Introduction

While infectious disease and hygiene have been key public health issues for centuries [1], allergic diseases have only relatively recently been regarded as a significant health burden. The marked increase in the prevalence of allergic disorders, like eczema [2], allergic rhinitis, and food allergy [3], has been a prominent trend over the past century in all regions of the world, but most characterized in Western countries [4, 5••].

Humans are ecosystems that host microbes, namely the human microbiome, and these microorganisms are necessary for maintenance of our health [6]. The immune system functions as a learning device, and it is similar to a computer that has sufficient hardware and software but has only scarce data. This lack of data must be compensated in the initial few years of life, by means of contact with microorganisms in the environment. In case this contact fails to provide this contiguity, the development of immune regulatory mechanisms may fail. Consequently, the immune system is not only responsible for elimination of harmful organisms that are responsible for infections but also may prevent the reactions triggered by agents responsible for allergic disorders [5••].

The optimal composition of the microbiota is maintained by diet [7], which needs to be diverse, and contains fiber (polysaccharides digested by the microbiota rather than the human host) [8] and polyphenols found in plant products [9,10,11]. A diet deficient in fiber can lead to progressive extinctions of important groups of organisms [12], which are cumulative and increasingly difficult to reverse in subsequent generations [13]. Polyphenols and also fish oils also appear to modulate the composition of the microbiota [5••, 14, 15].

Hygiene hypothesis implies not only an inverse relationship between the size of the family and occurrence of atopic diseases but also in general the contact with microbes in the environment in the early childhood that plays a role of protection such as pets, living in the countryside with livestock, unpasteurized food and nonsterilized water [16], and urban versus rural living [17]. Exposure to microbial pathogens and animals in infancy prevents atopy by Th1-like cytokine responses or by modifying Th2-like immune responses [18]. Yeşil et al. [19] reported that higher prevalence of anti-Helicobacter pylori antibody and higher serum levels of interleukin (IL)-10 in nonatopic subjects suggest that chronic infection and inflammation may protect against atopic disease.

The “hygiene hypothesis” suggests that a reason for the recent increase in allergic diseases can be associated with the lower incidences of infection in the early pediatric period. It is about living with siblings and getting more exposure to infections in early life. Families having pets or living in a farm getting exposure to microbes more have protection to allergies due to need for Th1 response and less of Th2. Some interpretations of the hygiene hypothesis are not upheld by further scientific data. The increase in the prevalence of atopic diseases may not necessarily correlate with the diminution of infection due to pathogenic microorganisms, nor can it be attributed to the alterations of domestic hygiene [20].

What Is Hygiene Hypothesis?

The hygiene hypothesis was initially proposed by Strachan in 1989 [21]. An inverse relationship was identified between the size of the family and occurrence of atopic disorders. Moreover, the cause of the increase in atopic disorders may be related with lower infection incidence in the early childhood period, which avoids the transmission of microorganisms. Further exploration of the concept by allergologists and immunologists yielded that the decrease in microbial exposure is a main cause for the recent increase in the incidence of atopy. Various factors including access to clean water and food as well as sanitation, medical and obstetric practice, and urban lifestyle may be responsible for the alteration of microbial exposure [21].

The original description of hygiene hypothesis [21] is based on the allergic diseases. In this perspective, the hygiene hypothesis explains the increase in prevalences of other immunologic diseases, including Th1-type I diseases and inflammatory bowel disease [22,23,24,25,26].

Strachan’s initial hypothesis for the role of the size of the family and exposure to infections in early childhood for allergic disorders has clearly advanced to merge the probable impacts of hygiene, elimination of parasitic infections, immunizations, improvements in home heating and ventilation, exposure to mites, duration of breastfeeding, diet, parental smoking, air pollution, and exposure to pets and farm animals [21, 27••].

The International Scientific Forum on Home Hygiene (www.ifh-homehygiene.org) carried out a critical review of the hypothesis to determine the implications related with hygiene [20].

