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The hygiene hypothesis: Current perspectives and future therapies


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Abstract: Developed countries have experienced a steady increase in atopic disease and disorders of immune dysregulation since the 1980s. This increase parallels a decrease in infectious diseases within the same time period, while developing countries seem to exhibit the opposite effect, with less immune dysregulation and a higher prevalence of infectious disease. The “hygiene hypothesis”, proposed by Strachan in 1989, aimed to explain this peculiar generational rise in immune dysregulation. However, research over the past 10 years provides evidence connecting the commensal and symbiotic microbes (intestinal microbiota) and parasitic helminths with immune development, expanding the hygiene hypothesis into the “microflora” and “old friends” hypotheses, respectively. There is evidence that parasitic helminths and commensal microbial organisms co-evolved with the human immune system and that these organisms are vital in promoting normal immune development. Current research supports the potential for manipulation of the bacterial intestinal microbiota to treat and even prevent immune dysregulation in the form of atopic disease and other immune-mediated disorders (namely inflammatory bowel disease and type 1 diabetes). Both human and animal model research are crucial in understanding the mechanistic links between these intestinal microbes and helminth parasites, and the human immune system. Pro-, pre-, and synbiotic, as well as treatment with live helminth and excretory/secretory helminth product therapies, are all potential therapeutic options for the treatment and prevention of these diseases. In the future, therapeutics aimed at decreasing the prevalence of inflammatory bowel disease, type 1 diabetes, and atopic disorders will likely involve personalized microbiota and/or helminth treatments used early in life.
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The hygiene hypothesis: current perspectives and
future therapies
Leah T Stiemsma1,2
Lisa A Reynolds3
Stuart E Turvey1,2,4
B Brett Finlay1,3,5
1Department of Microbiology &
Immunology, University of British
Columbia, 2The Child and Family
Research Institute, 3Michael Smith
Laboratories, University of British
Columbia, 4Department of Pediatrics,
University of British Columbia,
5Department of Biochemistry and
Molecular Biology, University of
British Columbia, Vancouver, BC,
Correspondence: B Brett Finlay
Michael Smith Laboratories, 2329 West
Mall, University of British Columbia,
Vancouver, BC, V6T 1Z4, Canada
Email b
Abstract: Developed countries have experienced a steady increase in atopic disease and
disorders of immune dysregulation since the 1980s. This increase parallels a decrease in infec-
tious diseases within the same time period, while developing countries seem to exhibit the
opposite effect, with less immune dysregulation and a higher prevalence of infectious disease.
The “hygiene hypothesis”, proposed by Strachan in 1989, aimed to explain this peculiar genera-
tional rise in immune dysregulation. However, research over the past 10 years provides evidence
connecting the commensal and symbiotic microbes (intestinal microbiota) and parasitic helminths
with immune development, expanding the hygiene hypothesis into the “microflora” and “old
friends” hypotheses, respectively. There is evidence that parasitic helminths and commensal
microbial organisms co-evolved with the human immune system and that these organisms are
vital in promoting normal immune development. Current research supports the potential for
manipulation of the bacterial intestinal microbiota to treat and even prevent immune dysregula-
tion in the form of atopic disease and other immune-mediated disorders (namely inflammatory
bowel disease and type 1 diabetes). Both human and animal model research are crucial in
understanding the mechanistic links between these intestinal microbes and helminth parasites,
and the human immune system. Pro-, pre-, and synbiotic, as well as treatment with live helminth
and excretory/secretory helminth product therapies, are all potential therapeutic options for
the treatment and prevention of these diseases. In the future, therapeutics aimed at decreasing
the prevalence of inflammatory bowel disease, type 1 diabetes, and atopic disorders will likely
involve personalized microbiota and/or helminth treatments used early in life.
Keywords: inflammatory bowel disease, microbiota, helminths, atopic disease, type 1
The Millennial generation (born 1980–1999) displays a marked increase in prevalence of
atopic diseases (asthma, anaphylaxis, allergic rhinitis, food allergy, and atopic dermatitis
[AD]) and immune-mediated disorders (including type 1 diabetes [T1D], and inflamma-
tory bowel disease [IBD]), which have been steadily increasing in developed countries
since the 1980s.1–3 These disorders comprise a unique sector within immune dysregulation
characterized by an irrational immune cell response to a foreign (or in the case of autoim-
munity, a self) antigen which would, under normal circumstances, not occur. The short
developmental timeframe of these diseases (from the 1980s onward, roughly within one
generation) decreases the likelihood that a changing genetic component is significantly
involved. Hence, researchers are assessing the potential effects of environmental factors,
such as diet and antibiotic exposure.4 Furthermore, the increase in immune disorders and
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atopic diseases parallels a decrease in prevalence of infectious
diseases over the same time period, which can be attributed
to increased vaccine and antibiotic treatments, and improved
sanitation standards.4 An in-depth look at the effects of these
“hygienic” environmental factors suggests that lack of expo-
sure to infectious agents may be the culprit for the increase in
immune-mediated and atopic disease prevalence, a concept
most commonly referred to today as the “hygiene hypothesis”.
This review aims to provide readers with the historical and
current perspectives of the hygiene hypothesis and to elabo-
rate on the modern scientific and medical applications of this
theory. We also discuss the increasing evidence connecting the
hygiene hypothesis to the development of atopic disease and
immune-mediated disorders, in addition to discussing future
therapies capitalizing on this knowledge.
A history of “hygiene” in immune
One of the first observations relating infectious agents and
immune dysregulation occurred in Western Nigeria, where
Greenwood noted the low incidence of rheumatoid arthritis
and deduced that this low incidence may be attributed to
immunological disturbance resulting from frequent exposure
to malaria (Figure 1).5 Greenwood et al also observed sup-
pressed spontaneous autoimmune disease, characterized by
delayed Coombs test positivity and reticulocytosis in mice
infected with Plasmodium berghei (a causative agent of
rodent malaria).6 In the late 1970s, a discrepancy between
urbanized and rural environments emerged when Gerrard
et al observed a lower prevalence of allergy in indig-
enous populations in Northern Canada compared to urban
Caucasian populations.7
In 1989, Strachan proposed the hygiene hypothesis
of allergic disease after observing that hay fever was less
common among children with older siblings.8 He reasoned
that children growing up in larger families may experience
increased exposure to microbes in early childhood due to
inevitable unhygienic contact with older siblings or prenatal
exposure from the mother infected by similar unhygienic con-
tact.8 Strachan proposed that this increased microbial exposure
in early life could protect children from developing immune
hypersensitivities later in life.8 Strachan et al supported this
theory by assessing family history, medical records, and
allergy skin prick test results in a cohort of 1 1,765 children and
found that household size was inversely correlated with the
development of hay fever.9 Additional epidemiological studies
supporting the hygiene hypothesis associate a reduction in
allergen sensitization with pet exposure, daycare attendance,
and an increased number of siblings.10,11 Early childhood
infections have also been associated with decreased atopy in
children. A retrospective case-control study showed that atopic
patients exhibited a lower prevalence of Toxoplasma gondii,
Helicobacter pylori, and hepatitis A when compared to non-
atopic controls.12 More recently, single-strand polymorphism
analysis and culture techniques were used to identify microbial
exposures among two cohort studies of European children.13
Gerrard et al observe lower
prevalence of allergy in indigenous
populations in Northern Canada
compared to urban Caucasian
Ege et al show that children
growing up on farms are exposed
to a wider range of microbial
exposures and lower prevalence of
asthma and atopy13
"Old friends" hypothesis
Strachan proposes
the "hygiene
Greenwood observes low incidence
of rheumatoid arthritis in Western
Nigeria where malaria exposure is
Greenwood et al show
suppressed spontaneous
autoimmune disease in New
Zealand mice infected with
Plasmodium berghei
Mosmann et al expose Th1 and Th2
cell subsets14
"Microflora" hypothesis
Strachan et al show inverse
correlation between household size
and the development of hay fever9
Matricardi et al correlate exposure to
childhood infections with reduced risk
of atopy later in life12
19701965 1975 1980 1985 1990 1995 2000 2005 2010 2015
1986 2005
1989 2000
Figure 1 Timeline displaying key ndings leading up to the proposal of the “hygiene hypothesis”, proposal of the “old friends” and “microora” hypotheses, and key
microbiological and immunological ndings in support of these theories.
Abbreviation: Th, T-helper.
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The hygiene hypothesis: a review
In both cohort studies, researchers found that children grow-
ing up on farms in Central Europe encountered a wider
range of microbial exposures and had a lower prevalence of
asthma and atopy than the reference group.13 A closer look
at the immunological mechanisms behind Strachan’s hygiene
hypothesis of allergic disease will enhance the connection
between early life infectious exposures and the development
of immune tolerance.
