanced in recent decades, so has our ability to detect and diagnose conditions like the aforementioned food allergies and asthma. And the reason why much of the evidence to support the hygiene hypothesis comes from industrialized countries is because these nations have greater medical infrastructure and resources to detect autoimmune dysfunctions than the developing world.

So while the number of children with asthma and food allergies is higher than in decades past, there’s no way to know if that’s because more kids actually have those conditions or if it’s because doctors are more able to recognize and diagnose those conditions.

Another problem with the hygiene hypothesis, Lynch notes, is that while getting exposed to some germs does help build up your immune systems, other types of bacteria and viruses can actually cause asthma or serious diseases.

That’s why researchers and medical professionals in Lynch’s field of infectious disease and immunology cringe at the name “hygiene hypothesis,” he says. It implies that good personal hygiene is related to higher rates of disease when, in fact, it’s the opposite.

Think about it this way: If the hygiene hypothesis is really accurate and being overly clean makes our immune systems malfunction, children who don’t wash their hands, are exposed to pathogens on a regular basis and live in unclean conditions would be the healthiest.

“Unfortunately, we know that people who live in places that lack access to hygiene die more frequently,” Lynch says.

How do you build up a child’s immune system?

It’s not that the hygiene hypothesis gets it all wrong. Children do need to be exposed to certain microorganisms in order to influence the right immune response and develop a robust immune system. And having a too-clean environment can hinder that in some ways.

“We don’t need to sterilize things with antibacterial products or create an incredibly hygienic environment,” Lynch says. “You don’t want to put any extra chemicals or agents in anything because that’s how you create antibiotic-resistant bacteria.”

In fact, your body is full of trillions of bacteria, fungi and viruses — an entire community called your microbiota — which are critical to your immune response and overall health.

Now here’s where glimmers of the hygiene hypothesis come in: Children develop a healthy microbiota by acquiring bacteria in a variety of ways, from vaginal birth and breastfeeding to getting kissed by their parents and sticking their fingers in their mouths as babies.

“That’s all normal,” Lynch says. “We don’t want women washing their breasts before breastfeeding or parents washing their lips before kissing their children.”

What also matters for immune development, though, is what you’re exposed to and how that affects your body. Getting a common cold virus is a totally normal part of childhood. But being exposed to an antibiotic-resistant superbug is a much more serious issue.

“When you’re talking about the hygiene hypothesis, the point of contention is that the focus should be less about hygiene and more about access to the right microbiota,” Lynch explains.

What’s the takeaway from the hygiene hypothesis controversy?

So while the hygiene hypothesis isn’t totally correct, going in the opposite direction to an overly sterilized childhood isn’t exactly healthy either. It can feel like the balance between exposing children to good bacteria and keeping them safe from the bad stuff is pretty much out of your control.

Just try to keep everything in perspective, Lynch says. Use common sense — and maybe go easy on the hand sanitizer.

“I like to think of it like this: Hand washing is important if you’re around someone who’s sick or if your kid is rolling around on the floor at a restaurant, but maybe not so much if they’re just playing outside at the park,” he says.

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What Is the Hygiene Hypothesis?

Many parents believe that their children must be kept in an environment that is as clean as possible, but some research suggests that being exposed to what many would call unclean conditions is good for a child's immune system. Research has indicated that children who are kept in very clean environments have a higher rate of hay fever, asthma and a wide range of other conditions. This is what is called the hygiene hypothesis.

The hygiene hypothesis was first introduced in the late 1980s by David P. Strachan, a professor of epidemiology, in the British Medical Journal. Strachan found that children in larger households had fewer instances of hay fever because they are exposed to germs by older siblings. This finding led to further research that suggests a lack of early childhood exposure to less than pristine conditions can increase the individual's susceptibility to disease.

For example, in the late 1990s, Dr. Erika von Mutius, a health researcher, compared the rates of allergies and asthma in East Germany and West Germany, which unified in 1999. Her initial hypothesis was that East German children, who grew up in dirtier and generally less healthful conditions, would have more allergies and suffer more from asthma than their Western counterparts. However, her research found the opposite: children in the polluted areas of East Germany had lower allergic reactions and fewer cases of asthma than children in West Germany. 

Further research has found that children in developing areas of the world are less likely to develop allergies and asthma compared with children in the developed world. 

Building the immune system

The idea is simple. When babies are inside the womb they have a very weak immune system because they are given protection by their mother's antibodies. When they exit the womb, though, the immune system must start working for itself. For the immune system to work properly, it is thought that the child must be exposed to germs so that it has a chance to strengthen, according to the U.S. Food and Drug Administration (FDA). 

The idea is similar to the training of a body builder. For a body builder to be able to lift heavy objects, the muscles must be trained by lifting heavier and heavier objects. If the body builder never trains, then he will be unable to lift a heavy object when asked. The same is thought to be true for the immune system. In able to fight off infection, the immune system must train by fighting off contaminants found in everyday life. Systems that aren't exposed to contaminants have trouble with the heavy lifting of fighting off infections.

