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Medical Hypotheses 93 (2016) 146–149 Contents lists available at ScienceDirect Medical
Hypotheses journal homepage: www.elsevier.com/locate/mehy A specific hygiene
hypothesis Cliff Shunsheng Han Los Alamos National Laboratory, Bioscience Division and
Quality Performance Assurance Division, MS, M888, Los Alamos, NM 87545, USA a r t i c l e i
n f o Article history: Received 25 November 2015 Accepted 24 May 2016 a b s t r a c t
Allergic diseases have reached epidemic proportions in Western populations in the last
several decades. The hygiene hypothesis proposed more than twenty years ago has helped
us to understand the epidemic and has been verified with numerous studies. However,
translational measures deduced from these studies to prevent allergic diseases have not
proven effective. Recent studies on immigrants’ allergies and any potential association
between oral infection and allergic diseases prompt me to propose a specific hygiene
hypothesis to explain how oral hygiene practices might have contributed to the uprising of
hay fever, the most common allergic disease. The historic oral hygiene level in US is closely
associated with the emerging allergic epidemic. Future studies to test the hypothesis are
needed and verification of the hypothesis can potentially yield highly effective measures to
prevent allergic diseases. Published by Elsevier Ltd. Introduction Allergies are a significant
health concern. Allergic diseases have reached epidemic proportions in Western
populations in the last decades. Hay fever (allergic rhinitis or seasonal allergy) is the most
common allergic disease, affecting 13.5% of the US population [1]. Its symptoms include any
combination of the following: a runny or stuffy nose, sneezing, itchiness, red eyes, coughing,
and congestion. The hygiene hypothesis was proposed by Strachan in 1989 to explain the
cause [2], which is referred to here as general hygiene hypothesis (GHH). Since then, a
variety of studies reported results consistent with GHH, including that rural farm living
significantly reduces the risk of developing hay fever and atopic sensitization [3,4]. These
environmental cues point to lack of access to microbial diversity as a possible cause of
allergies and autoimmune diseases [5–8]. The observed link between allergy and
commensal bacteria has provided the scientific rationale for microbiome reconstitution as
measure against the allergy epidemic [9]. However, the results from probiotic treatments
have been conflicting [10–13]. The continuous confirmation of the hygiene hypothesis [14]
and failure in current intervention methods suggest a need to research in new directions
[15,16]. Recent studies on immigrants indicated that environmental changes later in life
alone could lead to allergic diseases for adults who are equipped with immune systems
developed a in relatively traditional lifestyle [17–19]. In several studies of Italian
2. populations, immigrants who visited doctors with complaints of allergies had little family
history of atopy [18,19]. Only 16% had a clinical history of allergies before migration. The
time that elapsed between migration and onset of symptoms was 5.3 ± 3.1 years,
http://dx.doi.org/10.1016/j.mehy.2016.05.029 0306-9877/Published by Elsevier Ltd. with
a minimum of 0.5 and a maximum of 7 years. These immigrants were from Asia, Africa,
South America, and Eastern Europe. A study of US immigrant children showed that children
born outside the United States have a lower prevalence in allergic diseases that increases
after residing in the United States for a decade [20]. Hypothesis The combination of these
research results prompted me to propose a specific hygiene hypothesis (SHH) and a
capacity competition theory (CCT) to explain the rising of hay fever. SHH posits that
continuous improvement in oral hygiene practices in modern society is the major cause of
the increase in the prevalence of hay fever and perhaps some other allergic diseases as well
(Fig. 1A). CCT is proposed to explain how reduction of oral infection, one of the results of
modern oral hygiene, leads to development of allergy (Fig. 1B). CCT assumes that bacterial
antigens under chronic oral infections have a much higher concentration than pollens do in
oral-rhino cavities. The dominant bacterial antigens overwhelm the acquired immune
system residing in lymph nodes at the back oral-rhino opening or nearby places, which
limits the chance of immune system to access allergens and to produce B cell clones with
efficient antibodies against allergens. After removing oral infections with persistent modern
oral hygiene practices, reduced bacterial antigen concentration leaves extra antibody-
generating capacity to allergens, with relative concentration becoming higher. The
probability to produce B cell clones with highly efficient antibodies against allergens
increases. The elevated innate immune system under infectious conditions can also clean
allergens faster than that under conditions without infections, which further C. Shunsheng
Han / Medical Hypotheses 93 (2016) 146–149 147 Fig. 1. The specific hygiene hypothesis
and capacity competition theory. (A) Correlation between the number of dental hygienists,
asthma prevalence in the US (cor = 0.96, p 0.01), and reduction in prevalence of
periodontitis suggest a relationship between oral hygiene and allergy. (B) The capacity
competition theory (see text). reduces the competitive edge of allergens (Fig. 1B). For the
same reason, the stimulated innate immunity can likely protect against acute infections
[21]. CCT indicates that the competing bacterial antigens do not have to be from a/multiple
specific species. SHH is different from GHH in the following aspects: 1) it specifies modern
oral hygiene practices as the cause for the high rise of hay fever through the reduction of
oral infection (Fig. 1B). 2) This hypothesis suggests actionable practices to prevent allergy if
proved. 3) CCT indicates the importance of the local immune system in allergy
development, though some bacteria might systematically relieve allergic reaction [22]. 4)
CCT indicates lasting chronic infections have more protection against allergy than acute
infections. Besides the observed negative association between periodontitis, or periodontal
microflora, and respiratory allergic diseases, studies on the dose-response effects of
allergens also support the capacity competition theory [23–26]. A study found there is a
sigmoid dose-response curve for subsequent reactivity [27]. Another study shows that local
pollen counts are positively related to the prevalence of hay fever in children of different
states in the United States [23]. The first evidence for the SHH is a high correlation between
3. oral hygiene and the prevalence of allergic diseases (Fig. 1 and Supplementary Table 1). The
oral hygiene level in a population can be measured in several ways, such as the
consumption of oral hygiene products, frequency of dental visits, percentage of the
population with dental insurance, and/or dental health condition. I choose to use the
historical number of dental hygienists as the indicator of oral hygiene levels in US as data is
readily available at the US Bureau of Labor Statistics. The profession of dental hygienist is a
relatively new one, appearing first in 1915 with the main purpose of cleaning and polishing
teeth to prevent dental diseases. They also give visitors advice on their daily oral hygiene
practices. The employment in this occupation has been steadily increasing since its creation.
There were about 15 thousand dental hygienists in the US in 1965, before the increase in
allergic diseases, and now there is a total of more than 193 thousand dental hygienists in
US. The asthma prevalence data was collected from the Center for Disease Control. Linear
regression shows that the two data sets are closely associated with each other (r = 0.96, p
0.01, Fig. 1A and Supplementary Table 1). The traditional oral hygiene status is infectious.