Immunological support for the
hygiene hypothesis
In 1986, just prior to Strachan’s proposal of the hygiene
hypothesis, Mosmann et al described the T-helper (Th)1
and Th2 cell subtypes, providing an immunological basis
for this otherwise observational theory.14 They discovered
that fully differentiated murine CD4+ T-cells secreted two
separate cytokine profiles (Th1: IFN-γ; Th2: IL-4) and that
the different cytokines produced two different inflammatory
responses.14 Th2 cells play a primary role in the allergen
sensitization process.15 Infection with viruses and intracel-
lular bacteria generally stimulates Th1 immune responses,
which suppress Th2 cytokine activity through the induction
of IFN-γ.16,17 Consequently, the concept of a Th1 versus Th2
balance arose whereby a Th1-dominated immune phenotype
(brought on by early life microbial exposures) was thought to
inhibit atopic immunopathology. Research related to helminth
parasites stimulated the need for further explanation beyond
this binary view, as these organisms paradoxically induce Th2
responses while suppressing allergic reactivity.18 T-cell plas-
ticity and additional T-cell phenotypes (eg, Th17, Th9, and T
regulatory [Treg] cells) have more recently been implicated
in the control of hypersensitivity disorders.19,20 Additionally,
many innate cytokines (eg, IL-25, IL-33, and thymic stromal
lymphopoietin) and cell types (eg, eosinophils, basophils,
mast cells, and epithelial cells) also play significant roles
in hypersensitivity disease.21 It is now understood that the
process of allergen presentation and consequent initiation of
the allergic response involves both the innate and adaptive
branches of the immune system. Thus, the immunological
foundation of the hygiene hypothesis has been modified
to consider the balance between many adaptive and innate
immune cell populations. Further, extending the hygiene
hypothesis to account for the role of various parasites (ie,
intestinal helminths) and microbiota compositional shifts
provides insight into how early life environmental exposures
shape the human immune system. These extensions are
known as the “old friends” and “microflora” hypotheses,
The old friends hypothesis: parasitic
The old friends hypothesis, proposed by Rook et al, notes the
co-evolution of microorganisms and macroorganisms, such
as parasitic helminths, with the development of the human
immune system.22 Similar to the hygiene hypothesis, it sug-
gests that these organisms are required for normal immune
system development.22,24 For example, a study in Gabon found
that school children diagnosed with schistosomiasis, caused
by infection with helminth parasites from the Schistosoma
genus, exhibited lower levels of allergen reactivity than their
uninfected classmates.25 Since then, additional studies have
highlighted this seemingly protective effect of helminths in
many mouse models of allergic diseases.26–28 A live Helig-
mosomoides polygyrus (H. polygyrus; a murine helminth
parasite) infection reduces lung cellular influx, eosinophilia,
allergen recall responses, bronchial hyperreactivity, and
histopathology in ovalbumin (OVA)- and house dust mite
(HDM)-driven mouse models of asthma.26,27 Additionally,
Schistosoma mansoni infection has been shown to be protec-
tive in an experimental mouse model of fatal anaphylaxis,
probably due to the induction of a regulatory IL-10-producing
B cell population.28 There is also experimental animal model
evidence suggesting the ability of helminths to ameliorate
symptoms of T1D and colitis (Table 1). Non-obese diabetic
(NOD) mice spontaneously develop T1D, which is signifi-
cantly inhibited when they are infected with H. polygyrus or
the filarial nematode Litomosoides sigmodontis.29–32 Helm-
inth infection has also been shown to reduce inflammation
in murine models of colitis.33 Studies such as these support
live helminth infection as a potential therapy to combat
hypersensitivity and other immune disorders; however,
referring back to Strachan’s original hygiene hypothesis, the
question of whether live helminth infection in early life is
an effective treatment to protect against the development of
these disorders is still unclear. Future therapeutics to treat
immune dysregulation may involve the excretory/secretory
(ES) products of these parasites and/or the intestinal micro-
biota (Tables 1 and 2).
The microora hypothesis
The microflora hypothesis is another modern extension
of the hygiene hypothesis, which suggests that early life
perturbations (driven by factors such as antibiotic use,
infection, or diet) to the bacteria residing in the human
intestine (the intestinal microbiota) disrupt the normal
microbiota-mediated mechanisms promoting immunological
tolerance and consequently bias the immune system toward
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Stiemsma et al
a state that promotes hypersensitivity disorders.23 Current
research focuses on the mechanisms by which the intestinal
microbiota influences immune system development and
homeostasis, and potentially confers protection against
immune dysregulation.35–50
A mutualistic bond
The human intestine is a densely populated zone in the body
harboring a diverse microbial community of 500–1,000
different bacterial species among other microbes such as
archaea, eukarya, and viruses.34 The most striking illustration
Table 1 Helminth-based therapeutic studies
Organism Disease Treatment Description of effects Reference
Mouse OVA-alum and Der p1-alum
(HDM allergen)-driven models
of allergic airway inammation
H. polygyrus larvae H. polygyrus-infected mice had reduced airway cellular
inltrates (including reduced
eosinophilia and neutrophilia), reduced lung type 2
cytokines, and reduced lung histopathology
Mouse OVA-alum-driven model of
allergic airway inammation
H. polygyrus larvae H. polygyrus-infected mice had reduced airway
eosinophilia, reduced bronchial hyperreactivity,
and reduced allergen-specic Th2 responses
Mouse OVA-alum-driven model of
allergic airway inammation
HES HES given at allergen sensitization or challenge reduced
airway cellular inltrates and lung eosinophilia
Mouse Alternaria alternata-driven model
of allergic airway inammation
HES HES blocked lung eosinophilia, IL-33 release, and innate
lymphoid cell type 2 cytokine production
Mouse TNBS-induced colitis Schistosoma mansoni- or
Ancylostoma caninum-soluble
Intraperitoneal helminth protein administration
reduced macroscopic inammation scores and reduced
proinammatory cytokine release (IL-17 and IFN-γ)
Mouse Systemic–fatal anaphylaxis S. mansoni cercariae S. mansoni-infected mice were protected from anaphylaxis 28
Mouse T1D (spontaneous
development in NOD mice)
H. polygyrus larvae H. polygyrus infection delayed disease onset 29,30
Mouse T1D (spontaneous
development in NOD mice)
Litomosoides sigmodontis
L. sigmodontis infection prevented disease onset 31,32
Mouse OVA-alum-driven model of
allergic airway inammation and
DSS-induced colitis
Recombinant cysteine
protease inhibitor (cystatin)
of Acanthocheilonema viteae
A. viteae cystatin treatment during OVA sensitization or
prior to OVA challenge reduced airway BALF cell counts,
airway eosinophilia, bronchial hyperreactivity, and lung
histopathology. In the DSS–colitis model, intrarectal
A. viteae cystatin resulted in signicant reductions in
colonic inammatory index compared to control animals
Mouse DSS-induced colitis Ancylostoma ceylanicum crude
extract or ES products
Helminth-product-treated mice had reduced clinical and
colonic microscopic inammation scores compared to
control mice
Mouse T1D (spontaneous
development in NOD mice)
S. mansoni infection, or
treatment with soluble
worm or egg extracts
Exposure to worm or egg extract prevented disease
onset if given before 4 weeks of age
Mouse DSS-induced colitis ES products from A. caninum Exposure to helminth products reduced intestinal
proinammatory cytokine expression
Humans CD and UC Live Trichuris suis eggs Three out of four CD patients entered remission; fourth
patient had a reduction in symptoms. UC patients had a
reduction in clinical colitis activity index
Humans CD Live T. suis ova 79.3% of patients had a reduction in CD activity index or
Humans CD Live T. suis ova All doses tested were well tolerated and did not result in
treatment-related side effects. Efcacy of a reduction in
disease severity not assessed
Humans UC Live T. suis ova A reduction in disease activity was seen in helminth-
infected patients compared to placebo group, although
this did not reach statistical signicance
Humans CD Necator americanus larvae IBD questionnaire results were improved, and cumulative
CD activity index scores were decreased
Humans Allergic rhinoconjunctivitis N. americanus larvae Infection well tolerated; no signicant differences in
allergic symptoms between groups given placebo or
N. americanus larvae
Abbreviations: OVA, ovalbumin; alum, potassium aluminum sulfate; ES, excretory/secretory; HES, H. polygyrus excretory/secretory product; HDM, house dust mite; BALF,
bronchoalveolar lavage uid; IL, interleukin; IFN, interferon; DSS, dextran sulfate sodium; TNBS, 2,4,6-trinitrobenzene sulfonic acid; T1D, type 1 diabetes; NOD, non-obese
diabetic; CD, Crohn’s disease; UC, ulcerative colitis; IBD, inammatory bowel disease; Th, T-helper.