Mutius hypothesized that the reason children who are not exposed to germs and bacteria are sicklier is due to how the human immune system evolved. She thinks there are two types of biological defenses. If one of the defense systems isn't trained or practiced enough to fight off illness, the other system overcompensates and creates an allergic reaction to harmless substances like pollen.

Research by other scientists has found similar results. Exposure to germs triggered an internal inflammatory response in children who were raised in cleaner environments, leading to ailments such as asthma, according to a 2002 article in Science magazine.

One researcher has personal experience has leads him to back the hygiene hypothesis. "I believe that there is a role in the development of a child's immunity exposure to various germs and a vast microbiome diversity," said Dr. Niket Sonpal, an assistant professor of clinical medicine at Touro College of Osteopathic Medicine, Harlem Campus. "I was born in India but moved to the U.S. and went to college in Virginia and medical school in Europe. I am sure that the vast change in environment has played a role in my immunity. How has it? I don't think we know just yet." 

In 1997, some began to question if there is a correlation between the hygiene hypothesis and vaccinations. The number of children getting vaccinations was going up, but so were the number of children afflicted with allergies, eczema and other problems. Could depriving the developing immune system of infections using vaccines cause the immune system to eventually attack itself and cause autoimmune diseases like asthma and diabetes? This is a highly contested issue. 

Three studies conducted in the 1990s showed that vaccines had no correlation with children developing allergies and other ailments later in life. In fact, vaccinations may help prevent asthma and other health problems other than the diseases they were intended to prevent, according to The National Center for Immunization Research and Surveillance . The idea that vaccinations can cause health problems does not consider the fact that children, whether vaccinated or not, are still exposed to pathogens that help build the immune system. These pathogens also have no relation to the diseases that the vaccines prevent. 

The conflict between cleanliness and exposure can leave parents feeling confused. There are many microbes that can make children very sick, such as such as respiratory syncytial virus (RSV), E.coli and salmonella. So cleaning the home is still very important. What should children be exposed to and what should they be protected from? 

The CDC recommends regularly cleaning and disinfecting surfaces in the home, especially when surfaces have been contaminated by fecal matter or meat or have come in contact with those who have a virus. Children are also encouraged, though, to play outside , even if they may get dirty in the process. This balancing act may prove to help children stay healthy while still developing a healthy immune system. 

Sonpal thinks that the healthy growth of the immune system isn't just about coming in contact with dirt. It also has to do with what foods are consumed, what kind of environments the person grows up in and intrinsic genetics coupled with physical activity levels. Harvard Medical School noted that getting plenty of sleep, avoiding cigarette smoke, drinking in moderation and controlling blood pressure also all play a part in a healthy immune system.

Additional Resources

• Clinical & Experimental Immunology: The 'Hygiene Hypothesis' for Autoimmune and Allergic Diseases: An Update
• Mayo Clinic: Early germ exposure prevents asthma?
• U.S. National Library of Medicine: The Hygiene Hypothesis and home hygiene

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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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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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The coming-of-age of the hygiene hypothesis

• Fernando D Martinez MD 1  

Respiratory Research volume  2 , Article number:  129 ( 2001 ) Cite this article

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The hygiene hypothesis, as originally proposed, postulated an inverse relation between the incidence of infectious diseases in early life and the subsequent development of allergies and asthma. New evidence from epidemiological, biological and genetic studies has significantly enlarged the scope of the hypothesis. It now appears probable that environmental 'danger' signals regulate the pattern of immune responses in early life. Microbial burden in general, and not any single acute infectious illness, is the main source of these signals. The latter interact with a sensitive and complex receptor system, and genetic variations in this receptor system may be an important determinant of inherited susceptibility to asthma and allergies.

Introduction

There is now convincing evidence indicating that the prevalence of allergic diseases in general, and of asthma in particular, is on the rise in high income societies [ 1 ]. Many hypotheses have been proposed to explain these increases, but the most widely discussed and the most controversial is the so-called 'hygiene hypothesis' [ 2 , 3 ]. This hypothesis was first enunciated in quite straightforward terms: the Western lifestyle has succeeded in markedly decreasing the incidence of infections in early life, and these infections may have a protective effect on the subsequent development of allergies.

Initially, the hypothesis was mainly based on epidemiologic evidence of an inverse relation between indirect markers of increased infectious burden and prevalence of allergic diseases and allergic sensitization (reviewed in [ 4 ]). Concomitant studies on the development of the immune system in early life seemed to provide a biological basis for the hypothesis' main postulate. It has been reported that mononuclear cells obtained from cord blood showed markedly decreased cytokine responses to nonspecific stimuli [ 5 ]. This included both responses that characterize the T-helper (Th) 1 type (ie IFN-γ) and the Th2 type (ie IL-4). When studied both in cord blood and during the first year of life [ 6 , 7 ], however, Th1-like responses were particularly decreased among children with a family history of allergies and among those who would subsequently become sensitized to aeroallergens. Since IFN-γ is known to downregulate Th2-type responses, and these responses are essential for IgE synthesis by B cells, it was suggested that the development of IFN-γ responses could be stimulated by exposure to infectious agents postnatally [ 3 , 8 ], and that this could be the mechanism by which these infections protected against the development of allergic diseases.