The oral cavity is the entry to the digestive tract, which is where the battle between foreign
bio-agents and our immune system begins. Without intentional help from the human host,
the battle between foreign agents and the immune system is continuously visible. Oral
infections are common in the population without modern hygiene practices. The study of an
indigenous Native American population in Central America indicated a high prevalence of
pocketing, and 90% of adults (P35 years) had at least one site with clinical levels (CAL) P6
mm [28]. A study based on the US population indicated that close to 80% of youth (13–15
years old) have gingivitis and more than 95 percent of the older population (P35 years old)
had periodontitis in the 1950s [29]. Oral hygiene practices began in ancient times, before
recorded human history. Various excavations done throughout the world have recovered
sticks, tree twigs, bird feathers, animal bones and porcupine quills that were chewed on to
clean teeth [30,31]. However, only recently are we gradually winning the war against oral
microbiota, with better and better toothbrushes, toothpaste, mouthwash, and floss. Early
toothbrushes made of animal hair were neither effective, due to contamination of bacteria,
nor 148 C. Shunsheng Han / Medical Hypotheses 93 (2016) 146–149 Fig. 2. Hypothetical
relationships between outcomes of modern oral hygiene. Benefits of oral hygiene practice
include reducing the severity of oral infection and its impact on cardiovascular health,
increasing dental health. Potential harm according to SHH is the increasing odds of hay
fever. Future studies have to be designed to not only verify SHH, but also identify the
window of the best oral hygiene practices that yield the most benefits and are the least
harmful. popular, due to rare availability and ignorance of oral hygiene issues. DuPont
introduced modern toothbrushes made of nylon around World War II with a dime price.
Early toothpaste made of vinegar or urine did as much harm as good. The dust of brick or
china, mixed with soap, was later more effective. Modern toothpastes were introduced after
WWII with synthetic detergent agents and fluoride. Antibiotic triclosan was introduced into
toothpaste in the 1980s [32–35]. Floss, introduced in the 19th century, was originally made
of silk and later replaced by nylon floss, to which antibacterial agents were added relatively
recently. Water used in rinsing one’s mouth was replaced with mouthwashes that contain
much stronger antibiotic effects [36]. Now trending in oral hygiene is Oil-pulling, which is
4. an ancient Ayurvedic dental technique that involves swishing a tablespoon of oil in one’s
mouth, which proves effective in reducing oral infection [37–39]. The results of oral
cleaning include significant reductions in oral infection and higher teeth retention. From
2009 to 2012, only 46% (compare to more than 95% in the 1950s) of US adults, had
periodontitis [40]. Another study in Sweden showed that, in all age groups, the number of
edentulous individuals decreased dramatically as the number of teeth increased [41]. Over
30 years, the proportion of periodontally healthy individuals increased from 8% in 1973 to
44% in 2003, and the proportion of individuals with gingivitis and moderate periodontitis
decreased in Sweden. With the help of the hygiene industry and the promotion of health
organizations, modern societies are winning the war against oral microbiota. As an
unintentional result, oral microbiota might be among the most interrupted human
microbiota. Are there any unwanted consequences besides those beneficial outcomes? SHH
and CCT are proposed here to explain the possible link oral hygiene and allergy. SHH and
CCT can not only explain the high rising of hay fever, but also explain other characters of
allergy epidemics, such as the crucial time in early life and impact of antibiotic use. practices
that maintain an oral microbiota with controlled mild oral infections. We acknowledge great
benefits of modern oral hygiene, such as healthy teeth and likelihood in preventing
cardiovascular diseases, and speculate that there is likely an optimal level of oral hygiene
that will give intended benefits and the smallest odds to allergic diseases (Fig. 2). Testing
this, SHH and CCT will be a significant step forward in understanding the current allergy
epidemic. Proving or disproving the hypothesis will provide novel insights into the
mechanism of the observed trends and help to define future research directions. Conclusion
References This specific hygiene hypothesis, if proven, suggests a simple and economical
way to prevent allergy – personalized oral hygiene Conflicts of interest The author does not
have any financial interests associated with this publication. Acknowledgements This
project was supported by Los Alamos National Laboratory, Laboratory Directed Research
and Development, 20130779PRD1. I thank Joe Alcock, Melanie Martin, and Armand Dichosa
for previous stimulating collaborations in the microbiome study of the Tsimane people and
valuable comments during the preparations of the manuscript. I am grateful to Ruy Ribeiro
for his encouraging and constructive discussions. I am grateful that the critics for a grant
review from NIH have also helped to strengthen the discussions. Appendix A.
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(2018) 16–26 Contents lists available at ScienceDirect Acta Tropica journal homepage:
www.elsevier.com/locate/actatropica The hygiene hypothesis at a glance: Early exposures,
immune mechanism and novel therapies T Gabriel M. Alexandre-Silvaa, Pablo A. Brito-
Souzaa, Ana C.S. Oliveiraa, Felipe A. Cernib, ⁎ Umberto Zotticha, Manuela B. Puccaa, a b
7. Medical School, Federal University of Roraima, Boa Vista, RR, Brazil Department of
Biochemistry and Immunology, Medical School of Ribeirão Preto, University of São Paulo,
Ribeirão Preto, SP, Brazil A R T I C LE I N FO A B S T R A C T Keywords: Hygiene hypothesis
Allergy Autoimmune diseases Parasite Helminthic therapy Microbiota therapy The hygiene
hypothesis was proposed almost three decades ago. Nevertheless, its mechanism still
remains with relevant controversies. Some studies defend that early exposures during
childhood to microbes and parasites are key determinants to prevent allergies and
autoimmune diseases; however, other studies demonstrated that these early exposures can
even potentiate the clinical scenario of the diseases. Based on several studies covering the
influences of microbiome, parasites, related theories and others, this review focuses on
recent advances in the hygiene hypothesis field. In addition, the main immunological
mechanisms underlying the hygiene hypothesis are also discussed. We also strongly
encourage that researchers do not consider the hygiene hypothesis as a theory based
strictly on hygiene habits, but a theory combining diverse influences, as illustrated in this
review as the hygiene hypothesis net. 1. Introduction 2. The hygiene hypothesis Based on
experimental evidence as well as epidemiological results, it is possible to verify the notable
increasing incidence of allergic diseases during the last decades, especially on the western
countries. Today, worldwide sensitization to foreign proteins (IgE produced-antibodies) is
presented between 20–40% of the population. This worldspread allergy pattern involves
anaphylaxis, food allergy, asthma, rhinitis, conjunctivitis, eczema, allergy to bug-bite and
many others. According to the hygiene hypothesis, this allergy increase is caused due to low
exposures to a wide array of infections, which present the ability to modulate the human
immune system (Canonica et al., 2013; Jappe et al., 2017; Pawankar, 2014; Pawankar et al.,
2011; Versini et al., 2015). In this review, the current state of art of the hygiene hypothesis
and its role on allergies, autoimmune diseases and other diseases will be discussed.
Moreover, we will provide details on the hypothesis history, documented cases, the
induced-immune-mechanism, the controversial studies, as well as the recent use of the
theory to perform novel therapies. In 1989, David P. Strachan formulated a theory
proposing that the development of infections during the first period of childhood decreases
when there is non-hygienic contact with older siblings from the same family. Studying hay
fever, a seasonal allergic rhinitis, Strachan observed the so-called post-industrial revolution
epidemic, using 17,414 British children following them up for 23 years. A total of 16
variables divided between perinatal, environmental and social factors were analyzed.
Thanks to his evaluation, it was able to find a solid association on the incidence of hay fever
with family size and position in the household during the childhood. Thus, the hygiene
hypothesis was formulated based on an inverse relation between the size of a household
and the occurrence of atopic disturbs, suggesting that this theory could explain allergies.