The hygiene hypothesis was initially established for explaining the high prevalence of allergic diseases in Western countries. The high prevalence of atopic disorders displays a plateau in industrialized countries [28]. The asthma prevalence rate among Taiwanese children was only 1% when the first recordings were made in the 1980s, but nowadays its rate has raised to about 15% [29]. The asthma prevalence in American children has increased by 38% in the interval between 1980 and 2003 [30, 31]. Asthma prevalence, for example, increased by about 1% a year from around 1980 [32]. Among children 5–18 years of age, the increase has predominantly been among allergic individuals [33] and recent UK studies confirm that atopic, rather than nonatopic, asthma is responsible for much of the rise [34, 35].

A comparison of two British birth cohorts (1958 and 1970) showed increases from 3.1 to 6.4% for eczema and from 12 to 23.3% for hay fever at age 16 years [36].

Another point of view for the hygiene hypothesis implies that an atopic status may result in a higher prevalence of viral respiratory disease and other infections due to the deficit of Th1 response [37] or amelioration of Th1-mediated diseases by parasitic antigens and concurrent Th2 responses [38, 39].

Hygiene Hypothesis and Infectious Agents

The specific impacts of bacteria, viruses, and parasites on the immune response are dependent on the infectious agents as well as the time, severity, and duration of exposure [38]. The hygiene hypothesis that implies the preventive impact of respiratory viruses on atopic diseases is more applicable for food-borne microbes than for air-borne microorganisms [40]. Actually, respiratory viruses were linked with a higher risk of allergy [37, 41, 42]. Furthermore, differences can be emphasized in the same group of infectious microorganisms. Seropositivity for hepatitis A, H. pylori, and Toxoplasma gondii was linked with a decreased atopy prevalence, while seropositivity to Clostridium difficile, Campylobacter jejuni, and Yersinia enterocolitica was related with a definite atopy prevalence [43]. In conjunction, endotoxin was nominated as protective against atopy [44]; whereas, Staphylococcal enterotoxin had no preventive effect but was a potent inducer of IL-5 and served as a cofactor in the pathogenesis of allergy [38, 45].

Another mechanism for explanation of the hygiene hypothesis is that exposure of infants to microbial pathogens and pets living in the farm may avoid atopy by amplification of Th1-like cytokine reactions or by modification of Th2-like immune reactions [18, 46,47,48,49]. Atopy in adulthood is characterized with production of Th2 cytokines like IL-4 and IL-5, which trigger production of immunoglobulin E (IgE) and recruitment of eosinophils which is typical for the allergic inflammatory response. On the other hand, nonatopic cases display a predominantly Th1 immune reaction. These reactions are initiated in the intrauterine period; and samples obtained from umbilical cord blood exhibit a prevailing Th2 profile [49]. Restriction of exposure to bacteria in the early infancy period shifts the immune to a predominant state of Th2 response which occurs in atopic patients [49,50,51,52] and viral infections that may cause wheezing can promote the likelihood of developing asthma [18, 53, 54].

Diminution of the variety of the infantile intestinal microbiota may have a noteworthy role in the occurence of allergy and asthma in pediatric population due to the significant impact of flora on mucosal immunity [18, 55,56,57].

A meta-analysis was performed to assess the impacts of probiotic supplementation in infants [55]. The results of this meta-analysis indicated that probiotic supplementation significantly diminished the risk of atopic sensitization, but it did not decrease the risk for asthma [55].

Human Helminths and Allergic Disease

Helminth infections are thought to induce the regulatory responses which control the inflammation. Nevertheless, these infections may elicit type-2-associated immune reactions such as helminth-specific IgE which can cross-react with environmental allergens and mediate the IgE-mediated responses. Therefore, there is a balance between the parasites’ allergic and anti-allergic influences which determine the helminth/allergy connection [58].

Multiple studies demonstrated that populations infected with helminths had reduced allergy prevalences [59,60,61]. Further evidence derived from people with hookworm infestations indicated a reduced incidence of asthma [62,63,64]. These findings reminded that experimental infections can be used on asthma patients for research [65]. The conspicuous suppression of Th2 responses by helminths had a neutral impact on concurrent allergic reactions [66]. van den Biggelaar et al. [59] demonstrated that the increase in IL-10 levels induced by schistosome infection was inversely associated with sensitivity for dust mite [67].