Infectious diseases versus microbial burden

Presented in this fashion, the 'hygiene hypothesis' was tested in relation to several infectious diseases. The results were contradictory: whereas markers of a previous infection with foodborne pathogens appeared to be associated with decreased risk of subsequent allergic sensitization, this was not the case for respiratory pathogens [ 9 ] or was confined to certain respiratory viruses [ 10 ]. Moreover, while some authors reported that contagious diseases such as measles were associated with decreased likelihood of developing allergic conditions [ 11 ], other workers were unable to confirm these observations [ 12 ]. The finding of an inverse relation between responses to tuberculin test and asthma and allergies in Japan was interpreted by some authors as indicating that infection with Mycobacterium tuberculosis could protect against allergies [ 13 ]. Other workers, however, contested that the association was more simply explained by a reduced Th1-type response to tuberculin in atopic subjects.

But perhaps the greatest challenge to the 'hygiene hypothesis', expressed simply in terms of an inverse relation between incidence of infectious diseases and allergies, has arisen from studies of children of farmers [ 14 , 15 , 16 , 17 ]. These studies have consistently found that growing up on farms confers significant protection against the development of atopy (as assessed by skin test reactivity to local allergens), allergic rhinitis and (to a lesser extent) asthma. A more detailed analysis of several of these studies showed that the factor that best explained the difference in the prevalence of allergies among children living on farms and those living in the same rural villages but not on a farm was having contact with livestock and poultry [ 16 ].

These results suggested that substances produced by farm animals, which could presumably also be abundant in homes located close to these animals quarters, could play a role in the prevention of allergies. In a study by von Mutius et al , dust collected from homes of children living on farms had markedly higher levels of endotoxin than that from homes of children living in the same rural communities but away from animal farms [ 18 ].

These findings suggest a broader approach to the understanding of the environmental factors that may influence the development of the immune system and, through this mechanism, decrease the likelihood of the development of allergies. Endotoxins are lipopolysaccharides (LPS) that form part of the outer structure of the cell wall of Gram-negative bacteria. An exquisitely sensitive mechanism that detects the presence of LPS is present in vertebrate immune systems. This receptor system is expressed mainly in antigen presenting cells, and constitutes the first, nonadaptive response to external microbial stimuli. The system in question is in fact made up of pattern-recognition receptors that are capable of detecting the presence of different structures present in Gram-negative and Gram-positive bacteria, mycobacteria, fungi, and even viruses [ 19 ]. This receptor system activates a complex intracellular signaling mechanism that will not be discussed in the present article in detail, but that results in the production of a set of cytokines and immune mediators by antigen presenting cells.

The finding that exposure to environmental bacterial products, that do not directly cause specific diseases in those exposed, may influence the pattern of immune responses in humans provides an entirely new framework for the understanding of the 'hygiene hypothesis'. The influence of potential infectious agents on the risk of allergies is thus not confined to those that directly produce infectious diseases in humans, but may comprise a much broader set of agents, including those to which the individual is exposed in the home, in schools, in daycare, etc. These agents may act through the respiratory system but also through the intestinal track [ 9 ], modulating the development of the immune system during the first years of life.

This new set of potential exposures may be very relevant for our understanding of the marked increases in the prevalence of allergies and asthma that have taken place in past decades. The widespread availability of products and practices that promote an aseptic environment for humans in general, and for young children in particular, may have markedly decreased the exposure of our species to the myriad of 'danger' signals coming from microbes and germs that has been part of our entourage since we first became a species or even earlier [ 20 ].

The coming-of-age of a hypothesis

The author believes that, with the discovery of specific markers of environmental microbial exposure, such as endotoxin, that interact with a well-known receptor system, the hygiene hypothesis has reached a new stage of maturity. Although no-one can reasonably propose or even believe that marked decreases in the burden of microbial exposure are the only causes of the increases in asthma and allergies observed recently, there is now strong indirect evidence suggesting that those exposures play a role in the postnatal maturation of immune responses. This evidence not only comes from studies performed in rural communities like those described earlier. Gereda et al [ 21 ], for example, assessed the concentration of endotoxin in house dust in a group of young children living in the Denver area, and subsequently assessed sensitization to local aeroallergens and cytokine responses by peripheral blood mononuclear cells. They found that children exposed to higher levels of endotoxin were significantly less likely to become sensitized to local aeroallergens. Gereda et al also reported that IFN-γ responses by peripheral blood T cells were significantly increased among children exposed to higher levels of endotoxins. Other studies in which house dust is being collected during infancy and in which subsequent development of asthma and allergies is being studied are now in progress, and they may provide important new information in the near future.