Ten years after the original article about hygiene hypothesis, Strachan held another
evaluation, this time covering both England and New Zealand. He studied the increase or
decrease of average family size between 1961 and 1991, trying to correlate these results
with the variation on the prevalence of hay fever on general population. The study
demonstrated that family size alone was not enough to justify the elevation of hay fever
prevalence, concluding that the household size was only one of the many risk factors that
9. our internal structure to survive and multiply, especially our intestine. A vast array of
microbes is responsible for occupying all space they can take there. However, we also gain
with their presence, as it helps our immune system to mature as well as balance the activity
of the immunological pathways (Th1, Th2 and Th17). The immune system presents four
major cells patterns of acquire immune response, which are composed by helper T cells
(Th) differentiation: Th1, Th2, Th17 and Treg (regulatory T cells). Studies have shown that
there are many ways 17 Acta Tropica 188 (2018) 16–26 G.M. Alexandre-Silva et al. less
representativity, Acanthocephala and Nematomorpha are also capable to cause human
parasitism, even being generally intermittent and without severe consequences (MacDonald
et al., 2002; Neves, 2005; Ponte et al., 2007). Helminths have evolved together animals in
order to survive. Therefore, they aim to parasite without killing the host along with their
capacity to suddenly form cysts to survive in the external environment. In this sense, it is
evident why helminths are mostly responsible for chronic diseases, as the longer they
remain in the body, the more cycles of reproduction they can complete in an attempt to
preserve the species. Indeed, this slow-paced development is not a coincidence. Parasites
themselves are capable of manipulating the human immunological system aiming to
prevent an efficient attack against them as well as to avoid sharing the host with other
species (in some cases, even with others from the same species) (McSorley and Maizels,
2012; Sorensen and Sakali, 2006; Zuckerman and Martin, 2016). The parasite induced-
immunomodulation is based on the modulation of cells and molecules of the host`s immune
system, especially on T CD4+ cells populations Th1, Th2, Th17 and Tregs. The mechanism
consists of using own parasitic proteins and other secretions to work as antigens to change
the balance of immunological response essentially into a Th2 response. The Th2 response
has the characteristic of not relying much inflammation and of having a modulating role
over Th1 and Th17 response, see details in section 8 (MacDonald et al., 2002; McSorley and
Maizels, 2012; Mesquita Júnior et al., 2009; Ponte et al., 2007; Sorensen and Sakali, 2006).
Nevertheless, the mechanism of helminth immune-regulation is not always effective.
Variations can occur according to the host, causing a contrast in patient profiles, ranging
from a patient carrying a heavy parasitic load and not showing any symptom to a patient
carrying a light parasitic load with serious symptoms, such as exacerbated inflammation or
even signals of hemorrhage (Manry and Quintana-Murci, 2013; McSorley and Maizels, 2012;
Ponte et al., 2007). Helminthic infections are majorly characterized as a prevalent disease
from poor countries, with no potable water, inadequate sanitation and low hygiene,
including countries from Latin America and Africa. On the other hand, allergies and
autoimmune diseases are more prevalent in high industrialized and developed countries
such as Canada, USA and countries from Europe. Nevertheless, the countries under
development demonstrated low reports of allergies and autoimmunity diseases, which have
been attributed to a protective effect of helminthic infections during childhood (Ponte et al.,
2007; Sitcharungsi and Sirivichayakul, 2013). Following this reasoning, soil-transmitted
helminths are correlated to this protection, as they possess high prevalence in poor
countries (Cruz et al., 2017; Hotez et al., 2008; McSorley and Maizels, 2012; Santiago and
Nutman, 2016). Ascaris lumbricoides infections in the slums of Caracas, Venezuela, reduced
the reaction of skin prick tests and serum levels of allergenspecific IgE (Hagel et al., 1993).
10. Schistosoma mansoni infection was able to reduce human reaction to house dust mite and
mold, as well as decreased responses to skin prick test with most of patients presenting
lower levels of allergen-specific IgE (Araujo et al., 2000). Regarding the same parasite, in
other study, it was also demonstrated that the parasite infection reduces the risk of the
development of allergy (Oliveira et al., 2014). The literature is also rich in evidences
correlating helminthic infection and protection of autoimmune diseases. The immune
system has the capacity to distinguish antigens between the group of self (natural to the
body) and non-self (external to the body). The phenomenon of not causing harm to oneself
is called self-tolerance and the loss of this tolerance may cause autoimmune diseases
(Mesquita Júnior et al., 2010; Schafer et al., 2005; Souza et al., 2010). Correale and Farez
demonstrated that multiple sclerosis (MS) patients affected with positive parasite stool
showed reduced number of exacerbations and minimal variation in disability scores.
Moreover, the mechanism of autoimmunity suppression was investigated and an increase of
Treg cells to interfere with the process of colonization and it is dynamic process that begins
during birth. Factors such as the size of the household (presence or absence of older
siblings), the way of birth delivery (cesarean or vaginal), and even the child diet (breast
milk, infant formula or cow’s milk) can affect the process of colonization and long term risk
to diseases (Azad et al., 2013; Biasucci et al., 2008; Neu and Rushing, 2011). Overall, the
early exposure of children to microorganisms can affect their colonization in two main
points: diversity of species or quantity of a certain specimen. As an example, domestic
animals such as dogs and cats are more prone to carry animal-specific and soil microbiome,
while siblings will serve as carriers of microbes found at soil, schools or daycares, and
human-specific. Animals have been related to be the main responsibles of affecting the
diversity of the gut microbiome by increasing the presence of Peptostreptococcaceae,
Clostridicaceae, Coprococcus; dogs increase the colonization by Veillonceae and decrease
the presence of Eggerthella, whereas cats decrease the presence of Bifidobacteriaceae. On
the other side, older siblings affect the quantity of certain species, mainly decreasing the
colonization by Peptoostreptococcaceae (Azad et al., 2013; Bunyavanich et al., 2016;
Fazlollahi et al., 2018). Therefore, the number of microorganisms and types of species in the
gut can modulate the immune system, which was called balanced signal hypothesis.
Moreover, when microbiome varies in number or diversity of pathogenic species these can
result in a mechanism called dysbiosis (Fazlollahi et al., 2018). Dysbiosis has been
associated with food allergies. In a study conducted with 226 children presenting milk
allergy it was demonstrated that in 56.6% patients, the milk allergy was resolved during the
first 8 years, with an enrichment of Clostridia and Firmicutes genera in the microbiome of
them (Bunyavanich et al., 2016). In other study conducting with 141 children with egg
allergy, the bacteria families Lachnospiraceae, Streptococcaceae, and Leuconostocaceae
were differentially abundant (Fazlollahi et al., 2018). Regarding microbiome and
autoimmune diseases, in a study conducted in vivo, it was demonstrated that the
colonization of a germ-free mice with a variety of intestinal bacteria was capable of
reducing diabetes type I in NOD-MyD88-negative mice (but not wild-type NOD mice),
favoring the balanced signal hypothesis. However, the molecules and mechanisms involved
in prevention or facilitation of the disease remained unknown (Burrows et al., 2015). The
11. same was observed in the animal model of multiple sclerosis or EAE (experimental
autoimmune encephalomyelitis). Mice maintained under germ-free conditions develop
significantly attenuated EAE with lower levels of proinflammatory cytokines (IFN-γ and IL-
17 A) and an increase in CD4+CD25+Foxp3+ regulatory T cells (Tregs). However, when
mice were colonized with intestinal segmented filamentous bacteria (SFB) they presented a
severe EAE with high IL-17 production and Th17 increasing (Lee et al., 2011). Recently,
based on the incidence of epilepsy in the developed countries compared to developing
countries (45.0 and 81.7 per 100,000/year, respectively) and the close relationship
between epileptogenesis and autoimmune diseases, researchers strongly believe that
intestinal microbiome composition are also responsible to the progression of epilepsy
(Ngugi et al., 2011; Wu et al., 2016). In this sense, the intestinal microbiome profoundly
impacts the balance between pro- and antiinflammatory immune responses during diseases
and suggest that modulation of gut bacteria may provide therapeutic targets for allergies,
autoimmune diseases and even epilepsies. 4. The influence of helminth infections The
helminth designation is used to refer to a group of animals composed mainly by
Platyhelminthes and Nematoda, since they are responsible for the most cases of parasitic
helminths. However, with 18 Acta Tropica 188 (2018) 16–26 G.M. Alexandre-Silva et al.
