Early-life environmental determinants of allergic diseases
and the wider pandemic of inflammatory noncommunicable
Susan L. Prescott, MD, PhDa,b,c
The unparalleled burden of a diverse range of chronic
noncommunicable diseases (NCDs) is a major global challenge
in the 21st century. Chronic low-grade inflammation is a
common feature of virtually all NCDs, indicating a central role
of the immune system. Furthermore, as the most common and
earliest-onset NCD, the epidemic of allergic diseases points to
specific vulnerability of the developing immune system to
modern environmental change. Indeed, many environmental
risk factors implicated in the rise of other NCDs have been
shown to mediate their effects through immune pathways. The
innate immune system provides a clear example of this
convergence, with evidence that physical activity, nutrition,
pollutants, and the microbiome all influence systemic
inflammation through Toll-like receptor pathways (notably Toll-
like receptor 4), with downstream effects on the risk of insulin
resistance, obesity, cardiovascular risk, immune diseases, and
even mood and behavior. Common risk factors will likely mean
common solutions, and interdisciplinary strategies to promote
immune health should be an integral part of NCD prevention,
with a greater focus early in the life course before disease
processes are established. In this context allergic disease
provides a very important early target to assess the effectiveness
of environmental strategies to reduce immune dysregulation.
(J Allergy Clin Immunol 2013;131:23-30.)
Key words: Allergic disease, early immune development, inflamma-
tion, pregnancy and early life, diet and nutrition, microbiome, envi-
ronmental pollutants and irritants, gene-environmental interactions,
developmental origins of health and disease, noncommunicable
diseases, obesity, disease prevention
Discuss this article on the JACI Journal Club blog: www.jaci-
Over millennia, our external environment has shaped the
myriad elaborate interwoven pathways that maintain constant
defense against a diverse range of potential threats. In equal
measure our survival has been dependent on evolutionary pres-
sure to limit and regulate immune responses that could be
otherwise detrimental to the host. Our complex relationship
with the environment is fundamental to understanding the very
existence and evolution of the immune system, as well as the
reasons for the unprecedented surge in noncommunicable in-
flammatory diseases in modern times.
A GLOBAL HEALTH CHALLENGE OF PANDEMIC
Dramatic environmental and lifestyle changes of the modern
age pose a significant threat to human health. An unparalleled
increase in a diverse range of chronic noncommunicable diseases
(NCDs) is one of the major global challenges of the 21st century.
This growing burden of NCDs currently poses the greatest threat
to health in both developed and developing regions and is a major
barrier to human development. The dominant focus of the NCDs
agenda is usually on ‘‘the big four’’: cardiovascular disease,
metabolic disease (obesity and type 2 diabetes), cancer, and
chronic lung disease. Although both asthma and smoking-related
diseases are considered in the context of chronic lung disease,
allergic diseases per se are typically overlooked in this agenda,
despite now being the most common and earliest-onset NCDs
in most regions. Already, approximately 30% to 40% of the
world’s population is affected by 1 or more allergic conditions,
with vast personal, social, and economic costs.1This needs to
be recognized as a major element in the wider public health
agenda, with strong efforts toward promoting immune health as
an integral part of NCD prevention.
INFLAMMATION AS A COMMON FEATURE OF
MANY NCDs: A CENTRAL ROLE OF THE IMMUNE
Chronic low-grade inflammation is a common feature of
virtually all NCDs, highlighting the central multisystem interac-
tionsoftheimmune system.2Thespecificvulnerabilityofthe im-
mune system to recent environmental changes is also reflected in
Fromathe School of Paediatrics and Child Health, University of Western Australia;bthe
Developmental Origins of Health and Disease (DOHaD) Consortium; andcthe Inter-
national Inflammation (in-FLAME) Network of the World Universities Network
Supported by a Practitioner Fellowship from the National Health and Medical Research
Council (NHMRC) of Australia.
Disclosure of potential conflict of interest: S. L. Prescott has received grants from the
National Health and Medical Research Council and is a board member for Nestl? e,
Danone, and ALK-Abell? o.
Received for publication September 7, 2012; revised November 14, 2012; accepted for
publication November 15, 2012.
University ofWestern Australia, Perth, Western Australia, PO Box D184, Princess Mar-
garet Hospital, Perth WA 6001, Australia. E-mail: firstname.lastname@example.org.
? 2013 American Academy of Allergy, Asthma & Immunology
NCD: Noncommunicable disease
PUFA: Polyunsaturated fatty acid
TLR: Toll-like receptor
the dramatic increase in virtually all inflammatory disorders and,
of life and detectable immune dysregulation at birth3provide
clear evidence of very early environmental effects. The risk fac-
tors that are specifically associated with early immune dysfunc-
tion include modern dietary patterns, environmental pollutants,
microbial patterns, and stress.4,5These all appear to promote in-
flammation and are common risks for many NCDs (Fig 1).2
Reducing the risk of inflammatory responses through lifestyle
and environmental interventions is likely to have benefits for
the risk and progression of many other NCDs.