The molecular mechanisms by which microbial burden in early life, and endotoxin exposure in particular, can influence asthma risk are beginning to be understood. It is now well established that early allergic sensitization is an important risk factor for the development of asthma [ 22 ]. We have suggested that the early establishment of a chronic, IgE-mediated immune response in the lungs may alter lung development and predispose to chronic airway hyperresponsiveness [ 3 ]. Our group has also shown that subjects who, by the age of 6 years, will become sensitized to Alternaria , the most asthma-related allergen in Tucson, Arizona, have significantly lower IFN-γ responses by peripheral blood mononuclear cells as compared with subjects who will not become sensitized to Alternaria [ 6 ]. It is thus possible that exposure to endotoxin, by stimulating the early development of IFN-γ responses, may prevent early allergic sensitization and, by this mechanism, prevent the development of asthma. A recent report by Tulic et al [ 23 ], suggesting that pre-exposure to endotoxin prevents subsequent sensitization to allergens in rats, strongly supports this hypothesis.

It is important to mention that, although exposure to endotoxin may be preventive in the development of allergies and asthma, it may be an important risk factor for more severe symptoms in subjects who have already developed the disease [ 24 ]. It is thus possible that, once an IgE-mediated response to aeroallergens has been established, endotoxin may enhance this response. Interestingly, in the Tulic et al report [ 23 ], exposure to endotoxin in rats after sensitization to allergens had already been established was shown to enhance the IgE-mediated response in these animals, thus providing experimental support for this contention.

Gene/environment interactions in the development of allergies

The use of endotoxin as a potential marker for microbial exposure not only provides a helpful epidemiologic tool, but it also allows the identification of a well-defined, specific biological pathway directly involved in immune responses to such exposure. It is plausible to surmise that polymorphisms in the genes that code for proteins involved in this pathway may determine, at least in part, individual susceptibility to the effects of endotoxin.

In our laboratories, we have begun the process of screening for polymorphism genes involved in the receptor system for LPS. We initiated this search with the CD14 gene, which codes for one of the main components of the endotoxin receptor system [ 19 ], and found a C→T variation at position -159 of the promoter region of the gene (CD14/-159). This polymorphism was very frequent in the population, with one-half of all chromosomes containing one or the other allele (C or T). Carriers of the T allele in homozygote form were shown to have significantly higher levels of circulating sCD14, the soluble form of the receptor. Researchers interested in genetic risk factors for myocardial infarction subsequently reported that the T allele was also associated with higher expression of CD14 on the surface of antigen presenting cells [ 25 ]. Our group found that homozygotes for the T allele had significantly lower levels of total serum IgE, especially if they were skin test positive to local aeroallergens. Moreover, atopic carriers of the T allele had significantly lower numbers of positive skin tests than carriers of the C allele. Two other research groups have reported similar findings [ 26 , 27 ], although not all researchers have been able to confirm our findings [ 28 , 29 ]. It thus appears that, at least in some populations, polymorphisms that increase the expression of CD14 may be associated with lower levels of IgE. A potential explanation for this finding could be that increased sensitivity to endotoxin and other microbial products that interact with CD14 could increase IL-12-mediated responses to these products, with increased likelihood of development of Th1-type responses and thus less likelihood of IgE-mediated immunity.

The presence of biologically meaningful polymorphisms in genes associated with the receptor system for endotoxin opens a new chapter for the assessment of the so-called hygiene hypothesis. It has now become possible to assess the role of these genetic variants as determinants of susceptibility to different allergy-related outcomes in individuals who are exposed to different levels of endotoxin in the environment. Variations in many genes involved in the response to endotoxins and other microbial products will be defined, as part of the Genome Project, in the very near future.

A better understanding of the biological effects of specific environmental products that are responsible for the inverse association between infectious burden and allergy and asthma will enhance our understanding of the gene/ environment interactions that cause these common and burdensome diseases. Moreover, this understanding may offer new strategies for the primary and secondary prevention of allergies and asthma in the near future. It may thus be possible to design prevention strategies based on exposure to innocuous surrogates of bacterial products in individuals who may be more or less susceptible to the preventive effects of these products depending on their specific genetic background.

Abbreviations

lipopolysaccharides

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Acknowledgements

This work was supported by National Heart Lung Blood Institute Grants HL 66447, HL 56177, HL 61892, HL 64307, and HL 66800.

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Martinez, F.D. The coming-of-age of the hygiene hypothesis. Respir Res 2 , 129 (2001). https://doi.org/10.1186/rr48

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• Published: 24 April 2012

Early exposure to germs and the Hygiene Hypothesis

• Dale T Umetsu 1  

Cell Research volume  22 ,  pages 1210–1211 ( 2012 ) Cite this article

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A recent paper suggests that reduced exposure to germs results in the expansion of a cell type called natural killer T cells, which predisposes to colitis and asthma. Such a scenario could explain the Hygiene Hypothesis, which has been a puzzle for decades.

The Hygiene Hypothesis was proposed more than twenty years ago by Strachan 1 to explain the dramatic increase in the prevalence of allergic diseases and asthma that has occurred over the past two to three decades. What Strachan observed was that the younger children in large families had less asthma and allergy, presumably due to increased exposure to infections that passed around in such large families. Later, the Hygiene Hypothesis was extended to explain the great increase in the prevalence of inflammatory bowel disease that occurred over the same time period. However, the exact scientific underpinnings for the Hygiene Hypothesis, e.g., the specific infections and the mechanisms by which infections affect the immune system to prevent disease, have remained a puzzle over the years for both scientists and clinicians.