(CD4+CD25+Foxp3+) with its non-inflammatory cytokines (IL-10 and TGF-β) demonstrated
to be essential to the autoimmune disease control (Correale and Farez, 2007). Another
study from the same group regarding MS shown that infected patients present lower
number of relapses, reduced disability scores and even a lower magnetic resonance imaging
(MRI) activity in comparison to patients uninfected. Helminthic infection control was
associated with significant increases in clinical and radiological MS activities, as well as
increases in INF-γ and IL-12 producing cells, suggesting that helminths were capable of
altering the disease course (Correale and Farez, 2011). In experimental studies conducted
in diabetic type I mice or multiple low dose streptozotocin-induced diabetes mice (MLDS),
infections by Taenia crassiceps was able to reduce hyperglycemia and insulitis preventing
pancreatic damage probably by suppressing or modulating autoreactive T cells (Espinoza-
Jimenez et al., 2010). Interestingly, diabetes type II has also been associated to helminthic
infections. Although the disease is related to other factors including diet, smoking and
stress, sedentary lifestyle and genetic risk factors, the exposures to helminths can also
contribute to the strong emergence of diabetes type II. The mechanism is attributed to the
helminth-induced Th2 responses, which modulate the obesity-induced activation of
inflammatory pathways that are associated with the development of insulin resistance, a
strong predictor of diabetes type II (de Ruiter et al., 2017). mice were inoculated (at the
same time) with the antigen induction and the parasite, they presented a less severe EAE
(Wallberg and Harris, 2005). 6. The impact of other infections Infections with gram-
negative bacteria, which contains endotoxins, can alter the immunological system to a non-
Th2 response and lead to less allergies (Braun-Fahrlander et al., 2002; Liu, 2002). A study in
South Africa established a protective effect against atopic manifestations in population
infected by Mycobacterium tuberculosis (Obihara et al., 2006). Moreover, in other study,
BCG (bacillus Calmette–Guérin) vaccination, the primarily vaccine used against
tuberculosis, had an effect on T-cell allergen responsiveness 7–14 years after vaccination
12. (Marks et al., 2003). Periodontitis, an inflammatory disease caused by microorganisms
present in the plaque biofilm, also have been related to a protective role in the development
of asthma and other allergic diseases (Reddy et al., 2014). In theory, any other childhood
infection, such as respiratory tract infections, measles, mumps and whooping cough, could
also protect further allergic diseases by a bystander mechanism (Holt et al., 1997; Marsland
et al., 2004; Wickens et al., 2002). In brief, the infection can activate the immune system
triggering an inflammatory response (mainly Th1) and inhibit the Th2-response (the atopic
response) (Romagnani, 2004a). 5. The influence of protist infections 7. The controversial
studies: when hygiene hypothesis failed Protozoa present great variation in their structure
and biochemical characteristics, which modulate the immune responses resulting in their
evasion from killing. It is important to mention that protozoa immunomodulation is distinct
from the ones caused by fungi, bacteria or viruses, and some of them can resist from
phagocytic attack and might even replicate inside macrophages. Therefore, these parasites
present a complexity interaction with both innate and adaptive immune responses. In
addition, the literature describes that some protozoa are capable of inducing alteration on
the host immune response by nonspecific and generalized immunosuppression, leading to
abnormalities in cytokine production and/or deficient T cell activation (e.g. Trypanosoma,
Leishmania, Toxoplasma, Entamoeba) (Arsic-Arsenijevic et al., 2003; Menzies et al., 2016).
Dientamoeba fragilis and Blastocystis have been detected in feces from patients with
irritable bowel syndrome (IBS). Therefore, a study investigated the prevalence of the
parasites in subjects with symptoms of IBS compared with asymptomatic subjects.
However, the results showed the reverse association of a higher prevalence of parasites in
asymptomatic individuals, which could be responsible for preventing IBD, although further
studies are still necessary to clarify the hypothesis (Krogsgaard et al., 2015). The infection
with Plasmodium chabaudi is capable of activating Treg cells and to modify the clinical
course of EAE in C57BL/6 mice. The tests consisted of infecting mice with P. chabaudi
during the clinical manifestation of EAE. The presence of an autoimmune response did not
alter the parasitemia levels, nor the corporal temperature. However, the EAE clinical score
was markedly diminished, which could be explained by the increase of Treg cells since
infected mice presented a percentage of Treg cells three-fold higher than controls (Farias et
al., 2011). Another protist that has demonstrated capacity of modulating EAE is
Trypanosoma cruzi. Using C57BL/6 mice, the study demonstrated that infection with the
parasite was able to prevent EAE development as well as induced complete and lasting
remission of the clinical sings in mice that had already developed disease manifestations
(Tadokoro et al., 2004). In other EAE study, using DBA/1 mice, infection with Trypanosoma
brucei brucei prevent the onset of the disease, or at least decreased the severity, through
induction of suppression on antigen presenting cells (APCs). In other words, when mice
were already infected with T. brucei brucei, they did not develop EAE after antigen
induction; however, if the Although the literature is rich in articles demonstrating the
protective effect of the microbiome and parasitic infections specially on allergies and
autoimmune diseases, this mechanism cannot be considered a rule, as it also might
potentiate the clinical scenario of the diseases. Following the pillars that guide the hygiene
hypothesis two main points should be considered: a) early exposure to antigens of various
13. origins can reduce atopic and autoimmune diseases; b) the parasite infection capable of
inducing immunomodulation can attenuate the clinical condition of an already established
disease. However, there are exceptions since there are several evidences where the hygiene
hypothesis is inconsistent (failed) with a few examples described below (Ercolini and
Miller, 2009; Oliveira et al., 2017; Strachan, 2000; Yazdanbakhsh et al., 2002). Helminths
present a small range of antigens that can be homologous to common allergens. These
antigens induce IgE production resulting in important responses for protection against the
parasite. However, in some circumstances, helminths can enhance responses to allergens,
probably due cross-reaction (Tyagi et al., 2015). The phenomenon of cross-reaction may
also lead to allergies to previously innocuous antigens, such as vanilla ice cream, pollen,
corn, peanut and shellfish (Jappe et al., 2017; Sitcharungsi and Sirivichayakul, 2013;
Strachan, 1989). Patients from Ascaris lumbricoides endemic area and infected by the
parasite shown enhanced IgE-mediated reactivity to common inhaled allergens in both
allergic and clinically non-allergic subjects. The same conception was also observed by
evaluating a rural population from China, associating the infection with the increased risk of
childhood asthma and atopy in a way that the risk did not depend on the sensitization to
aeroallergens. Once again, a higher risk for atopy was associated with A. lumbricoides in
South Africa. In that study, it was observed the increasing of IgE response to house dust
mites and its paper as indicator of asthma severity (Buendia et al., 2015; Joubert et al.,
1980; Obihara et al., 2006; Palmer et al., 2002). Parasites that are commonly found in fishes,
such as Anisakis simplex, or associated with poor hygiene near, such as S. mansoni, Necator
americanus, Strongyloides stercoralis, Trichuris trichiura, Mansonella perstans and
A.lumbricoides were all associated to increase the risk of atopic 19 Acta Tropica 188 (2018)
16–26 G.M. Alexandre-Silva et al. mediated response against innocuous antigens (allergens)
and triggered by Th1 cell against self-antigens. The main two hypothesis that explain the
immunological mechanism are described below. The hypothesis 1 and 2 can explain the
prevalence of allergies and the hypothesis 2 the development of autoimmune diseases: (1)
Missing immune deviation: the reduced microbial infections during childhood due to high
hygiene habits result in low stimulation of innate immune cells such as DC and,
consequently, low levels of IL-12, a Th1 polarizing-cytokine. Thus, the Th2 response is
enhanced, resulting in allergic diseases (Fig. 3). (2) Reducing immune regulation: the
westernized hygiene lifestyle can also reduce the stimulation of Treg cells resulting into the
activation of Th1 or Th2 response, which are related to autoimmunity and allergies,
respectively (Fig. 4). For further information about these hypothesis see (Romagnani,
2004b). It is important to mention that DC as well as barrier epithelial cells can be also
influenced by microbiome diversity during early life (Lambrecht and Hammad, 2017).