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The hygiene hypothesis: a review
Table 2 Microbiota-based therapeutic studies
Organism Disease Treatment Description of effects Reference
Rat HLA-B27 transgenic rats
(colitis model)
Inulin and FOS Decreased severity of intestinal inammation (FOS treatment
resulted in less disease severity than inulin)
Rat T1D (BB-DP rat model) Lactobacillus johnsonii Administration of L. johnsonii isolated from BB-diabetes-
resistant rats resulted in decreased incidence of T1D and
reduced levels of IFNγ and inducible nitric oxide synthase in
BB-diabetes-prone rats
Mouse T1D (spontaneous
development in NOD mice)
VSL#3 (probiotic compound:
containing Bidobacteria,
Lactobacilli, and Streptococci
Reduced insulitis and decreased beta cell destruction 124
Mouse HDM-driven model of
allergic airway inammation
Diet supplemented with 30%
Increased concentrations of SCFAs and decreased allergic
inammation in the lungs of murine HDM model of airway
Mouse OVA-alum-driven model of
airway inammation
scGOS/lcFOS, and scGOS/
lcFOS + pAOS
Suppressed airway inammation and hyperresponsiveness 134
Mouse CMA model scGOS/lcFOS + Bidobacterium
Increased serum galectin-9 and galectin-9 expression by
intestinal epithelial cells. Also, reduced acute allergic skin
reaction and mast cell degranulation
Rat T1D (STZ model) Lactobacillus gasseri engineered
to secrete GLP-1(1-37)
GLP-1(1-37) secreted by L. gasseri stimulated rat intestinal
epithelial cells to become glucose-responsive insulin-secreting
cells. Resulted in increased insulin levels and glucose tolerance
in diabetic rats
Mouse IBD (IL-10-decient colitis
Lactobacillus plantarum Prior to SPF ora exposure, treatment of GF IL-10 decient
mice with L. plantarum and continued L. plantarum therapy
attenuated colitis
Mouse IBD (DSS-induced colitis
Lactobacillus rhamnosus,
L. plantarum, Lactobacillus casei,
Lactobacillus lactis, Bidobacterium
lactis, Bidobacterium bidum,
Bidobacterium adolescentis,
Bidobacterium infantis
Mice receiving the probiotic mixture for 7 days prior to DSS
induction of colitis showed reduced mucosal inammation
and damage compared to controls that did not receive the
Mouse IBD (IL-10-decient and
DSS-induced colitis models)
Lactobacillus salivarius Oral treatment with L. salivarius did not attenuate colitis
symptoms in IL-10-decient or DSS-treated mice
Mouse OVA-alum-driven model of
airway inammation
Bidobacterium longum Protected against airway inammation in OVA-sensitized mice
and blocked induction of OVA-specic IgE
Mouse OVA-alum-driven model of
airway inammation
Lactobacillus reuteri, L. salivarius L. reuteri decreased airway hyperresponsiveness. L. salivarius
had no effect
Human Eczema Lactobacillus rhamnosus and
L. reuteri
After 6 weeks of probiotic therapy, 56% of children (aged
1–13 years) experienced improved eczema, while only 15%
of placebo controls reported improved symptoms
Human UC Enema solution containing
L. reuteri
Improved mucosal inammation and decreased inammatory
cytokines in children with UC
Human AR L. johnsonii + levocetirizine Compared with patients receiving levocetirizine only,
L. johnsonii + levocetirizine improved AR symptoms including
increased IFNγ and IL-10 and decreased IL-4 concentrations,
and improved FVC and FEV1 spirometry measurements in a
24-week, two-phase crossover treatment program
Human Pollen allergy B. longum Reduced ocular symptom scores during exposure to Japanese
cedar pollen
Human Peanut allergy L. rhamnosus + peanut oral
Subjects (82.1%) receiving combination peanut oral
immunotherapy + L. rhamnosus achieved possible sustained
unresponsiveness to peanut 2–5 weeks after discontinuation
of treatment compared to only 3.6% receiving placebo
Human AD, recurrent wheeze,
allergic urticaria
scGOS + lcFOS Prebiotic group had signicantly lower incidences of allergic
Human AD scGOS/lcFOS + B. breve
Increased galectin-9 expression and reduced AD in infants
with IgE-mediated eczema 12 weeks posttreatment
Human Asthma scGOS/lcFOS + B. breve
Decreased prevalence of frequent wheezing and usage of
asthma medications in children with AD after 1 year follow-
up evaluation
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Stiemsma et al
of the importance of the intestinal microbiota for mammalian
immune development comes from studies conducted in germ-
free (GF) mice, in which the lack of a microbiota results in
reduced Peyer’s patches, smaller germinal centers and fewer
plasma cells, and increased susceptibility to pathogen invasion
when compared to conventionally raised mice.35–38 Although
GF murine models are valuable in mechanistic studies, they
do have many caveats.39 To fully elucidate the underlying
mechanisms driving the relationship of the gut microbiota
with atopic disease development, many different murine
models, including GF, gnotobiotic, and antibiotic-treated
models, along with models supplemented with specific bac-
terial species, should be used. In addition, murine systems
with a reconstituted human immune system would be even
more valuable.
Specific bacterial species within the microbiota have
been shown to induce expression of antimicrobial peptides
(eg, Bacteroides thetaiotaomicron induction of regenerat-
ing islet-derived 3 γ expression by Paneth cells) and mucin
production, which ultimately confers protection against
pathogen invasion, and combined with regular stimulation
of pattern recognition receptors, contributes to intestinal
homeostasis.40–42 The presence of the microbiota can
stimulate CD4+ T-cell proliferation, Th17 cell differentia-
tion through the induction of IL-1β, and accumulation of
colonic Tregs.43–45 The intestinal microbiota also metabo-
lizes food components that are indigestible by mammalian
enzymes, such as human milk oligosaccharides (HMOs)
and dietary fiber.46,47 This produces short-chain fatty acids
(SCFAs), which are essential energy sources for many host
tissues and prominent immune modulators.48–50 There are
many factors that likely contribute to the development of
immune dysregulation: perturbations to the composition of
the intestinal microbiota, caused by environmental factors
such as antibiotic exposure, birth mode, or diet, are one
potential explanation linking early life hygiene with the
development of atopic and immune-mediated disorders
(Figure 2).
The intestinal microbiota in atopic
disease: human studies
A longitudinal study comparing the early life intestinal micro-
biota compositions of school-age asthmatic and non-asthmatic
children showed that significant decreases in overall gut micro-
bial diversity at 1 week and 1 month of age were correlated
with asthma development at school age.51 Additionally, a recent
characterization of the gut microbiota of 166 Canadian infants
revealed an increased Enterobacteriaceae/Bacteroidaceae ratio
in children sensitized to food allergens at 3 months and 1 year
of age compared to non-sensitized children.52 Also, lower gut
microbial richness was observed at 3 months of age only.52
Studies such as these suggest that therapeutic microbial inter-
vention early in human life may be favorable, and highlight the
need for animal studies in which experimentation to confirm
causality is possible.
Many human studies lend support for the hygiene and
microflora hypotheses by assessing the impact of early
life environmental factors known to disturb the intestinal
microbiota on atopic disease development later in life. For
example, antibiotic usage in the first 2 years of life has been
associated with the development of asthma at 7.5 years of
age in a dose-dependent manner.53 Additionally, antibiotic
usage was reported to precede the manifestation of wheeze
in the first 2 years of life in a questionnaire-based analysis
of the KOALA (acronym in Dutch for “Child, parents and
health: lifestyle and genetic constitution”) Birth Cohort
Table 2 (Continued)
Disease Treatment Description of effects Reference
Human Asthma, eczema, allergic
L. reuteri Oral supplementation with L. reuteri ATCC 55730 in the
last month of gestation through the rst year of life is not
associated with lower prevalence of allergic disease at
7 years of age
Human UC Escherichia coli Nissle
Mutaor® is as effective at preventing relapses as the
established mesalazine therapy in patients with UC. Patients
(36.4%) receiving Mutaor for 12 months experienced
relapses compared to 33.9% in the mesalazine group
Human UC Inulin-oligofructose
(Synergy® 1) + B. longum
Reduced chronic inammatory markers of UC (TNFα and
Abbreviations: HLA, human leukocyte antigen; FOS, fructooligosaccharide; T1D, type 1 diabetes; BB-DP, bio-breeding diabetes-prone; NOD, non-obese diabetic;
IFN, interferon; IL, interleukin; OVA, ovalbumin; alum, potassium aluminum sulfate; SCFA, short-chain fatty acid; DSS, dextran sulfate sodium; scGOS, short-chain
galactooligosaccharide; lcFOS, long-chain fructooligosaccharide; pAOS, pectin-derived acidic oligosaccharide; CMA, cow’s milk allergy; GLP, glucagon-like peptide; UC,
ulcerative colitis; STZ, streptozotocin; SPF, specic pathogen-free; GF, germ-free; AD, atopic dermatitis; AR, allergic rhinitis; HDM, house dust mite; IBD, inammatory bowel
disease; FVC, forced expiratory vital capacity; FEV1, forced expiratory volume in 1 second; ATCC, American Type Culture Collection; Ig, immunoglobulin.