A clear biological explanation for the Hygiene Hypothesis though, may be at hand, as proposed in an article recently published in Science , using mouse models 2 . Blumberg and his colleagues showed that mice raised under sterile, germ free conditions were more likely to develop experimental colitis, called oxazolone-induced colitis, and more likely to develop an experimental form of allergic asthma. Importantly, reestablishment of the intestinal commensal bacteria, collectively known as microbiota, in the germ-free mice with standard mouse colony bacteria prevented their predisposition to severe colitis or asthma. However, the beneficial effects from the microbiota developed only when very young mice were exposed to the bacteria, whereas exposure of adult germ-free mice to the microbiota did not reduce the predisposition to colitis or asthma. Thus, exposure of pregnant germ-free mice to the microbiota, which then affected the pups when they were born, prevented the later predisposition of the pups as adults to colitis and asthma, consistent with the idea that exposure of young children to germs prevents asthma and allergy.

Blumberg and colleagues went on to show that in the mice shielded from exposure to microbes, the predisposition to colitis and asthma was caused by an expansion of an inflammatory cell type called invariant natural killer T (iNKT) cells. Thus, in the colon and in the lungs of the germ-free mice, the investigators found a significant increase in the number of iNKT cells, which are required for the development of colitis and allergic asthma 3 , 4 . Moreover, treatment of the germ-free mice with an anti-CD1d mAb, which prevented the activation of iNKT cells, also prevented the development of oxazolone-induced colitis and allergic asthma.

NKT cells comprise a fascinating subset of T cells that share characteristics with NK cells. NKT cells have been subdivided into two major groups, type I and type II. Type I NKT cells express a semi invariant (i) TCR and are known as invariant NKT (iNKT) cells, whereas type II NKT cells express a more diverse TCR repertoire. Both are activated by glycolipid antigens presented in the context of a class 1-like MHC molecule, called CD1d. Because the iTCR of iNKT cells is highly conserved in most mammals, and because iNKT cells with the iTCR are already widely expanded in vivo even in naïve mice, and are poised to rapidly respond and secrete large amounts of cytokines, including IFN-γ and IL-4, iNKT cells are thought to play an important role in innate immunity. iNKT cells can respond to some bacteria by directly recognizing glycolipid antigens expressed by bacteria such as Sphingomonas , Helicobacter pylori , Streptococus pneumonea and Group B streptococcus , and can respond indirectly to many other bacteria such as Salmonella enterica and Staphylococcus aureas . Of note, glycolipids from H. pylori can expand a suppressor iNKT cell subset that can prevent the development of experimental asthma in mice 5 . Finally, iNKT cells can respond to glycolipid allergens present in pollens and in some foods 6 , 7 . However, the precise reasons why inflammatory iNKT cells expand in germ-free mice, or how exposure to environmental bacteria prevents the expansion of iNKT cells is not yet known.

While the role of iNKT cells in mouse models of colitis and asthma has been extensively studied, the role of iNKT cells in human disease is less well understood. In humans with ulcerative colitis, a form of inflammatory bowel disease, type II NKT cells producing large amounts of IL-13, appear to be associated with disease. In humans with asthma, iNKT cells have been found to be present in the lungs of some but not all individuals with asthma, leading to some controversy regarding the importance of iNKT cells in human asthma. However, it has become clear over the last few years from studies in humans and in mice that asthma is very heterogeneous, and that multiple pathways are involved in the development of asthma, each involving distinct cell types, including Th2 cells, iNKT cells, Th17 cells, nuocytes, Th9 cells and others. Finally, iNKT cells in humans have been shown to regulate transplantation tolerance, cancer and infection, suggesting that exposure to microbiota could have significant effects on a number of distinct human diseases.

The idea that mice growing up in “germless” environments develop an expansion of iNKT cells, which then predispose them to the development of colitis and allergic asthma, may be very relevant to humans. Epidemiological studies have already shown that birth by Caesarian section, which may limit early exposure to microbiota from the mothers' vaginal tracts, or extensive use of antibiotics in young children, which may also reduce the intestinal microbiota, also predisposes to the development of asthma and allergy. On the other hand, living on a farm in Western Europe, or having multiple pets, which may increase the early exposure to a more diverse community of microbiota, in some way prevents the development of asthma and allergy 8 . Thus, early events in young children related to microbial exposures appear to have lasting effects on the innate and adaptive immune systems, and as proposed by the Blumberg study, on iNKT cells.

The striking effects of commensal microbiota on the development iNKT cells are in line with other recent studies showing that specific strains of intestinal bacteria in mice, such as segmented filamentous bacteria, and clostridia are required for the development of Th17 cells 9 and regulatory T cells 10 , respectively. Thus, it is becoming clear that a symbiotic relationship exists between bacteria and our immune system. As we understand this relationship better, perhaps in the future we could see the development of therapies that mimic the beneficial effects of “infection”, for example, encouraging early exposure of infants to a “standard” disease-preventing collection of germs.