Importantly, overcoming the adverse consequences of lifestyle
changes will logically require somewhat more holistic ap-
proaches than the more focused pharmaceutical approach of
immune therapies. Although there remains a clear role for
developing better pharmaceutical interventions, holistic ap-
proaches are more likely to simultaneously modify a variety of
innate immune responses—analogous to the multiple environ-
mental changes currently acting simultaneously on many organ
systems to exert chronic inflammatory changes.
As practicing allergists, we must embrace the challenge of
more fully understanding the interaction between the environ-
ment and immunity. We have the opportunity to be the specialty
that leads the way in advising families about the significance of
the immune system for many aspects of health, including the
limitations of our current understanding. Clinicians often ignore
the answers are not clear, we need to be educated so we can put
this in context for patients.
EARLY LIFE: A CRITICAL TIME OF RISK AND
Prevention is the ultimate approach to reducing the burden of
NCDs, and thegreatest potential for this lies in early life. There is
already substantive evidence that initiatives to promote a healthy
start to life can reduce the risk of both early and later NCDs, with
wide social and economic benefits.6,7The early environment in
both pregnancy and early childhood can determine physiologic,
structural, immune, metabolic, and behavioral development
and modify response patterns that influence future disease
Although many NCDs might not become apparent until later in
life.8This is the clearest indication that the developing immune
together with mounting evidence that these effects must begin in
eration need to be considered. Allergy is a systemic disease asso-
distal recruitmentofinflammatory progenitorsinto thecirculation
from the bone marrow.9Low-grade systemic inflammation has
now been clearly linked with the risk for metabolic dysregulation
and vascular disease.10Although there are some associations
between cardiovascular disease and allergic disease in later
mation in earlier life have not yet been determined, particularly in
the current high-prevalence generation yet to reach maturity.
Health and Disease (DOHaD) movement is to promote a life-
course approach to disease prevention, beginning with maternal
health before conception. It is important to encourage a specific
theDOHaDagenda becausethisislikely tobecentralinreducing
the wider burden of NCDs and inflammatory pathology in the
future. Studying the early effects of lifestyle interventions on
early immune function and allergic disease will provide a useful
early barometer in evaluating effectiveness.
COMMON RISK FACTORS MEAN COMMON
SOLUTIONS: THE NEED FOR INTERDISCIPLINARY
Although genetic factors can determine individual susceptibil-
ity and patterns of disease, only environmental change can
FIG 1. Inflammation: a common element in many NCDs. HPA, Hypothalamic-pituitary-adrenal axis.
J ALLERGY CLIN IMMUNOL
account for the rapid increase in NCDs. This also suggests
common risk factors and the need for common solutions. Moving
forward, there is a clear imperative for coordinated interdiscipli-
nary strategies, particularly those focused on early life. There are
a number of good examples of immunomodulatory interventions
explored for allergy prevention that might have additional mul-
tisystem benefits. Anticipating a new collaborative era of pre-
ventive medicine, these are considered here in a more
Multisystem benefits of anti-inflammatory v-3
polyunsaturated fatty acid
With well-recognized anti-inflammatory properties, v-3 poly-
unsaturated fatty acid (PUFA)–rich fish oils have been logical
interventions for the prevention and treatment of a number of
inflammatory conditions. In one of the earliest intervention
studies for allergy prevention, we supplemented allergic women
with fish oil from 20 weeks’ gestation, with immunomodulatory
effects in their neonates13-15and reduced risk of subsequent aller-
gen (egg) sensitization and eczema severity.13More recently, in a
much larger, more definitive randomized controlled trial of 706
pregnant women, we observed that fish oil supplementation also
achieved a reduction in egg sensitization by 12 months of age
in high-risk infants.16Rates of atopic eczema (eczema with asso-
ciated sensitization) were also less in the fish oil group. We also
examined the effects of early postnatal fish oil supplementation
in high-risk infants (n 5 420) from birth to 6 months.17The inter-
decreased allergen-specificTH2 responses and increased polyclo-
associated with lower risk of eczema and recurrent wheeze, there
was no effect of the intervention per se on the primary study out-
comes (intention to treat analysis).19However, in a per-protocol
plementation (the highest adherence quartile) had a significantly
lower prevalence of eczema at 12 months in the fish oil group.19
These findings suggest that achieving higher v-3 PUFA levels in
infancy gives some protection against allergic outcomes but that
postnatal supplementation is not an effective strategy. Even be-
fore these more recent large studies, the collective literature ap-
peared to be gathering strength to support an allergy-protective
effect of fish oil in pregnancy rather than the postnatal period,
as suggested by a 2011 systematic review.20The inclusion of ad-
ditional data from the new studies (above)16,19in repeated meta-
analyses is expected to provide stronger data that will be better
positioned to inform clinical practice recommendations in the
very near future.