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The hygiene hypothesis: a review
Study in the Netherlands.54 Birth by Caesarean sec-
tion was associated with lower total microbial diversity,
delayed colonization with Bacteroidetes, and decreased
Th1 responses in the first 2 years of life.55 Breastfeeding
promotes colonization with commensal microbes such as
Bifidobacteria spp. and provides the intestinal microbiota
with necessary nutrients in the form of HMOs.46,56 Specific
HMOs, short-chain galactooligosaccharides (GOSs) and
long-chain fructooligosaccharides (FOSs), administered
in the first 6 months of life have been shown to reduce
the cumulative incidences of AD, recurrent wheezing,
and allergic urticaria.57 In line with Strachan’s original
proposal, one study found that an increased number of
older siblings was associated with decreased colonization
with Clostridium difficile and Clostridium cluster 1, and
a decreased risk of developing AD.58 Correlative human
studies such as these shed light on the environmental fac-
tors that may be associated with atopic disease through
manipulation of the intestinal microbiota; however,
research regarding factors such as antibiotic exposure,
breastfeeding, and birth mode remains controversial, and
there are studies that suggest these factors have little or
no effect on atopic disease development.59–64 Additional
longitudinal human studies are necessary to determine
which early life factors are most influential in promoting
the intestinal dysbiosis associated with the development
of immune hypersensitivities, and animal model research
is a crucial complementary approach to elucidate the
mechanisms behind these associations.
The intestinal microbiota in atopic disease:
mouse models
Murine model studies mechanistically support a link between
the intestinal microbiota and atopic disorders through the
experimental manipulation of microbiota compositions. In
an OVA-driven model of asthma, Forsythe et al show that
oral supplementation with live Lactobacillus reuteri reduced
airway hyperresponsiveness as well as levels of TNFalpha,
monocyte chemotactic protein 1, IL-5, and IL-13 in the
bronchoalveolar lavage fluid (BALF), while treatment with
Lactobacillus salivarius had no effect.65 Intranasal supple-
mentation of mice, polysensitized to birch and grass pollen
allergens, with Bifidobacterium longum and Lactobacillus
paracasei at the time of sensitization resulted in reduced
IgE-dependent basophil degranulation in response to allergen
challenge.66 Only B. longum displayed protective effects when
mice were supplemented prior to allergen sensitization.66
Additionally, oral supplementation of mice with B. longum
protected against airway inflammation, increased Peyer’s
patch and splenic Tregs, and blocked serum IgE induction in
OVA-sensitized animals.67
More recent research focuses on the earliest time point at
which gut microbial intervention must occur to prevent the
onset of hypersensitivity disease. In an OVA-driven model of
allergic inflammation, neonatal (but not adult) exposure of
previously GF mice to a conventional microbiota reduced the
severity of allergic inflammation characterized by decreased
accumulation of invariant natural killer (NK) T-cells to the
lung and reduced serum IgE levels and eosinophil frequencies
Early life exposures
• Diet (breast milk vs
• Birth mode (vaginal
vs Caesarean section)
• Infection
• Antibiotic exposure
• Household size and
number of siblings
Intestinal homeostasis
Immune tolerance
Immune dysregulation
(atopic disease, T1D, and
• Furred pet exposure
Figure 2 A depiction of the early life environmental exposures differentially associated with promoting a healthy intestinal microbiota, which results in intestinal homeostasis
and immune tolerance, and a dysbiotic (unhealthy) intestinal microbiota, which may induce the development of immune dysregulation.
Abbreviations: vs, versus; T1D, type 1 diabetes; IBD, inammatory bowel disease.
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Stiemsma et al
in the BALF.68 Arnold et al show in OVA- and HDM-driven
mouse models of allergic inflammation that oral infection
of neonatal mice with H. pylori prior to OVA or HDM chal-
lenge resulted in the significant reduction of eosinophils in
the BALF, and a decrease in IL-5 and IL-13 cytokine levels
when compared to uninfected mice and infected adult mice.69
Russell et al found that perinatal vancomycin treatment of
OVA-challenged mice alters gut microbial composition
and exacerbates asthma-related immune responses, which
may be driven by increased serum IgE levels and reduced
Treg populations.70 Interestingly, perinatal treatment with
streptomycin did not result in exacerbated disease after OVA
challenge, but perinatally streptomycin-treated mice showed
exaggerated lung inflammation when compared to untreated
or vancomycin-treated mice in a Th1/Th17-driven model of
hypersensitivity pneumonitis.70,71 This highlights the ability
of altered microbiota compositions to differentially control
disease severity depending on the immunological basis of
the disease.71 Additional studies including human subjects
and supporting mechanistic animal models are necessary
to provide a holistic view of the role of the intestinal micro-
biota in atopic disease. Currently, there is also increasing
evidence supporting a role of the intestinal microbiota and
early life environmental exposures in other immune-mediated
disorders.72 For the purpose of this review, we focus on IBD
and T1D.
The hygiene and microora
hypotheses and immune-
mediated disorders
IBD is an inflammatory disorder of the gastrointestinal (GI)
tract encompassing Crohn’s disease (CD) and ulcerative
colitis (UC), both of which are highest in prevalence in North
America and Europe.73 The presence of intestinal bacteria
appears to be required for the development of experimental
colitis, while the composition influences the severity of IBD.
GF IL-10-deficient mice show no evidence of experimental
colitis, while IL-10-deficient mice housed under specific
pathogen-free (SPF) conditions spontaneously develop
the disease.74 Additionally, antibiotics have been shown to
attenuate the symptoms of experimental colitis.75–77 Exposure
of SPF IL-10-deficient mice to antibiotics displays differ-
ential and localized roles of specific bacteria in mediating
experimental colitis.77 For example, treatment of SPF IL-10-
deficient mice with vancomycin–imipenem and metronida-
zole eliminated anaerobic bacteria and reduced colonic injury,
while ciprofloxacin and vancomycin–imipenem decreased
cecal inflammation and reduced the prevalence of Escheri-
chia coli and Enterococcus faecalis.77
Some human studies suggest that early life antibiotic
exposure is associated with IBD.78–80 This discrepancy is
likely because antibiotics in murine IBD experiments are
typically given as treatment after disease onset, whereas
human studies are often retrospective and assess the effects
of antibiotic exposure prior to disease onset. In a nested case-
control study, children diagnosed with IBD at approximately
8 years of age were 2.9 times more likely to have received
antibiotics in the first year of life.80 Additionally, antibiotic
exposure in the first 3 months of life was associated with
childhood CD.79 Conversely, antibiotic combination therapy
has been shown to be effective in treating UC in humans.81
Thus, effects after antibiotic exposure in humans are likely
disease specific and/or dependent on when antibiotics are
administered (ie, before or after disease onset).
Diet may also play an important role in IBD. Maternal
secretory IgA (a component of breast milk) has been shown
to alter the intestinal microbiota composition and the expres-
sion of genes associated with intestinal inflammation.82
Additionally, a systematic review negatively correlated breast
milk exposure with the development of early onset IBD in
humans, suggesting a protective effect of breastfeeding on
IBD development.83
Altogether, these results suggest that IBD is driven by the
composition of the intestinal microbiota, which is strongly
influenced by early life environmental factors. Early life diet
(breastfeeding) is likely protective against IBD development,
while effects of antibiotic exposure are more complicated.
If antibiotics are given in early life, they may result in an
intestinal microbiota that promotes IBD development.79,80
However, after disease onset, antibiotics alleviate disease
severity by shifting the prevalence of specific microbes that
may be promoting the disease.75–77,79,81 Regardless, factors
related to early life hygiene are involved in IBD development,
and there is also evidence that the hygiene and microflora
hypotheses are applicable to immune-mediated disorders not
associated with the GI tract, such as T1D.84–96
The prevalence of childhood T1D, an autoimmune disorder
resulting from T-cell mediated destruction of beta cells in the
pancreas, is steadily increasing worldwide, and developed
countries such as Canada and the UK exhibit the highest
incidences of the disease.84,85 Epidemiological evidence sup-
ports a link between environmental factors associated with
ImmunoTargets and Therapy 2015:4 submit your manuscript |
The hygiene hypothesis: a review
the hygiene hypothesis and the onset of T1D. Having older
siblings is negatively correlated with childhood onset T1D,
suggesting a protective effect.86 Furred pet exposure seems
to also play a role, as one study found in a birth cohort of
3,000 children: children exposed to an indoor dog were less
likely to develop T1D than unexposed children.87 Breast-
feeding has been associated with protection from T1D, and
children born by Caesarean section exhibit a higher risk of
T1D than children born vaginally.88–90
Lending support for the microflora hypothesis, a recent
study compared the gut microbial compositions of children
with T1D and healthy children and concluded that children
with T1D showed a significant increase in Bacteroides spp.,
which was later reduced to that of controls after insulin
treatment for 2 years.91 Oral administration of Lactobacillus
johnsonii isolated from bio-breeding (BB) diabetes-resistant
rats was shown to delay the onset of T1D in BB-diabetes
prone rats.92 Additionally, MyD88-deficient NOD mice
are protected from disease onset in SPF environments,
and segmented filamentous bacteria have been reported to
protect female NOD mice from disease development.93,94
Additionally, antibiotic therapy in mice has been shown to
protect against virus-induced T1D through the alteration of
intestinal microbiota composition.95 However, in humans the
contribution of antibiotics to T1D development is currently
unclear, as a population-based human cohort study found
no association between T1D and antibiotic exposure in the
first 8 years of life.96 Thus, similar to atopic disease and IBD,
early life factors common to industrialized countries such
as birth mode, diet, and antibiotic exposure seem to play a
role in T1D development. However, additional mechanistic
research is needed before significant conclusions regarding the
gut microbial composition and immunological consequences
can be made. The use of appropriate animal models will be
critical in continuing to determine whether the relationship
between microbiota composition and immune dysregulation
is causal, or an effect of a dysregulated immune environment.