Strachan DP . Hay fever, hygiene, and household size. BMJ 1989; 299 :1259–1260.

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Olszak T, An D, Zeissig S, et al . Microbial exposure during early life has persistent effects on natural killer T cell function. Science 2012; 336 :489–493.

Heller F, Fuss I, Nieuwenhuis E, Blumberg R, Strober W . Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells. Immunity 2002; 17 :629–638.

Akbari O, Stock P, Meyer E, et al . Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity. Nat Med 2003; 9 :582–588.

Chang YJ, Kim HY, Albacker LA, et al . Influenza infection in suckling mice expands an NKT cell subset that protects against airway hyperreactivity. J Clin Invest 2011; 121 :57–69.

Agea E, Russano A, Bistoni O, et al . Human CD1-restricted T cell recognition of lipids from pollens. J Exp Med 2005; 202 :295–308.

Brennan PJ, Tatituri RV, Brigl M, et al . Invariant natural killer T cells recognize lipid self antigen induced by microbial danger signals. Nat Immunol 2011; 12 :1202–1211.

Ege MJ, Mayer M, Normand AC, et al . Exposure to environmental microorganisms and childhood asthma. N Engl J Med 2011; 364 :701–709.

Ivanov II, Atarashi K, Manel N, et al . Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 2009; 139 :485–498.

Atarashi K, Tanoue T, Shima T, et al . Induction of colonic regulatory T cells by indigenous Clostridium species. Science 2011; 331 :337–341.

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Umetsu, D. Early exposure to germs and the Hygiene Hypothesis. Cell Res 22 , 1210–1211 (2012). https://doi.org/10.1038/cr.2012.65

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The healing power of knowledge

Over the past few decades, there's been an increase in the incidence of dysbiosis and other inflammatory conditions. In fact, rates of allergies and autoimmune disorders have soared since the 1950s, while the incidence of most infectious diseases have fallen dramatically. ( Source ) By the 1990s, scientists began to suspect that these two trends were connected and looked to the past for answers.

During the 1800s, profound improvements to sanitation and water quality were made in North America and Europe. These changes, including the introduction of toilets and sewer systems, the cleanup of city streets, and cleaner water, led to a rapid decline in infectious diseases. ( Source , Source )

In 1989, scientist David Strachan suggested that the rising rates of diseases like asthma or allergies were linked to reduced exposure to germs through smaller family sizes, less contact with animals, and higher standards of cleanliness. ( Source ) In the decades since Strachan introduced his hypothesis, scientists have further clarified the active role that the gut microbiome plays in human health and reformulated the initial theory (more on that later).

Today, we'll dig into the so-called “hygiene hypothesis,” examine the double-edged sword of modern cleanliness, and uncover the scientific reason why you should give your furry friend a kiss.

What Is the "Hygiene Hypothesis" and Why Should I Care?

It's a theory about the increased incidence of immune-related conditions.

‍ The “hygiene hypothesis” proposed that a rapid rise in childhood allergies was due to lack of exposure to infections during childhood. From a study of 17,000 British children, Strachan observed a link between family size and the risk of allergies, noting that infants born into households with many siblings were less susceptible to eczema and hay fever than those from smaller families. Based on the assumption that more children means more germs, Strachan postulated that early childhood infections protect against allergic disease. ( Source )

It's a bit of a misnomer

‍ Scientists have called for the abandonment of the term “hygiene hypothesis,” as the original simplistic theory fails to incorporate other factors that are linked to immune-mediated conditions. The belief that obsessive hygiene has caused the rise in allergies has evolved. Data has shown that other lifestyle factors, including diet and antibiotics, play a larger role in relevant microbial exposures. Health professionals are also concerned that undermining public trust in good hygiene decreases important disease prevention practices such as handwashing. ( Source )

It has evolved with scientific understanding

‍ Rather than childhood infections, the “old friends hypothesis” suggests that early, regular exposure to a diverse set of “friendly” microorganisms helps educate the immune system to properly respond to stimuli. These ancestral microbes, which have co-evolved with us over millennia, have been instrumental in the development of our immune system throughout human evolution. When we lose contact with these ancient microbial allies, our immune system can fail to distinguish friend from foe, leading to increased inflammation and autoimmune activity. ( Source , Source )

It's caused by our modern lives

‍ Although radical improvements in sanitation, food, and water in the late 20th century were likely involved in reducing our exposure to microbes, other factors have played a larger role, especially in early life. Both C-section births and antibiotic use in children have been linked to increased risk of allergy and asthma. As we covered in the microbiome edition , Western diets lacking in plant-based fibers (hello polyphenols and resistant starch !) intensify this loss of biodiversity. Urbanization has also accelerated loss of exposure to the natural environment, which is a source of many of the microbial partners that we need. ( Source )

What Does the Research Show About the "Hygiene Hypothesis"?