manifestation in endemic communities (Daschner et al., 2005; Webb et al., 2016). In a
Brazilian study, it was demonstrated the relationship of A. lumbricoides and T. trichiura
previous infection, not the active infection, with wheezing and atopy (Alcantara-Neves et al.,
2010). In Istanbul, infection by Enterobius vermicularis was associated with recurrent
wheezing (Bahceciler et al., 2007). A study done in Korea with 1116 patients from an
endemic area of Clonorchis sinensis (the Chinese liver fluke) demonstrated that the
parasitic infection was associated with atopy and high levels of serum IgE without
14. establishing direct relationship with wheezing, asthma, allergic rhinitis or airway
hyperresponsiveness (Choi et al., 2011). A double-blind trial performed to evaluate the
effect of N. americanus infection upon patients with celiac disease demonstrated that 50%
of patients who received a wheat challenge presented painful transient enteritis (Daveson
et al., 2011). Another study developed in Cuba demonstrated that human toxocariasis could
boost preexistent allergy symptoms. On that study, the presence of Toxocara sp. in atopic
children stimulates the onset of allergic diseases such as asthma, while previously the
toxocariasis was associated to diminish lung function (Kanobana et al., 2013; Walsh, 2011).
Therefore, due to significant evidences, some authors concern over the safety of
administrating living parasites (section 8) with known human morbidity (Briggs et al.,
2016). 9. The future of hygiene hypothesis: insights into therapeutic implications After
several evidences of the benefits provided by childhood infections and the extensive
hygiene hypothesis studies, it is not surprising that the hypothesis has been used as a
therapeutic strategy. The most known therapy is the helminthic therapy, which works
through the parasite capacity to induce immunoregulation upon the host. However,
preferably the new approaches use helminth-derived products, focusing on key molecules
responsible for the host immunomodulation. This kind of drugs are most desired because
they would easily fit into the current drug pipeline, since intact helminths do not fit well
with current regulatory policy (Briggs et al., 2016; Maruszewska-Cheruiyot et al., 2018;
Villeneuve et al., 2018). It is also important to mention that not all helminths are considered
parasites. In some cases, they do not cause infections (Parker, 2017). Therefore, some
authors suggest referring to them as symbionts rather than parasites to capture the
diversity of their ecological roles (Lukes et al., 2015). A few examples of experimental and
clinical-based studies based on helminthic therapies are discussed below and summarized
on Table 1. Based on S. mansoni capacity in switching immunological response from Th1 to
Th2, non-obese diabetic (NOD) mice were treated with the parasites r their eggs aiming to
prevent the spontaneous development of diabetes mellitus. The two experimental
approaches presented success: the infection with live parasites or injection with parasite
eggs alone (Cooke et al., 1999). In other study, the infection with the S. mansoni significantly
reduced the incidence and delayed the clinical onset of EAE (La Flamme et al., 2003). Mice
exposure to S. mansoni eggs and posterior exposure to trinitrobenzesulfonic acid
demonstrated attenuation of induced-acid colitis and protection of lethal inflammatory
reaction. On the immunological point of view, the exposure to the eggs decreased the levels
of INF-γ and enhanced the production of IL-4. In another study regarding colitis, using mice
model of dextran sodium sulfate (DSS, an experimental model of inflammatory bowel
disease) immunized with S. mansoni eggs, it was demonstrated that egg antigen succeeded
in acting like a prophylactic helminthic therapy because of its modulatory effect on induced
colitis model (Elliott et al., 2003; Hasby et al., 2015). Trichuris suis is also involved in human
protection against inflammatory bowel diseases (IBD), also considered an autoimmune
disease. This helminth is not a human parasite (it parasites pig herds); however, its eggs are
capable of colonizing humans for some weeks being eliminated by feces thereafter without
any therapy. A clinical trial performed with four patients presenting Crohn`s disease and
three with ulcerative colitis, whom orally received a single dose of 2500 live eggs of T. suis,
15. demonstrated that all patients improved the clinical scenario, without any adverse events
or laboratory abnormalities. 8. The hygiene hypothesis and the cross-talk with the immune
system To activate the adaptive immune system, first the antigen (such as a microbe) is
introduced by dendritic cells (DCs) to T CD4+ cells. The DCs are cells from the innate
immunity also known as specialized antigenpresenting cells. These cells present pattern
recognition receptors or PRRs, such as toll-like receptors or TLRs, which recognize
conserved pathogen-associated molecular patterns or PAMPs (conserved structures from
diverse pathogens). After PAMP recognition, the DC processes and introduces it to a T CD4+
naïve cell through peptide-MHCII complexes, which, along with costimulators binding and
environmental cytokines, differentiates into Th different subsets: Th1, Th2, Treg, Th17 or
Th22 (Fig. 2), for detail see (Abbas et al., 2015). Since 1986 T CD4+ cells (helper cells) were
classified into two main populations, Th1 and Th2, which were distinguished by cytokine
patterns, transcription factors and functions (Mosmann et al., 1986). Briefly, Th1 cells
produce IFN-γ and are regulated by IL-12 and the transcription factor T-bet, being
responsible for immune responses against intra- and extracellular pathogens. On the other
hand, Th2 cells produce mainly IL-4, IL-5 and IL-13 and are regulated by the transcription
factor GATA3, which are important to the immune responses against parasites and
allergens (Abbas et al., 2015; Zhu et al., 2010). A third Th population was described in 2001,
the Treg cells (CD4+CD25+Foxp3+), although there was previous evidence of their
existence since the seventies. These cells produce high levels of IL-10 and are regulated by
the Foxp3 transcription factor besides being related to prevent autoimmune diseases by
induced-immunomodulation (Brunkow et al., 2001; Gershon and Kondo, 1970; Sakaguchi et
al., 2008; Shevach, 2001). Th17 population was described soon after by Zhang et al. (2003).