Regardless, research related to the hygiene, old friends, and
microflora hypotheses supports early life intervention as
the primary therapeutic component for averting immune
dysregulation in the form of atopic and immune-mediated
Future therapeutics
Future therapeutic options to prevent the development of
immune dysregulation will likely involve the millions of
micro- and macroorganisms living commensally or symbi-
otically (microbiota), or even parasitically (helminths) in the
human body. In this section, we discuss potential helminth-
based (Table 1) and microbiota-based therapies (Table 2) in
the prevention of these disorders.
Helminth-based therapies
Clinical trials to date have focused on the use of live helminth
infection as an ameliorative, rather than preventative, strategy
due to the potential for diminished vaccine responsiveness in
mice and humans infected with helminths early in life.97–101
The majority of early phase clinical trials to determine the
safety and efficacy of live helminth infection have been con-
ducted in CD and UC patients.102 Initial clinical trials using
ova from the porcine whipworm, Trichuris suis, or larvae
from the human hookworm, Necator americanus, have not yet
found any cause for major safety concerns in IBD or asthma
patients.103–107 T. suis ova administration seemed to reduce
intestinal inflammation in a small number of CD and UC
patients, and administration of N. americanus larvae to CD
patients resulted in a nonsignificant improvement in intestinal
inflammation scores.104–108 These initial clinical trials were
promising, although follow-up studies with the inclusion of
placebo control groups show mixed results.102,107,108
Live helminth parasites release a suite of ES immu-
nomodulatory products that likely mediate many of their
suppressive effects in models of allergic disease and experi-
mental colitis.109 In mice exposed to both OVA- and Alter-
naria alternata-driven asthma models, administration of ES
material from the murine intestinal nematode, H. polygyrus
(HES), was sufficient to suppress lung eosinophilia and
histopathology in response to antigen challenge.110,111 HES
appears to suppress lung inflammation when given at the
point of antigen sensitization and antigen challenge, making
it a promising therapeutic candidate.110 Soluble products from
several different helminth parasites have also been shown
to reduce measures of disease severity in murine models of
trinitrobenzene sulfonic acid-induced and dextran sulfate
sodium-induced colitis and T1D.112–116 Administration of
helminth ES products rather than live helminths has not yet
begun in human patients, but evidence from murine models
suggests that this is a promising approach for future clinical
Researchers are beginning to elucidate the mechanisms
that mediate the potent immunoregulatory effects of these hel-
minth products. ES products from N. americanus mediate the
rapid proteolysis of eotaxin, an eosinophil chemoattractant,
and HES can stimulate the induction of Tregs through a TGF-
β-dependent pathway.117,118 Whether the administration of
helminth products modifies the composition of the intestinal
ImmunoTargets and Therapy 2015:4
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Stiemsma et al
microbiota is not yet reported. However, infection of mice
with live helminth parasites results in a marked disruption of
intestinal microbiota composition, suggesting that the immu-
nosuppressive effects following helminth infection could be
due to an indirect modulation of the microbiota.119–121 The
relative contribution of the microbiota or helminth-secreted
products in ameliorating immune dysregulation remains to
be determined. If microbiota compositional shifts following
helminth infection are shown to have a direct role in disease
modulation, future probiotic administration to drive the
microbiota composition toward that seen during helminth
infection may be a novel therapeutic approach.
Microbiota-based therapies
Probiotics are live bacteria which, when administered, are
beneficial to host health. Animal model research using
probiotics shows their ability to ameliorate symptoms in
atopic disease, IBD, and T1D.66,92,119,122–125 Additionally, pro-
biotic administration in humans has been shown to protect
against allergic rhinitis, peanut allergy, AD, and UC.124,126–129
However, research thus far reveals many gaps in probiotic
therapy, likely due to individualized disease phenotypes that
may or may not be linked to the specific microbial species
tested.130–132 Consequently, prebiotic and synbiotic therapeu-
tics are also being explored.
Prebiotics are chemicals or food components (eg, inu-
lin, pectin, GOSs, and FOSs), which are indigestible by
pancreatic and intestinal enzymes, but are important in the
growth and proliferation of intestinal microbiota.133 Prebiotic
substances can induce the production of SCFAs by intestinal
microbes, which have been shown to promote effector (Th1
and Th17) and anti-inflammatory IL-10-producing FoxP3+
and non-FoxP3+ T-cell differentiation.48,49 As such, they con-
tinue to be a promising microbe-based therapeutic option to
modulate intestinal immune responses. Supplementation of
mice with a mixture of short-chain GOS, long-chain GOS,
and pectin-derived acidic oligosaccharides prior to OVA
challenge suppressed airway inflammation and hyperrespon-
siveness compared to controls.134 Additionally, Trompette
et al show that a high-fiber diet (diet supplemented with
30% pectin) metabolized by the gut microbiota increases
the concentrations of circulating SCFAs and decreases aller-
gic inflammation in the lungs of an HDM-driven model of
allergic inflammation.47 In humans, prebiotic oligosaccharide
formula supplementation in the first 6 months of life has been
associated with decreased incidences of allergic manifesta-
tions until 2 years of age, supporting early life intervention
in humans.57 Additionally, prebiotics have been implicated
in protection from IBD development. Human leukocyte
antigen-B27 transgenic (HLA-B27, TG) rats supplemented
with FOS and inulin prior to disease onset showed decreased
intestinal inflammation compared to untreated rats; however,
FOS-treated rats compared to inulin-treated rats showed less
intestinal inflammation, suggesting FOS as a more effective
prebiotic treatment for spontaneous colitis.135 Conversely,
FOS was not an effective treatment for CD, as patients
receiving the treatment after 4 weeks exhibited higher GI
symptoms compared to the placebo group, despite the
reduced IL-6 and increased IL-10 production from lamina
propria dendritic cells.136
Synbiotic therapies involve supplementation with both
pre- and probiotics. In a murine model for cow’s milk allergy,
mice fed the synbiotic mixture (GOS, FOS, and Bifidobacte-
rium breve M-16V) showed increased galectin-9 expression
by intestinal epithelial cells, which correlated with reduced
acute skin reaction and mast cell degranulation.137 Similar
results were measured in humans fed the synbiotic mixture,
suggesting a mechanism by which this therapy may be
effective in protecting against AD in humans.137 Conversely,
a clinical trial using a similar synbiotic mixture, Immuno-
fortis®, found no difference in AD severity in the synbiotic
group versus the placebo group.138 However, this research
group did later find in infants with AD that supplementation
with this mixture for 12 weeks correlated with decreased
prevalence of wheezing and asthma medication usage after
1 year.139 Synbiotics are also potential therapeutics for IBD.
In a controlled pilot trial involving 18 patients with active
UC, short-term synbiotic therapy combining B. longum and
inulin-oligofructose significantly reduced chronic inflamma-
tory biomarkers of the disease, including decreased TNFα
and IL-1α levels.140
The effects of early life factors such as diet and antibiotic
exposure discussed throughout this review suggest that the
application of live helmiths/helminth ES products, and pro-,
pre-, and synbiotics prior to disease onset may be key in
averting disease development, because interventions occur-
ring later in life or after disease onset may be ineffective after
the neonatal immune developmental window has closed. The
timing of this developmental window could be driven by
epigenetic alterations to specific, microbially regulated fac-
tors, such as the CXCL16 gene described by Olszak et al.68
In previously GF mice colonized neonatally with a conven-
tional microbiota, the presence of a conventional microbiota
decreased hypermethylation of CXCL16, which consequently
decreased accumulation of invariant NK T-cells in the colon
(this did not occur in previously GF mice colonized until
ImmunoTargets and Therapy 2015:4 submit your manuscript |
The hygiene hypothesis: a review
they reached adulthood). This suggests that microbe-based
therapeutics aimed at protecting against hyperinflammatory
diseases are age-sensitive.67 Additionally, the incongruity of
current research highlights the need for future microbiota-
based treatments that are constructed as individualized thera-
peutics specific to the disease phenotype and microbiota of
the affected patient.