As noted above, the effects of the “hygiene hypothesis” are most likely mediated through a complex interaction between environmental factors, rather than a single factor. Given the lack of evidence on how to reduce rates of inflammatory disease, researchers have called for more randomized controlled trials to test interventions that restore the immune system. Here's what we know so far:

It may explain the uneven geographical distribution of autoimmune diseases in the world

‍ Migration studies have revealed that young individuals immigrating from countries with low incidence of autoimmune diseases to countries with high incidence tend to develop the disease with the frequency of the host country. Epidemiological data from the World Health Organization indicates that some autoimmune diseases, including multiple sclerosis and type 1 diabetes, that are uncommon in rural African and Asian populations are more prevalent in these same populations after they migrate to developed countries (e.g., United States). Researchers have also found a positive correlation between urban areas and the rate of inflammatory bowel disease. ( Source , Source )

You should thank your siblings

‍ Studies suggest that children from large families are at a lower risk of developing allergies, possibly because more siblings means greater exposure to bacteria and viruses. One study examining the relationship between family size and incidence of asthma reported a protective effect of three or more older siblings on children between three and five years of age. Infants with older siblings were also shown to have a lower likelihood of developing allergy-related atopic diseases due to differences in their gut microbiota. However, whether this is related to older sibling’s germs or some other factor, such as exposure to maternal antibodies in utero, remains to be seen. ( Source , Source , Source )

No amount of cleaning can make our homes “clean enough ” ‍

Microbiological studies indicate that daily or weekly cleaning routines have no sustained effect on levels of microbes in our homes. That's because microbes are everywhere — as soon as they're removed from one surface, they are quickly replaced by other microbes from dust, outdoor air, the human body, or our pets. To date, there is no confirmed evidence of a link between personal or household cleanliness and increased risk of developing allergic disease. ( Source )

It underscores the power of the great outdoors

‍ Farms have been shown to have protective effects on our immune responses due to their microbial diversity. It seems as though early exposure to farm life is critical to garner the full benefits (even beginning in utero!). In one study, every additional animal an expectant mother had exposure to increased the immune benefit for her unborn child. Even if you're not on a farm, studies in Finland show that living close to green space and agriculture rather than a town increases the diversity of the skin microbiome and correlates with reduced sensitivity to allergies. ( Source , Source , Source )

So What Should I Do About the "Hygiene Hypothesis"?

Experiment with different strategies.

‍ Evidence suggests a multi-faceted approach may help to restore a healthy microbiome and reduce the risk of inflammatory disease. Our microbiomes are most malleable in our first few years, so opting for childbirth via vaginal delivery and breastfeeding when possible are ideal for building a strong foundation. Other strategies include spending more time outdoors, eating fiber-filled diets, and using antibiotics only when absolutely needed. ( Source )

Bring the outside inside

‍ There are many ways to increase the transport of outdoor microbes into the home, including wearing outdoor shoes indoors, caring for indoor plants, or even just opening the windows. Beyond sparking joy, potted houseplants offer a source of microbial biodiversity, providing beneficial microorganisms. The takeaway? Keep your home clean, but maximize your exposure to the natural environment when possible. ( Source , Source , Source )

‍ In case you needed another reason to be “Team Dog,” epidemiological studies show that children who grow up in households with dogs have a lower risk of developing inflammatory diseases. This is likely due to the diversity of microbes that these animals bring inside our homes (researchers found that 56 different classes of bacterial species were more abundant in homes with dogs). Early-life exposure to household furry pets also increases the richness and diversity of the human gut microbiome. ( Source , Source , Source , Source )

Where Can I Go to Learn More About Topics Related to the “Hygiene Hypothesis”?

On how to take care of our microbial friends.

‍ In this 15-minute TED talk , Graham Rook, the professor who coined the expression “ old friends hypothesis ,” explains the adaptive immune system and how it operates similar to a computer — suggesting that it needs data in the form of environmental inputs. ( Source )

Recommended For You

The hygiene hypothesis has evolved. We now know that early exposure to microbes is essential for immune system development.

The effects of the hygiene hypothesis are most likely mediated through a complex interaction between environmental factors, rather than a single factor.

Our immune systems are not born with a predisposition to allergies, but rather develop that way due to our exposure to microbes.

A few ways to increase your exposure to healthy microbes include spending more time outdoors, eating a fiber-filled diet, caring for indoor plants, and getting a dog.

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• v.22(8); 2012 Aug

Early exposure to germs and the Hygiene Hypothesis

Dale t umetsu.

1 Division of Immunology, Karp Laboratories, Rm 10127, Children's Hospital Boston, Harvard Medical School, One Blackfan Circle, Boston, MA 02115, USA

The Hygiene Hypothesis was proposed more than twenty years ago by Strachan 1 to explain the dramatic increase in the prevalence of allergic diseases and asthma that has occurred over the past two to three decades. What Strachan observed was that the younger children in large families had less asthma and allergy, presumably due to increased exposure to infections that passed around in such large families. Later, the Hygiene Hypothesis was extended to explain the great increase in the prevalence of inflammatory bowel disease that occurred over the same time period. However, the exact scientific underpinnings for the Hygiene Hypothesis, e.g., the specific infections and the mechanisms by which infections affect the immune system to prevent disease, have remained a puzzle over the years for both scientists and clinicians.