Notably, these early interventions with fish oil aimed at allergy
prevention in early childhood18,19,21also have benefits for meta-
bolic programming22and reducing cardiovascular risk.23,24
A recent follow-up of one of these allergy prevention studies
tation over the first 5 years of life reduced the carotid intima-
media thickening (as a noninvasive measure of subclinical
atherosclerosis) that had been associated with reduced fetal
growth.23This might be mediated, at least in part, by a reduction
in the low-grade systemic inflammation that has been linked di-
rectly with the risk for cardiometabolic disease.25In keeping
with this, we have previously shown that fish oil supplementation
like receptor (TLR) 4–mediated inflammatory responses.15
Furthermore, in addition to immunomodulation13,18and allergy
reduction,13,16we have also seen beneficial effects on aspects of
neurodevelopment after both prenatal26and early postnatal27
fish oil supplementation. In summary, restoring the higher v-3
PUFA levels seen in subjects with more traditional diets is a clear
example of an early immunomodulatory intervention that has
Effects of the gut microbiome, probiotics, and other
Changing microbial exposure and diversity remains one of the
leading explanations for the increase in rates of many inflamma-
tory diseases. Animal models provide clear evidence that the gut
microbiota modulates immune programming and that manipula-
autoimmune phenomena29but also the risk of obesity, cardiovas-
cular and metabolic disease,30and even modulate mood and be-
havior (Fig 2).31,32
Importantly, there is accumulating evidence that many of these
multisystem effects are mediated through the immune system
fat, low-fiber Western diet) are associated with altered gut barrier
function, increased systemic endotoxin levels,33and antigenic
load and evidence of increased low-grade systemic inflammation
(as detected by increased C-reactive protein levels and higher
biota can also directly regulate the host genes involved in lipid
metabolism,35with associated effects of insulin resistance, food
forming the host into a highly efficient lipid-making and lipid
storage machine.30,35-37A critical role for TLR4 was defined by
observations that mice with a loss-of-function mutation in TLR4
resist becoming obese on a high-fat diet.38Long-chain fatty acids
the adipose tissue, muscle, brain, and liver to initiate metabolic
These physiologic and metabolic adaptations can be reversed
through restoring a more ‘‘favorable’’ gut microbiome.37It is
also notable that, the positive metabolic effects of exercise are
also mediated, in part, through downregulation of TLR4.41
Even more unanticipated effects of modifying the gut micro-
Germ-free mice respond differently to stress, and in colonized
mice, disturbing the gut microflora with antibiotics also alters be-
havior through changes in brain-derived neurotrophic fac-
tor.31,32,42A surprising new study has found that addictive
behavior is mediated through TLR4 pathways, demonstrating
unique and specific links between innate immune pathways and
At this stage, the long-term effects of early-life strategies have
not been investigated in human subjects; however, a new land-
mark murine study by Cho et al44showed that changes in the gut
microbiome induced by exposure to antibiotics in early life in-
creased the risk of adiposity, with significant metabolic effects
on short-chain fatty acid levels and hepatic metabolism of lipids
and cholesterol. Notably, this effect was seen with subtherapeutic
doses akin to the antibiotic levels used extensively in agricul-
ture.44This underscores the need to more fully examine diverse
J ALLERGY CLIN IMMUNOL
VOLUME 131, NUMBER 1
health outcomes in relation to the early microbiome. Existing al-
lergy prevention cohorts with probiotics might provide an oppor-
tunity to examine this.
There are now a considerable number of interventions using
various probiotic strains in pregnancy, the early postnatal period,
or both for allergy prevention.45Most of these studies have thus
far focused primarily on early outcomes of allergic disease,
such as eczema and IgE-mediated food allergy, and approxi-
mately half of these showed a significant reduction in the devel-
opment of eczema (25% to 50%) but no consistent effects on
any other allergic outcomes.45There is considerable heterogene-
ity in virtually all aspects of these studies. Several meta-analyses
published in the last 12 months have concurred that probiotics re-
duce the risk of eczema but not other allergic outcome.46,47The
most recent of these47included 13 preventionstudies and demon-
strated that probiotic treatment reduced the incidence of eczema
by 21% (relative risk, 0.79; 95% CI, 0.71-0.88). This effect was
still present when the analysis was restricted to studies of
patients with IgE-associated eczema.