The progression of research since Strachan’s 1989 proposal
of the hygiene hypothesis exemplifies the scientific method
in health research, progressing from observational theory
to experimental therapy. The hygiene hypothesis has been
expanded today to include commensal and symbiotic intes-
tinal microbes, which are profoundly involved in human
immune development, and parasitic helminths, which are
also strong therapeutic candidates to protect against immune
dysregulation. More research addressing the early life “critical
window” for microbiota intervention, currently being assessed
in mice for hypersensitivity diseases, is needed if researchers
hope to use these therapeutics to prevent immune dysregulation
in humans.68–71 Children undergo large shifts in their intestinal
microbiota compositions throughout the first few months of
life; thus, it may be possible in the near future to shift the gut
microbial composition using pro-, pre-, and synbiotics toward
a microbiota that promotes immune tolerance.72
LT Stiemsma is supported by the University of British
Columbia Four-Year Fellowship. SET holds the Aubrey
J Tingle Professorship in Pediatric Immunology and is a
clinical scholar of the Michael Smith Foundation for Health
Research. Work in the Finlay and Turvey labs is supported by
a Canadian Institutes of Health Research (CIHR) Emerging
Team Grant in partnership with Genome BC and AllerGen
NCE, the Allergy, Genes and Environment Network.
The authors report no conflicts of interest in this work.
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The hygiene hypothesis: a review
... To counterbalance this effect, different interventions have been tested to improve microbial diversity and reduce the risk of inflammatory disorders. Typically, studies have focused on probiotics, prebiotics, postbiotics and fecal transplants, and while, for instance, in the treatment of Clostridium difficile infection fecal transplantation treatment has proven successful [26], often attempts to address dysbiosis and immune disorders have shown mixed results [27][28][29][30][31][32]. Most methods rely on one or a few strains of bacteria while little attention has been given to exposure to natural microbial biodiversity as an immunomodulatory and therapeutic method [33]. ...
... To test this, immunomodulatory interventions to recapitulate natural microbial diversity in laboratory conditions without confounding factors are needed. In contrast to many previous studies and therapeutic interventions, which have focused on recapitulating existing microbiome and interventions using a single or a few microbial strains [27][28][29][30][31][32], our group has shown potentially beneficial immunological effects in human microbiota interventions using highly diverse intervention materials [34][35][36][37][38]. To dissect the molecular mechanisms behind these observed findings, animal models and the comprehensive immunological studies of different immunologically active organs and cells are needed. ...
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Background . Lack of exposure to the natural microbial diversity of the environment has been linked to dysregulation of the immune system and numerous noncommunicable diseases, such as allergies and autoimmune disorders. Our previous studies suggest that contact with soil material, rich in naturally occurring microbes, could have a beneficial immunoregulatory impact on the immune system in mice and humans. However, differences in the immunomodulatory properties of autoclaved, sterile soil material and non-autoclaved, live soil material have not been compared earlier. Results . In this study, we exposed C57BL/6 mice to autoclaved and live soil powders that had the same rich microbiota before autoclaving. We studied the effect of the soil powders on the mouse immune system by analyzing different immune cell populations, gene expression in the gut, mesenteric lymph nodes and lung, and serum cytokines. Both autoclaved and live soil exposure were associated with changes in the immune system. The exposure to autoclaved soil resulted in higher levels of Rorγt , Inos and Foxp3 expression in the colon. The exposure to live soil was associated with elevated IFN-γ concentration in the serum. In the mesenteric lymph node, exposure to live soil reduced Gata3 and Foxp3 expression, increased the percentage of CD8 + T cells and the expression of activation marker CD80 in XCR1 ⁺ SIRPα ⁻ migratory conventional dendritic cell 1 subset. Conclusions . Our results indicate that exposure to the live and autoclaved soil powders is not toxic for mice. Exposure to live soil powder slightly skews the immune system towards type 1 direction which might be beneficial for inhibiting type 2-related inflammation. Further studies are warranted to quantify the impact of this exposure in experimental type 2 inflammation.
... The concept of Anthropocene-related disease can be extended from the evolutionary principles of mismatch. For example, explanations for the rapid rise in the prevalence of allergic disease have generally been based on the "hygiene hypothesis" and the consequences of avoidance of parasites and allergens in early life (129). Other modern interventions such as Cesarean sections, the use of antibiotics, and cow's milk-based formula feeding from birth may lead to long-term changes in the microbiota with broad health implications (128, 130). ...
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Evolutionary medicine – i.e. the application of insights from evolution and ecology to biomedicine – has tremendous untapped potential to spark transformational innovation in biomedical research, clinical care and public health. Fundamentally, a systematic mapping across the full diversity of life is required to identify animal model systems for disease vulnerability, resistance, and counter-resistance that could lead to novel clinical treatments. Evolutionary dynamics should guide novel therapeutic approaches that target the development of treatment resistance in cancers (e.g., via adaptive or extinction therapy) and antimicrobial resistance (e.g., via innovations in chemistry, antimicrobial usage, and phage therapy). With respect to public health, the insight that many modern human pathologies (e.g., obesity) result from mismatches between the ecologies in which we evolved and our modern environments has important implications for disease prevention. Life-history evolution can also shed important light on patterns of disease burden, for example in reproductive health. Experience during the COVID-19 (SARS-CoV-2) pandemic has underlined the critical role of evolutionary dynamics (e.g., with respect to virulence and transmissibility) in predicting and managing this and future pandemics, and in using evolutionary principles to understand and address aspects of human behavior that impede biomedical innovation and public health (e.g., unhealthy behaviors and vaccine hesitancy). In conclusion, greater interdisciplinary collaboration is vital to systematically leverage the insight-generating power of evolutionary medicine to better understand, prevent, and treat existing and emerging threats to human, animal, and planetary health.
... In adolescents, having only one older sibling was positively associated with increase of AR, as proposed by Strachan 21 and corroborated by other authors, 22,23 and with allergic rhinoconjunctivitis and severe forms of rhinitis. In summary, frequent contact with viral infections would stimulate the development of standard Th1 immune response. ...
Full-text available
Objective: To determine the prevalence of allergic rhinitis and associated factors in adolescents and in their parents/guardians. Methods: A cross-sectional study, applying a standardized and validated written questionnaire. Adolescents (13-14 years old; n=1,058) and their parents/guardians (mean age=42.1 years old; n=896) living in the city of Uruguaiana, southern Brazil, responded to the Global Asthma Network standard questionnaires. Results: The prevalence of allergic rhinitis in adolescents was 28.0%, allergic rhinoconjunctivitis, 21.3%, and severe forms of allergic rhinitis, 7.8%. In the adults, the prevalence of allergic rhinitis was 31.7%. Some associated factors with allergic rhinitis in adolescents include low physical exercise (OR 2.16; 95%CI 1.15-4.05), having only one older sibling (OR 1.94; 95CI 1.01-3.72) and daily meat consumption (OR 7.43; 95% CI 1.53-36.11). In contrast, consuming sugar (OR 0.34; 95%CI 0.12-0.93) or olive oil (OR 0.33; 95%CI 0.13-0 .81) once or twice a week, and eating vegetables daily (OR 0.39; 95%CI 0.15-0.99) were considered factors negatively associated. In adults, exposure to fungi at home (OR 5.25; 95%CI 1.01-27.22) and consumption of meat once or twice a week (OR 46.45; 95CI 2.12-1020.71) were factors associated with the medical diagnosis of allergic rhinitis, while low education (OR 0.25; 95%CI 0.07-0.92) was found to be a factor negatively associated. Conclusions: The prevalence of allergic rhinitis in adolescents is high, as well as its medical diagnosis in adults living in Uruguaiana. Environmental factors, especially food habits, were associated with findings in both groups.
... Over the past decade, the microbiome has emerged as a significant component of human health (8). Many studies have revealed that the gut microbiome communicates with the host and participates in the regulation of the systemic immune, metabolic, and nervous systems, as well as gut metabolism (9). ...
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Introduction Sleep deprivation (SD) and obesity are common in modern societies. SD and obesity frequently coexist, but research on the combined consequences of SD and obesity has been limited. In this study, we investigated the gut microbiota and host responses to SD and high-fat diet (HFD)-induced obesity. In addition, we attempted to identify key mediators of the microbiota-gut-brain axis. Methods C57BL/6J mice were divided into four groups based on whether they were sleep deprived and whether they were fed a standard chow diet (SCD) or HFD. We then performed fecal microbiome shotgun sequencing, gut transcriptome analysis using RNA sequencing, and brain mRNA expression analysis using the nanoString nCounter Mouse Neuroinflammation Panel. Results The gut microbiota was significantly altered by the HFD, whereas the gut transcriptome was primarily influenced by SD. Sleep and diet are both important in the inflammatory system of the brain. When SD and the HFD were combined, the inflammatory system of the brain was severely disrupted. In addition, inosine-5' phosphate may be the gut microbial metabolite that mediates microbiota-gut-brain interactions. To identify the major drivers of this interaction, we analyzed the multi-omics data. Integrative analysis revealed two driver factors that were mostly composed of the gut microbiota. We discovered that the gut microbiota may be the primary driver of microbiota-gut-brain interactions. Discussion These findings imply that healing gut dysbiosis may be a viable therapeutic target for enhancing sleep quality and curing obesity-related dysfunction.
... The hygiene hypothesis states that childhood exposure to particular microorganisms protects against allergic diseases by the development of the immune system. 16 The BCG scar size can be used to measure the level of immunity against infection in all age groups. Also, the BCG vaccination can be used for augmentation of the immune system against infection in general. ...