A clear biological explanation for the Hygiene Hypothesis though, may be at hand, as proposed in an article recently published in Science , using mouse models 2 . Blumberg and his colleagues showed that mice raised under sterile, germ free conditions were more likely to develop experimental colitis, called oxazolone-induced colitis, and more likely to develop an experimental form of allergic asthma. Importantly, reestablishment of the intestinal commensal bacteria, collectively known as microbiota, in the germ-free mice with standard mouse colony bacteria prevented their predisposition to severe colitis or asthma. However, the beneficial effects from the microbiota developed only when very young mice were exposed to the bacteria, whereas exposure of adult germ-free mice to the microbiota did not reduce the predisposition to colitis or asthma. Thus, exposure of pregnant germ-free mice to the microbiota, which then affected the pups when they were born, prevented the later predisposition of the pups as adults to colitis and asthma, consistent with the idea that exposure of young children to germs prevents asthma and allergy.

Blumberg and colleagues went on to show that in the mice shielded from exposure to microbes, the predisposition to colitis and asthma was caused by an expansion of an inflammatory cell type called invariant natural killer T (iNKT) cells. Thus, in the colon and in the lungs of the germ-free mice, the investigators found a significant increase in the number of iNKT cells, which are required for the development of colitis and allergic asthma 3 , 4 . Moreover, treatment of the germ-free mice with an anti-CD1d mAb, which prevented the activation of iNKT cells, also prevented the development of oxazolone-induced colitis and allergic asthma.

NKT cells comprise a fascinating subset of T cells that share characteristics with NK cells. NKT cells have been subdivided into two major groups, type I and type II. Type I NKT cells express a semi invariant (i) TCR and are known as invariant NKT (iNKT) cells, whereas type II NKT cells express a more diverse TCR repertoire. Both are activated by glycolipid antigens presented in the context of a class 1-like MHC molecule, called CD1d. Because the iTCR of iNKT cells is highly conserved in most mammals, and because iNKT cells with the iTCR are already widely expanded in vivo even in naïve mice, and are poised to rapidly respond and secrete large amounts of cytokines, including IFN-γ and IL-4, iNKT cells are thought to play an important role in innate immunity. iNKT cells can respond to some bacteria by directly recognizing glycolipid antigens expressed by bacteria such as Sphingomonas , Helicobacter pylori , Streptococus pneumonea and Group B streptococcus , and can respond indirectly to many other bacteria such as Salmonella enterica and Staphylococcus aureas . Of note, glycolipids from H. pylori can expand a suppressor iNKT cell subset that can prevent the development of experimental asthma in mice 5 . Finally, iNKT cells can respond to glycolipid allergens present in pollens and in some foods 6 , 7 . However, the precise reasons why inflammatory iNKT cells expand in germ-free mice, or how exposure to environmental bacteria prevents the expansion of iNKT cells is not yet known.

While the role of iNKT cells in mouse models of colitis and asthma has been extensively studied, the role of iNKT cells in human disease is less well understood. In humans with ulcerative colitis, a form of inflammatory bowel disease, type II NKT cells producing large amounts of IL-13, appear to be associated with disease. In humans with asthma, iNKT cells have been found to be present in the lungs of some but not all individuals with asthma, leading to some controversy regarding the importance of iNKT cells in human asthma. However, it has become clear over the last few years from studies in humans and in mice that asthma is very heterogeneous, and that multiple pathways are involved in the development of asthma, each involving distinct cell types, including Th2 cells, iNKT cells, Th17 cells, nuocytes, Th9 cells and others. Finally, iNKT cells in humans have been shown to regulate transplantation tolerance, cancer and infection, suggesting that exposure to microbiota could have significant effects on a number of distinct human diseases.

The idea that mice growing up in “germless” environments develop an expansion of iNKT cells, which then predispose them to the development of colitis and allergic asthma, may be very relevant to humans. Epidemiological studies have already shown that birth by Caesarian section, which may limit early exposure to microbiota from the mothers' vaginal tracts, or extensive use of antibiotics in young children, which may also reduce the intestinal microbiota, also predisposes to the development of asthma and allergy. On the other hand, living on a farm in Western Europe, or having multiple pets, which may increase the early exposure to a more diverse community of microbiota, in some way prevents the development of asthma and allergy 8 . Thus, early events in young children related to microbial exposures appear to have lasting effects on the innate and adaptive immune systems, and as proposed by the Blumberg study, on iNKT cells.

The striking effects of commensal microbiota on the development iNKT cells are in line with other recent studies showing that specific strains of intestinal bacteria in mice, such as segmented filamentous bacteria, and clostridia are required for the development of Th17 cells 9 and regulatory T cells 10 , respectively. Thus, it is becoming clear that a symbiotic relationship exists between bacteria and our immune system. As we understand this relationship better, perhaps in the future we could see the development of therapies that mimic the beneficial effects of “infection”, for example, encouraging early exposure of infants to a “standard” disease-preventing collection of germs.

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