Studying the murine model of multiple sclerosis (EAE), the research group demonstrated
that the immunopathological response of EAE was independent of IL-12, i.e., it was not
caused by a Th1 response (Zhang et al., 2003). However, only in 2006 the Th17 cells were
characterized, highlighting the importance of IL-6 and TGF-β cytokines in their
differentiation and in the activation of their RORγt transcription factor (Mangan et al., 2006;
Veldhoen et al., 2006). Th22 is also a well-characterized cell, being a Th cell producer of IL-
22 without IFN-γ, IL-4 and IL-17 (Duhen et al., 2009; Trifari et al., 2009). The hygiene
hypothesis would come to proclaim that reduced parasite infection and/or microbial
burden during childhood can result in activation of the adaptive immune system triggered
by Th2 cell20 Acta Tropica 188 (2018) 16–26 G.M. Alexandre-Silva et al. Fig. 2. T CD4+ cells
activation and differentiation into T helper cell subsets. Fig. 3. Missing immune deviation
hypothesis. (A) The reduced microbial burden during childhood results in decreased
stimulation of innate immune cells such as dendritic cell and reduced the production of IL-
12. Thus, the immune response to innocuous antigen (allergens) results in a prevalent Th2
response. (B) The increased microbial burden during childhood results in increased
stimulation of innate immune cells such as dendritic cell and high levels of IL-12 production
and a Th1polarizing response, which protects against allergic disease. 21 Acta Tropica 188
(2018) 16–26 G.M. Alexandre-Silva et al. Fig. 4. Reducing immune regulation hypothesis. (A)
The increased microbial burden during childhood results into regulatory T cells (Tregs)
activation, which prevent Th1 and Th2 response. Thus, Tregs cells induce
16. immunomodulation and inhibited allergic (Th2) and autoimmune (Th1) diseases. (B) The
reduced microbial burden during childhood prevents regulatory T cells (Tregs) activation.
Thus, allergic (Th2) diseases can be developed. (C) The presentation of self-antigens during
childhood in the absence of Treg cells can result in autoreactive Th1 and Th17 activation.
Thus, autoimmune diseases (Th1 and/or Th17) can be developed. diminuta was capable to
reduce the disease inflammatory display. In other study, H. diminuta therapy was more
effective than dexamethasone in preventing the colitis manifestation (Johnston et al., 2010;
Melon et al., 2010). Heligmosomoides polygyrus bakeri was also used to study colitis
models and the dendritic-cell-based mechanism triggered by helminth. The immune
mechanism was related to the increase numbers of Treg cells (Blum et al., 2012; Hang et al.,
2013). Strongyloides venezuelensis was able to protect the diabetes development induced
by streptozocin in mice (Peres et al., 2013). Litomosoides sigmodontis was also related to
protect against diabetes in NOD mice. The presence of the helminth as well as the infection
with the crude worm antigen was capable to protect against the type 1 diabetes, which was
associated with the shift of the Th2 response (Hübner et al., 2009). The same protective
effect over type 1 diabetes was described in Moreover, six of the seven patients achieved
remission (Summers et al., 2003). On the other hand, in other recent clinical trial, the
administration of T. suis eggs over 12 weeks did not show relevant effect over placebo for
induction of clinical remission of Crohn`s disease (Scholmerich et al., 2017). As an
alternative to T. suis, a study was conducted with infective larvae (L3i) of N. americanus as
clinical therapy to Crohn`s disease. During the evaluation of nine patients, seven presented
an improved of the disease score (Croese et al., 2006). In other study, it was demonstrated
that the extract of Ascaris suum either prophylactically or as therapy was effective in
reducing the severity of zymosan-induced arthritis and collagen-induced arthritis in mice
(Rocha et al., 2008). In mice with colitis induced by dinitrobenzene sulfonic acid, the use of
phosphate-buffered saline-soluble extract of adult Hymenolepis Table 1 Experimental and
clinical novel therapies based on helminthic therapies. Therapy Disease Model References
Achantocheilonema vitae (ES-62) Airway hypersensitivity Oxazolone-induced immediate
hypersensitivity Collagen induced arthritis Arthritis Type 1 diabetes Colitis Colitis Colitis
Colitis Type 1 diabetes Type 2 diabetes Crohn`s disease Multiple sclerosis Mice Helmby,
2015 McInnes et al., 2003 Melendez et al., 2007 Mice Mice Mice Mice Mice Mice Mice Mice
Human Human Rocha, Leite et al., 2008 Lund et al., 2014 Blum et al., 2012 Hang et al., 2013
Melon et al., 2010 Johnston et al., 2010 Hübner et al., 2009 Berbudi et al., 2016 Croese et al.,
2006 Correale and Farez, 2011 Insulin dependent diabetes mellitus Experimental
autoimmune encephalomyelitis Colitis Colitis Diabetes Crohn`s disease disease and
Ulcerative colitis Crohn`s disease Mice Mice Cooke et al., 1999 La Flamme et al., 2003 Mice
Mice Mice Human Elliott et al., 2003 Hasby et al., 2015 Peres et al., 2013 Summers et al.,
2003 Human Summers et al., 2005 Ascaris suum Fasciola hepatica Heligmosomoides
polygyrus bakeri Heligmosomoides polygyrus bakeri Hymenolepis diminuta Hymenolepis
diminuta extract Litomosoides sigmodontis Litomosoides sigmodontis Necator americanos
larvae Hymenolepis nana, Trichuris trichiura, Ascaris lumbricoides, Strongyloides
stercolaris, and Enterobius vermicularis Schistosoma mansoni Schistosoma mansoni
Schistosoma mansoni eggs Schistosoma mansoni eggs Strongyloides venezuelensis
17. Trichuris suis eggs Trichuris suis eggs 22 Acta Tropica 188 (2018) 16–26 G.M. Alexandre-
Silva et al. nasogastric/nasojejunal tube, gastroscope, colonoscope or an enema. The
therapy presents success of 89% (Bakken, 2009; Di Bella et al., 2013). Nevertheless, only in
2013, the first randomized clinical trial on the infusion of stool for treating CDI was
published. The study was conducted in patients with recurrent CDI and demonstrated that
FMT improves duodenal diversity and work as a therapeutic factor for C. difficile, which
procedure was defined as a better approach than the use of vancomycin (van Nood et al.,
2013). Another study focused on the therapy for C. difficile infection conducted during
2012–2016 demonstrated that 82% of patients that received FMT achieved fast clinical
improvement (in three days). The study concluded that the transplant is an effective
treatment for recurrent infection even for elders (over sixty years), debilitated and severely
ill patients, and with low adverse events (Friedman-Korn et al., 2018). A trial with
concentrated cryopreserved fecal-derived bacteria, administered via ingested capsules,
demonstrated that the results was 89% similar to the rates achieved with conventional FMT
methods (e.g. enema with nasoduodenal tube or colonoscopy administration), suggesting
that the orally transfer of microbiome is effective (Hirsch et al., 2015). Remission of active
ulcerative colitis using FMT was also documented (Borody et al., 2003; Moayyedi et al.,
2015). Although CDI is recognized as the most immediate indication for FMT, other
potential indications are also being applied. In a study conducted in patients with active