Soil microbiomes continue to evolve and shape the human microbiota according to external anthropogenic and climate change effects. Ancient microbes are being exposed as a result of glacier melting, soil erosion and poor agricultural practices. Soil microbes subtly regulate greenhouse gas emissions and undergo profound alterations due to poor soil maintenance. This review highlights how the soil microbiome influences human digestion processes, mineral and vitamin production, mental health and mood stimulation. Although much about microbial functions remains unknown, increasing evidence suggests that beneficial soil microbes are vital for enhancing human tolerance to diseases and pathogens. Further research is essential to delineate the specific role of the soil microbiome in promoting human health, especially in light of the increasing anthropogenic pressures and changing climatic conditions.
The objective of this experiment was to investigate the effects of dietary crude protein (CP) content and crystalline amino acids (CAA) supplementation patterns in low CP (LCP) diets on intestinal bacteria and their metabolites in weaned pigs raised under clean (CSC) or unclean sanitary conditions (USC). One hundred forty-four piglets (6.35 ± 0.63 kg) were assigned to 1 of 6 treatments in a 3 × 2 factorial arrangement based on CP content and sanitary conditions in a randomized complete block design to give 8 replicates with 3 pigs per pen over a 21-d period. Diets consisted of a high CP (HCP; 21%) and two LCP (18%) diets supplemented 9 CAA (Lys, Met, Thr, Trp, Val, Ile, Leu, His, and Phe) or only 6 CAA (Lys, Met, Thr, Trp, Val, and Ile) to meet the requirements. The CSC room was washed weekly, whereas the USC room had sow manure spread in the pens from the beginning of the study and was not washed throughout the experiment. Jejunum and colon digesta were sampled on d 21. Both jejunum and colon digesta were analyzed for ammonia nitrogen, short-chain fatty acids, and biogenic amines, but only colon digesta was analyzed for microbiome composition (16s rRNA sequencing on MiSeq). Data were analyzed using R software for 16S rRNA and the MIXED procedure of SAS for microbial metabolites. Sanitation, CP content, and CAA supplementation patterns did not affect the diversity of colonic bacterial composition in weaned pigs. Pigs raised under USC had greater (P < 0.05) jejunal ammonia nitrogen concentration than those raised under CSC. Pigs fed LCP diets had reduced (P < 0.05) jejunal ammonia nitrogen concentration compared to those fed the HCP diet. Interactions between sanitation and dietary CP content were observed (P < 0.05) for 1) jejunal acetate and 2) colonic spermidine and spermine, whereby 1) acetate concentrations decreased from NCP to LCP in pigs raised under the CSC but those concentrations increased under the USC, and 2) spermidine and spermine concentrations increased in LCP diets compared to HCP diet under USC, unlike CSC which did not show any difference between HCP and LCP. In conclusion, reducing dietary CP lowered ammonia nitrogen content regardless of the sanitation and increased microbial metabolites in weaned pigs raised under USC. However, LCP diets with different CAA supplementation patterns did not affect bacterial diversity in weaned pigs, regardless of the hygienic conditions where the animals were housed.
Multiple sclerosis (MS) is an autoimmune neurodegenerative disease. Since the modulation of the immune system by parasites has been proven, and there have been reports of a reduction in the clinical symptoms of MS in people with toxoplasmosis, this study aimed to investigate the effect of toxoplasmosis on MS in an animal model. MS model was induced by the ethidium bromide injection in the areas specified in the Rat's brain in the stereotaxic device and Toxoplasma gondii RH strain injection of the rat's peritoneal for creation of toxoplasmosis. The effect of acute and chronic toxoplasmosis on the MS model was evaluated by examining the development of clinical symptoms of MS, body weight, changes in the levels of inflammatory cytokines, inflammatory cell infiltration, cell density, and spongy tissue in the brain. The body weight in the acute toxoplasmosis with MS was the same as the MS group, and a significant decrease was observed, but no weight loss was observed in the chronic toxoplasmosis with MS. In the chronic toxoplasmosis, the progress of clinical signs such as Immobility of limbs, including tail, hands, and feet, was observed less compared to other groups. The histology results in the group of chronic toxoplasmosis showed high cell density and inhibition of spongy tissue formation, and the infiltration of inflammatory cells in this group was less. TNF-α and INF-γ decreased in MS with chronic toxoplasmosis compared to the MS group. Our findings showed that chronic toxoplasmosis with inhibition of spongy tissue formation and prevention of cell infiltration and. As a result, the reduction of inflammatory cytokines could reduce clinical symptoms in MS in the animal model.
To understand life in all its varieties, we must undertake to understand our cells and, most particularly, acknowledge that all cells are problem-solving, communicating, self-referential agents. As a result, our traditional conceptions of intelligence and problem-solving must be thoroughly redefined. This radical new approach explains precisely why our human choices are centered within the same cellular rules that enable our cells to seamlessly sustain our lives. While the partnership between our cells and our microbes has largely been thought of as “host” and “guest,” the reciprocal interactions between essential living fractions in holobionts is so intimate that we should regard ourselves as a consensual 'we'. Exploring the extent of the deep integration of our cellular networks yields profound insights about ourselves, our health and well-being, our social systems, and our permanent relationship with the planet and the cosmos.
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Foxp3-expressing regulatory T (T reg) cells have been implicated in parasite-driven inhibition of host immunity during chronic infection. We addressed whether parasites can directly induce T reg cells. Foxp3 expression was stimulated in naive Foxp3⁻ T cells in mice infected with the intestinal helminth Heligmosomoides polygyrus. In vitro, parasite-secreted proteins (termed H. polygyrus excretory-secretory antigen [HES]) induced de novo Foxp3 expression in fluorescence-sorted Foxp3⁻ splenocytes from Foxp3-green fluorescent protein reporter mice. HES-induced T reg cells suppressed both in vitro effector cell proliferation and in vivo allergic airway inflammation. HES ligated the transforming growth factor (TGF) β receptor and promoted Smad2/3 phosphorylation. Foxp3 induction by HES was lost in dominant-negative TGF-βRII cells and was abolished by the TGF-β signaling inhibitor SB431542. This inhibitor also reduced worm burdens in H. polygyrus-infected mice. HES induced IL-17 in the presence of IL-6 but did not promote Th1 or Th2 development under any conditions. Importantly, antibody to mammalian TGF-β did not recognize HES, whereas antisera that inhibited HES did not affect TGF-β. Foxp3 was also induced by secreted products of Teladorsagia circumcincta, a related nematode which is widespread in ruminant animals. We have therefore identified a novel pathway through which helminth parasites may stimulate T reg cells, which is likely to be a key part of the parasite's immunological relationship with the host.
Conference Paper
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Abstract Background: The impact of exposure to multiple pathogens concurrently or consecutively on immune function is unclear. Here, immune responses induced by combinations of the bacterium Salmonella Typhimurium (STm) and the helminth Nippostrongylus brasiliensis (Nb), which causes a murine hookworm infection and an experimental porin protein vaccine against STm, were examined. Methodology/Principal Findings: Mice infected with both STm and Nb induced similar numbers of Th1 and Th2 lymphocytes compared with singly infected mice, as determined by flow cytometry, although lower levels of secreted Th2, but not Th1 cytokines were detected by ELISA after re-stimulation of splenocytes. Furthermore, the density of FoxP3+ T cells in the T zone of co-infected mice was lower compared to mice that only received Nb, but was greater than those that received STm. This reflected the intermediate levels of IL-10 detected from splenocytes. Co-infection compromised clearance of both pathogens, with worms still detectable in mice weeks after they were cleared in the control group. Despite altered control of bacterial and helminth colonization in co-infected mice, robust extrafollicular Th1 and Th2- reflecting immunoglobulin-switching profiles were detected, with IgG2a, IgG1 and IgE plasma cells all detected in parallel. Whilst extrafollicular antibody responses were maintained in the first weeks after co-infection, the GC response was less than that in mice infected with Nb only. Nb infection resulted in some abrogation of the longer-term development of anti- STm IgG responses. This suggested that prior Nb infection may modulate the induction of protective antibody responses to vaccination. To assess this we immunized mice with porins, which confer protection in an antibody-dependent manner, before challenging with STm. Mice that had resolved a Nb infection prior to immunization induced less anti-porin IgG and had compromised protection against infection. Conclusion: These findings demonstrate that co-infection can radically alter the development of protective immunity during natural infection and in response to immunization.