Family Size and Structure and Atopy

An inverse relationship was established between family size and atopy in studies which utilized markers like hay fever, skin prick positivity, and specific IgE levels [68,69,70]. Haby et al. [71] noted a protective effect of three or more older siblings for children aged 3 to 5 years. They used an extensive clinical definition for asthma, such as diagnosis of cough or wheeze in the preceding 12 months. Another study yielded that children (aged 3 to 4 years) clinically diagnosed for asthma had a smaller family size compared to healthy controls [72].

The protective effect observed in large families was more apparent than that of older siblings [73] and that of brothers compared with sisters [74, 75]. Interestingly, Bodner et al. [76] has shown that older siblings reduced the likelihood of hay fever and eczema, while the risk of asthma was decreased by the presence of younger siblings. The ALSPAC study analyzed the allergic profiles of 11,042 children [68] and a protective effect of brothers was evident for inhalant allergy. However, there were no remarkable findings for the impacts of family size. Notably, share of a bedroom by children, which is more common in large families, had a preventive role on the consecutive risk for further atopic disorders [74].

Karmaus et al. [77] proposed that the impact of siblings was achieved in the intrauterine period and the inverse relationship between infection and atopic manifestation was not necessarily causal. Another study has shown that the IgE levels in umbilical cord blood decreased with increasing birth order. Further studies [78] demonstrated that maternal IgE was reduced with birth order, which implies that the diminution in cord serum was an indirect impact of the decrease in maternal IgE. This could be an explanation for the reduced incidence of atopy in younger siblings [20].

Ball et al. [79] suggested that asthma was less common in children with ≥1 siblings at home or those who received daycare service in the initial 6 months of life. Nevertheless, children with more exposure to other children at home or in daycare suffered from more frequent wheezing attacks at the age of 2, but this tendency decreased from the age of 6 to 13 years.

Farm and Other Rural Exposure

Attention has been paid for the differences between urban and rural lifestyles. Recent publications supported that the farm, rather than the general rural environment, had a protective role against atopy. For instance, a lower incidence of hay fever has been reported in children of farmers, rather than that in other rural dwellers [46, 48, 80, 81]. Several factors including contact with animals, exposure to stables, and consumption of raw and unpasteurized farm milk were linked with the reduced prevalence of some allergies [20, 46, 48, 82].

Moreover, high levels of serum IgE were found in rural areas in Venezuela [83] and Indonesia [84], corresponding with low prevalences of allergic diseases too [85]. In contrast, the incidence of these disorders in the USA and Europe appears to have doubled in some decades of the last century, especially during the 1960s and 1970s [86].

Hygiene Hypothesis and Vitamin D Deficiency

A high correlation was observed between vitamin D deficiency, malfunction of vitamin D receptors (VDR), composition of gut microbiota, and autoimmune disorders. The biologically active form of vitamin D, 1,25(OH)2 D3, can serve as the primary ligand for VDRs, that plays a fundamental role in reduction of symptoms for autoimmune diseases. Even though the biological roles of VDR, the impacts of its genetic variants, and the influences of epigenetic profiles in its promoter region are not very well known in humans, studies in murine models seem to document that VDRs may have a critical role for suppression of symptomatology for autoimmune diseases. This effect occurs via regulation of autophagy and the production of antimicrobial peptides, such as cathelicidin and β-defensin, which may modify the composition of intestinal microbiota to a more healthy composition [87••].

Environmental Exposures and Epigenetic Changes

Environmental exposures may lead to epigenetic alterations via DNA methylation, histone acetylation, and micro-RNA changes, and these reactions modify the immune response against the microbes [88, 89]. As the multiple genome-wide association studies (GWAS) are completed worldwide, various genes associated with asthma and its related phenotypes, as well as other genes including those in the GSDMB/ORMDL3 region (17q12-q21 region) [84], NFKBI, IL1R2, LBP, IL18RAP, and TLR1 interacted with viral infections for modification of the risk for asthma and allergic diseases in the first year of life [18, 53, 90, 91].

Conclusion

The hygiene hypothesis implies that modern living conditions can be responsible for the rise in the incidences of allergic disease and asthma. A country’s gross domestic products or an individual’s affluence or exposure to infection risk factors may be important for hygiene hypothesis. It means less exposure to microbes that induce Th1 response. The hygiene hypothesis may not be applicable to all populations worldwide, but it is more relevant in populations with increasing affluence or subsequent to migration from less to more affluent countries [92].