Crohn’s disease, FMT was able to promote improvement in clinical and laboratorial aspect
in most of patients, while not causing harm or collateral effect (Suskind et al., 2015). There
is a case report that describes a female patient suffering from refractory colonic Crohn’s
disease. After several approaches with prednisone, mesalazine, 6-mercaptorine and
infliximab the patient keeps showing active colitis upon colonoscopy. Then, the FMT was
performed and one week after the transplant the patient felt well presenting 1 to 2 bowel
movements per day and no abdominal pain. The remission was achieved and sustained for
twelve months (Bak et al., 2017). In addition, besides CDI and IBD (such as Chron’s disease),
today the microbiota transplantation has been used to different emerging applications
including constipation, metabolic syndromes, obesity, anorexia nervosa, chronic fatigue
syndrome, food allergies, idiopathic thrombocytopenic purpura, as well as systemic
autoimmune disease such as multiple sclerosis (Borody and Khoruts, 2011). Table 2 Human
therapies based on microbiome transplantation. Therapy Disease Reference FMT Ulcerative
colitis Borody et al., 2003 Bennet and Brinkman, 1989 Moayyedi et al., 2015 van Nood et al.,
2013 Hirsch et al., 2015 Friedman-Korn et al., 2018 Eiseman et al., 1958 Suskind et al., 2015
Bak et al., 2017 Borody et al., 1989 Andrews et al., 1995 Borody et al., 2011b (Borody et al.,
2011a) (Borody, 1995) (Vrieze et al., 2012) (Kleiman et al., 2015) (Liu et al., 2017)
Pseudomembranous colitis caused by Clostridium difficile infection (CDI) Inflammatory
Bowel Diseases (IBD) Severe Constipation Severe Multiple Sclerosis Idiopathic
Thrombocytopenic Purpura Chronic Fatigue Syndrome Metabolic Syndrome Anorexia
Nervosa Allergic colitis FMT: Fecal Microbiota Transplantation. mice infected with Fasciola
hepatica (Lund et al., 2014). Additionally, a study conducted with insulin resistance mice
demonstrated that L. sigmodontis infection drives a Th2 response with an improving of
animals’ glucose tolerance (Berbudi et al., 2016). The best helminthic product that has been
18. used as therapy is ES-62 from the nematode Achantocheilonema vitae. ES-62 is a
glycoprotein able to deviate Th2 activation and, consequently, to inhibit the Th1 and Th17
polarizations, thus, being able to reduce inflammatory manifestations. The effectiveness of
this molecule creates a perspective of treatment of exacerbated immunological reaction
(e.g. autoimmune diseases) along with safety for not use the entire parasite (Adisakwattana
et al., 2009; Harnett, 2014; Helmby, 2015; McInnes et al., 2003; Melendez et al., 2007).
Interestingly, no protists have been tested for their potential to stimulate an immune
system in a manner beneficial for humans (Lukes et al., 2014). Therefore, there are no
supporting data on their possible therapeutic applications. Helminthic therapy is not the
only one studied by research adepts of the hygiene hypothesis. The handling of the
microbiome is also being used to therapeutic proposals (Table 2) (Caicedo et al., 2005;
Fazlollahi et al., 2018; Imdad et al., 2017). However, the use of bacteria to promote therapy
can be considered less popular when people refers to hygiene hypothesis probably because
bacteria, especially of the gut, are mostly affected by diet, not by hygiene (Turnbaugh et al.,
2009). Moreover, it is important to distinguish between symbiotic bacteria of the gut
(mostly affected by diet) and pathogenic microbes that cause “crowd infections”. Crowd
infections increased following the agricultural revolution but decreased by modern hygiene.
In addition, these crowd infections do not modulate the immune system in a healthy
manner and normally lead to disease. Indeed, Parker had already mention that the biome
depletion should be a better term to be used instead of hygiene hypothesis (Parker, 2014;
Rook, 2012). The best reliable and effective microbiome therapy that is saving thousands of
lives is the fecal microbiome transplantation (FMT) (Fleming, 2013; Stiemsma et al., 2015).
The first FMT therapy reported in humans dates 1958 (Eiseman et al., 1958). FMT was
performed against pseudomembranous colitis (caused by Clostridium difficile infection or
CDI). The approach consists of changing the composition of microbiome within donor liquid
suspension of stool to a patient with CDI. The liquid can be transferred in the
gastrointestinal tract by 10. Final remarks Although the hygiene hypothesis, described
almost three decades ago (1989), presented high contribution in the study of specific
diseases development (e.g. allergies and autoimmune diseases), currently it is a
straightforward wrong idea to correlate the increase prevalence of these diseases only with
hygiene habits. Indeed, cutting an individual hygiene may increase infections, which will
present a high impact on the immune modulation. Nevertheless, based on the vaccines and
antibiotics advances and the consequently decrease of some infections in the world
population (e.g. tuberculosis, mumps, measles), it is evident that decreasing of early
exposures to a diverse range of friendly microbes, especially during the childhood, is the
main responsible to change the immune response and to cause such westernized diseases.
Indeed, Parker had already mention that the hygiene hypothesis is a misnomer and that
biome depletion should be a better term to be used (Parker, 2014). As exposed in this
review, the hygiene hypothesis from today received many influences from other studies.
Therefore, we strongly encourage that the researchers consider hygiene hypothesis not a
theory based strictly on hygiene habits, but a theory combining diverse influences, as
illustrated in this review as the hygiene hypothesis net. Acknowledgments We thank the
financialsupport of Fundação de Amparo à Pesquisa 23 Acta Tropica 188 (2018) 16–26 G.M.
19. Alexandre-Silva et al. do Estado de São Paulo (FAPESP, São Paulo Research Foundation,
scholarship to FAC n. 2017/14035-1) and Conselho Nacional de Desenvolvimento Científico
e Tecnológico (CNPq, The National Council for Scientific and Technological Development,
scholarship to MBP, n. 307155/2017-0). severity. World Allergy Organ. J. 8, 1–11.
Bunyavanich, S., Shen, N., Grishin, A., Wood, R., Burks, W., Dawson, P., Jones, S.M., Leung,
D.Y.M., Sampson, H., Sicherer, S., Clemente, J.C., 2016. Early-life gut microbiome composition
and milk allergy resolution. J. Allergy Clin. Immunol. 138, 1122–1130. Burrows, M.P.,
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Spotlights Trends in Microbiology July 2015, Vol. 23, No. 7 Infectious asthma triggers: time
to revise the hygiene hypothesis? Wilmore C. Webley and Kelly L. Aldridge University of
Massachusetts Amherst, Amherst, MA, USA The hygiene hypothesis supports an inverse
relationship between respiratory infections in early-life and atopic diseases. However, a
recent study supports growing evidence that early-life infection and airway microbiome
composition can significantly influence asthma inception and exacerbation later in life. This
reignites discussions on infection-mediated asthma phenotypes and potential therapeutics.