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Background The impact of exposure to multiple pathogens concurrently or consecutively on immune function is unclear. Here, immune responses induced by combinations of the bacterium Salmonella Typhimurium (STm) and the helminth Nippostrongylus brasiliensis (Nb), which causes a murine hookworm infection and an experimental porin protein vaccine against STm, were examined. Methodology/Principal Findings Mice infected with both STm and Nb induced similar numbers of Th1 and Th2 lymphocytes compared with singly infected mice, as determined by flow cytometry, although lower levels of secreted Th2, but not Th1 cytokines were detected by ELISA after re-stimulation of splenocytes. Furthermore, the density of FoxP3+ T cells in the T zone of co-infected mice was lower compared to mice that only received Nb, but was greater than those that received STm. This reflected the intermediate levels of IL-10 detected from splenocytes. Co-infection compromised clearance of both pathogens, with worms still detectable in mice weeks after they were cleared in the control group. Despite altered control of bacterial and helminth colonization in co-infected mice, robust extrafollicular Th1 and Th2-reflecting immunoglobulin-switching profiles were detected, with IgG2a, IgG1 and IgE plasma cells all detected in parallel. Whilst extrafollicular antibody responses were maintained in the first weeks after co-infection, the GC response was less than that in mice infected with Nb only. Nb infection resulted in some abrogation of the longer-term development of anti-STm IgG responses. This suggested that prior Nb infection may modulate the induction of protective antibody responses to vaccination. To assess this we immunized mice with porins, which confer protection in an antibody-dependent manner, before challenging with STm. Mice that had resolved a Nb infection prior to immunization induced less anti-porin IgG and had compromised protection against infection. Conclusion These findings demonstrate that co-infection can radically alter the development of protective immunity during natural infection and in response to immunization.
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To investigate the association between exposure to antibiotics in fetal and early life and asthma in childhood, with adjustment for confounding factors. Nationwide prospective population based cohort study, including sibling control design. Swedish population identified from national demographic and health registers. 493 785 children born 2006-10; 180 894 of these were eligible for sibling analyses. Asthma defined as having both an asthma diagnosis and dispensed asthma drugs. The association between antibiotic exposure and asthma was investigated in the whole cohort with Cox proportional hazard regression. A stratified proportional hazards model conditional on sibling group was used to adjust for shared factors within families. Confounding by respiratory infections was assessed by investigating whether specific groups of antibiotics were associated with asthma. Antibiotic exposure in fetal life was associated with an increased risk of asthma in cohort analyses (hazard ratio 1.28, 95% confidence interval 1.25 to 1.32), but not in sibling analyses (0.99, 0.92 to 1.07). In cohort analyses, antibiotics used to treat respiratory infections in childhood were associated with a more pronounced increased risk of asthma (4.12, 3.78 to 4.50) than antibiotics used for urinary tract and skin infections (1.54, 1.24 to 1.92). In sibling analyses, the excess risks after exposure to antibiotics for respiratory infections decreased (2.36, 1.78 to 3.13) and disappeared for antibiotics for urinary tract and skin (0.85, 0.47 to 1.55). Previous positive associations between exposure to antibiotics in fetal and early life and subsequent childhood asthma could have been caused by confounding by shared familial factors, in addition to confounding by respiratory infections. © Örtqvist et al 2014.
Aims To examine incidence and trends of Type 1 diabetes worldwide for the period 1990-1999. Methods The incidence of Type 1 diabetes (per 100 000/year) was analysed in children aged <= 14 years from 114 populations in 112 centres in 57 countries. Trends in the incidence of Type 1 diabetes were analysed by fitting Poisson regression models to the dataset. Results A total of 43 013 cases were diagnosed in the study populations of 84 million children. The age-adjusted incidence of Type 1 diabetes among 112 centres (114 populations) varied from 0.1 per 100 000/year in China and Venezuela to 40.9 per 100 000/year in Finland. The average annual increase in incidence calculated from 103 centres was 2.8% (95% CI 2.4-3.2%). During the years 1990-1994, this increase was 2.4% (95% CI 1.3-3.4%) and during the second study period of 1995-1999 it was slightly higher at 3.4% (95% CI 2.7-4.3%). The trends estimated for continents showed statistically significant increases all over the world (4.0% in Asia, 3.2% in Europe and 5.3% in North America), except in Central America and the West Indies where the trend was a decrease of 3.6%. Only among the European populations did the trend in incidence diminish with age. Conclusions The rising incidence of Type 1 diabetes globally suggests the need for continuous monitoring of incidence by using standardized methods in order to plan or assess prevention strategies.
The inactive full-length form of GLP-1(1-37) stimulates conversion of both rat and human intestinal epithelial cells into insulin-secreting cells. We investigated whether oral administration of human commensal bacteria engineered to secrete GLP-1(1-37) could ameliorate hyperglycemia in a rat model of diabetes by reprogramming intestinal cells into glucose-responsive insulin-secreting cells. Diabetic rats were fed daily with human lactobacilli engineered to secrete GLP-1(1-37). Diabetic rats fed GLP-1-secreting bacteria showed significant increases in insulin levels and, additionally, were significantly more glucose tolerant than those fed the parent bacterial strain. These rats developed insulin-producing cells within the upper intestine in numbers sufficient to replace ∼25-33% of the insulin capacity of nondiabetic healthy rats. Intestinal tissues in rats with reprogrammed cells expressed MafA, PDX-1, and FoxA2. HNF-6 expression was observed only in crypt epithelia expressing insulin and not in epithelia located higher on the villous axis. Staining for other cell markers in rats treated with GLP-1(1-37)-secreting bacteria suggested that normal function was not inhibited by the close physical proximity of reprogrammed cells. These results provide evidence of the potential for a safe and effective nonabsorbed oral treatment for diabetes and support the concept of engineered commensal bacterial signaling to mediate enteric cell function in vivo. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
The gut microbiota is established during infancy and plays a fundamental role in shaping host immunity. Colonization patterns may influence the development of atopic disease, but existing evidence is limited and conflicting. To explore associations of infant gut microbiota and food sensitization. Food sensitization at 1 year was determined by skin prick testing in 166 infants from the population-based Canadian Healthy Infant Longitudinal Development (CHILD) study. Fecal samples were collected at 3 and 12 months, and microbiota was characterized by Illumina 16S rRNA sequencing. Twelve infants (7.2%) were sensitized to ≥1 common food allergen at 1 year. Enterobacteriaceae were over-represented and Bacteroidaceae were under-represented in the gut microbiota of food-sensitized infants at 3 months and 1 year, whereas lower microbiota richness was evident only at 3 months. Each quartile increase in richness at 3 months was associated with a 55% reduction in risk for food sensitization by 1 year (adjusted odds ratio 0.45, 95% confidence interval 0.23-0.87). Independently, each quartile increase in Enterobacteriaceae/Bacteroidaceae ratio was associated with a 2-fold increase in risk (2.02, 1.07-3.80). The latter was partially explained by breastfeeding, but neither association was altered by caesarean delivery or antibiotic exposure. At 1 year, the Enterobacteriaceae/Bacteroidaceae ratio remained elevated among sensitized infants, who also tended to have decreased abundance of Ruminococcaceae. Low gut microbiota richness and an elevated Enterobacteriaceae/Bacteroidaceae ratio in early infancy are associated with subsequent food sensitization, suggesting that early gut colonization may contribute to the development of atopic disease, including food allergy. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Some helminths are major human pathogens. Recently, however, increased understanding of the immunoregulatory responses induced by this class of parasites, in combination with epidemiologic and animal studies, suggest that helminths may have therapeutic potential in autoimmune diseases (AD) and other conditions. This article reviews the rationale for and results of clinical trials to test the safety and efficacy of helminth therapy in AD. Also discussed are future prospects for investigation and the possibility that helminth treatment may serve as a probe to help reveal the pathogenesis of AD. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Coadministration of a bacterial adjuvant with oral immunotherapy (OIT) has been suggested as a potential treatment for food allergy. To evaluate a combined therapy comprising a probiotic together with peanut OIT. We performed a double-blind, placebo-controlled randomized trial of the probiotic Lactobacillus rhamnosus CGMCC 1.3724 and peanut OIT (probiotic and peanut oral immunotherapy [PPOIT]) in children (1-10 years) with peanut allergy. The primary outcome was induction of sustained unresponsiveness 2 to 5 weeks after discontinuation of treatment (referred to as possible sustained unresponsiveness). Secondary outcomes were desensitization, peanut skin prick test, and specific IgE and specific IgG4 measurements. Sixty-two children were randomized and stratified by age (≤5 and >5 years) and peanut skin test wheal size (≤10 and >10 mm); 56 reached the trial's end. Baseline demographics were similar across groups. Possible sustained unresponsiveness was achieved in 82.1% receiving PPOIT and 3.6% receiving placebo (P < .001). Nine children need to be treated for 7 to achieve sustained unresponsiveness (number needed to treat, 1.27; 95% CI, 1.06-1.59). Of the subjects, 89.7% receiving PPOIT and 7.1% receiving placebo were desensitized (P < .001). PPOIT was associated with reduced peanut skin prick test responses and peanut-specific IgE levels and increased peanut-specific IgG4 levels (all P < .001). PPOIT-treated participants reported a greater number of adverse events, mostly with maintenance home dosing. This is the first randomized placebo-controlled trial evaluating the novel coadministration of a probiotic and peanut OIT and assessing sustained unresponsiveness in children with peanut allergy. PPOIT was effective in inducing possible sustained unresponsiveness and immune changes that suggest modulation of the peanut-specific immune response. Further work is required to confirm sustained unresponsiveness after a longer period of secondary peanut elimination and to clarify the relative contributions of probiotics versus OIT. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.