Asthma affects approximately 300 million people worldwide, and its prevalence has
increased considerably over the past 30 years [1]. There are few chronic illnesses which
present such a therapeutic challenge to physicians as chronic asthma. Asthma is primarily a
developmental disease and several studies show that as many as 50– 80% of children who
have asthma develop symptoms before their fifth birthday [1]. Numerous molecular and
immunesystem pathways are now implicated in different manifestations of a disease once
considered uniform and well understood. However, the mechanisms underlying asthma
pathogenesis continue to evolve as various phenotypes and endotypes of the disease are
better defined. By following a cohort of more than 17 000 British children born in 1958 for
23 years, Strachan observed an inverse relationship between the number of older siblings
in the household and the prevalence of hay fever, therefore concluding that allergies could
be prevented by infections in early childhood and giving birth to what is now known as the
27. ‘hygiene hypothesis’ [2]. It is important to note here that the hygiene hypothesis did not
originate from observations about early-life infection. Rather, it emerged from data
suggesting a relationship between atopy, family size, and birth order. Therefore, the link to
infection was based on the assumption that early-life infections were essential for the
appropriate development of the immune system, although the exact mechanism by which
this occurred remained unknown. Over the years, the hygiene hypothesis has been
expanded to encompass asthma and many studies support this link. However, increasing
research and epidemiological evidence also strongly suggest that p…
![Read the articles and come up with a response to the question.
Medical Hypotheses 93 (2016) 146–149 Contents lists available at ScienceDirect Medical
Hypotheses journal homepage: www.elsevier.com/locate/mehy A specific hygiene
hypothesis Cliff Shunsheng Han Los Alamos National Laboratory, Bioscience Division and
Quality Performance Assurance Division, MS, M888, Los Alamos, NM 87545, USA a r t i c l e i
n f o Article history: Received 25 November 2015 Accepted 24 May 2016 a b s t r a c t
Allergic diseases have reached epidemic proportions in Western populations in the last
several decades. The hygiene hypothesis proposed more than twenty years ago has helped
us to understand the epidemic and has been verified with numerous studies. However,
translational measures deduced from these studies to prevent allergic diseases have not
proven effective. Recent studies on immigrants’ allergies and any potential association
between oral infection and allergic diseases prompt me to propose a specific hygiene
hypothesis to explain how oral hygiene practices might have contributed to the uprising of
hay fever, the most common allergic disease. The historic oral hygiene level in US is closely
associated with the emerging allergic epidemic. Future studies to test the hypothesis are
needed and verification of the hypothesis can potentially yield highly effective measures to
prevent allergic diseases. Published by Elsevier Ltd. Introduction Allergies are a significant
health concern. Allergic diseases have reached epidemic proportions in Western
populations in the last decades. Hay fever (allergic rhinitis or seasonal allergy) is the most
common allergic disease, affecting 13.5% of the US population [1]. Its symptoms include any
combination of the following: a runny or stuffy nose, sneezing, itchiness, red eyes, coughing,
and congestion. The hygiene hypothesis was proposed by Strachan in 1989 to explain the
cause [2], which is referred to here as general hygiene hypothesis (GHH). Since then, a
variety of studies reported results consistent with GHH, including that rural farm living
significantly reduces the risk of developing hay fever and atopic sensitization [3,4]. These
environmental cues point to lack of access to microbial diversity as a possible cause of
allergies and autoimmune diseases [5–8]. The observed link between allergy and
commensal bacteria has provided the scientific rationale for microbiome reconstitution as
measure against the allergy epidemic [9]. However, the results from probiotic treatments
have been conflicting [10–13]. The continuous confirmation of the hygiene hypothesis [14]
and failure in current intervention methods suggest a need to research in new directions
[15,16]. Recent studies on immigrants indicated that environmental changes later in life
alone could lead to allergic diseases for adults who are equipped with immune systems
developed a in relatively traditional lifestyle [17–19]. In several studies of Italian](https://image.slidesharecdn.com/readthearticlesandcomeupwitharesponseto-230531145205-843e3c7d/85/Read-the-articles-and-come-up-with-a-response-to-docx-1-320.jpg)
![populations, immigrants who visited doctors with complaints of allergies had little family
history of atopy [18,19]. Only 16% had a clinical history of allergies before migration. The
time that elapsed between migration and onset of symptoms was 5.3 ± 3.1 years,
http://dx.doi.org/10.1016/j.mehy.2016.05.029 0306-9877/Published by Elsevier Ltd. with
a minimum of 0.5 and a maximum of 7 years. These immigrants were from Asia, Africa,
South America, and Eastern Europe. A study of US immigrant children showed that children
born outside the United States have a lower prevalence in allergic diseases that increases
after residing in the United States for a decade [20]. Hypothesis The combination of these
research results prompted me to propose a specific hygiene hypothesis (SHH) and a
capacity competition theory (CCT) to explain the rising of hay fever. SHH posits that
continuous improvement in oral hygiene practices in modern society is the major cause of
the increase in the prevalence of hay fever and perhaps some other allergic diseases as well
(Fig. 1A). CCT is proposed to explain how reduction of oral infection, one of the results of
modern oral hygiene, leads to development of allergy (Fig. 1B). CCT assumes that bacterial
antigens under chronic oral infections have a much higher concentration than pollens do in
oral-rhino cavities. The dominant bacterial antigens overwhelm the acquired immune
system residing in lymph nodes at the back oral-rhino opening or nearby places, which
limits the chance of immune system to access allergens and to produce B cell clones with
efficient antibodies against allergens. After removing oral infections with persistent modern
oral hygiene practices, reduced bacterial antigen concentration leaves extra antibody-
generating capacity to allergens, with relative concentration becoming higher. The
probability to produce B cell clones with highly efficient antibodies against allergens
increases. The elevated innate immune system under infectious conditions can also clean
allergens faster than that under conditions without infections, which further C. Shunsheng
Han / Medical Hypotheses 93 (2016) 146–149 147 Fig. 1. The specific hygiene hypothesis
and capacity competition theory. (A) Correlation between the number of dental hygienists,
asthma prevalence in the US (cor = 0.96, p 0.01), and reduction in prevalence of
periodontitis suggest a relationship between oral hygiene and allergy. (B) The capacity
competition theory (see text). reduces the competitive edge of allergens (Fig. 1B). For the
same reason, the stimulated innate immunity can likely protect against acute infections
[21]. CCT indicates that the competing bacterial antigens do not have to be from a/multiple
specific species. SHH is different from GHH in the following aspects: 1) it specifies modern
oral hygiene practices as the cause for the high rise of hay fever through the reduction of
oral infection (Fig. 1B). 2) This hypothesis suggests actionable practices to prevent allergy if
proved. 3) CCT indicates the importance of the local immune system in allergy
development, though some bacteria might systematically relieve allergic reaction [22]. 4)
CCT indicates lasting chronic infections have more protection against allergy than acute
infections. Besides the observed negative association between periodontitis, or periodontal
microflora, and respiratory allergic diseases, studies on the dose-response effects of
allergens also support the capacity competition theory [23–26]. A study found there is a
sigmoid dose-response curve for subsequent reactivity [27]. Another study shows that local
pollen counts are positively related to the prevalence of hay fever in children of different
states in the United States [23]. The first evidence for the SHH is a high correlation between](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)