Thus although the use of specific probiotic supplements has
been of interest in assessing the short-term preventive benefits on
inflammatory disease in early childhood (ie, allergic disease),
slowing the long-term effects of chronic, systemic, low-grade
inflammation associated with aging and age-related NCDs re-
quires more sustainable strategies. Ultimately, a more balanced
more traditional dietary patterns early in life, and this is likely to
be of multisystem benefit.
Benefits of anti-inflammatory soluble dietary fiber
Decreasing dietary fiber levels in modern diets has been
specifically associated with an increased risk for a number of
NCDs, including allergic disease. Soluble fiber (prebiotic carbo-
hydrate) is a major substrate for bacterial growth, selectively
stimulating the growth, activity, or both of beneficial members of
the gut microbiota, particularly bifidobacteria.48,49Of at least
equal importance, the resulting fermentation products, short-
chain fatty acids, have direct anti-inflammatory effects50and
promote intestinal integrity through effects on epithelial cell pro-
liferation and differentiation.51As anticipated, dietary interven-
tions to increase dietary fiber levels have benefits for both
immune52,53and metabolic54homeostasis, reducing systemic
endotoxin levels and antigenic load.55
In the context of allergy prevention, initial studies with
prebiotics in early infancy have shown promise in infants at
both high risk48,56and low risk57of allergic disease; however,
more studies are needed to confirm this, and the results of at least
1 other large-scale multicenter trial are expected soon. Improving
intake of soluble dietary fiber is likely to have moreglobal effects
on colonization than adding a single probiotic strain. It is also
likely to have more multisystem benefits for the longer-term pro-
pensity for many other metabolic and inflammatory disease pro-
cesses. Again, this emphasizes the need to address long-term
dietary habits beginning in very early life.
Effects of other dietary exposures
Dietary patterns associated with higher consumption of vege-
have been associated with reduced risk for a number of inflam-
matory diseases.58For example, a Mediterranean diet, which is
associated with lower rates of cardiovascular disease and obe-
sity,59has also been associated with protection against childhood
asthma and wheeze,60,61particularly higher consumption of veg-
etables, fruits, legumes, and fish during pregnancy.61,62Although
the protective elements within these diets are likely to include se-
lenium, zinc, folate, vitamin E, and other antioxidants, the effects
ofspecific supplementshavebeeninconsistentand even paradox-
ical (as reviewed by Shaheen58). These inconsistencies are likely
to reflect the inherent complexity of dietary influences or the dif-
ficulty in accurately measuring these influences or replicating the
FIG 2. A central role of the immune system in mediating the multisystem effects of diet, physical activity,
and the microbiota.
J ALLERGY CLIN IMMUNOL
effects with specific supplements. Again, the most logical and
sustainable strategies are to promote a healthy balanced diet
over the life course.
Multisystem effects of sunlight and vitamin D
Yet another modern behavioral change associated with a broad
a progressively more sedentary indoor lifestyle and increasing
rates of vitamin D insufficiency. The long list of epidemiologic
associations with decreasing sunlight exposure includes hyper-
tension, type 2 diabetes, multiple sclerosis, type 1 diabetes (and
other autoimmunity), bone disease, some cancers (breast and
hematological), susceptibility to infection, food allergy, and
asthma.63,64Although these relationships can be explained in
part by the recognized immunomodulatory effects, studies with
vitamin D supplementation have been inconsistent.65Although
large-scale randomized controlled trials of vitamin D supplemen-
tation in pregnancy are still underway, there is also speculation
that vitamin D might be a surrogate marker for independent im-
munomodulatory effects of UV radiation. Indeed, UV radiation
mediates direct release of a range of immunomodulatory factors
in the skin that promote regulatory cell differentiation in regional
nodes and suppression of immune responses at distal sites (as re-
viewed by Hart et al66). Moreover, UVB appears to imprint
changes in dendritic cells, which shift from an immunogenic to
a more regulatory phenotype (as reviewed by Hart et al66). These
prostaglandin E2–mediated effects are systemic and act on bone
marrow precursors to reduce inflammatory propensity. Although
more studies are needed, this could indicate that the protective ef-
fects of some exposure to natural light might be multifaceted and
might not be fully compensated by vitamin D supplementation.66
Other factors with multisystem effects
A range of other exposures in modern environments are linked
with adverse effects on general health and longevity, many with
immune effects. These include smoking,67persistent organic pol-
lutants and other modern toxins,68stress,69,70and decreasing
physical activity.71Although a detailed discussion of each of
these is beyond the scope of this review, a number of these expo-
sures have epigenetic effects72and might have effects on immune
development early in life.
EPIGENETICS, GENETICS, AND EVOLUTIONARY
The TH2 responses that characterize allergic disease are not in-
herently pathological and only cause disease when excessive or
misdirected. Provoking new thoughts and challenging long-held
concepts that TH2 responses have primarily evolved to defend
against helminthes, Palm et al73have recently proposed that the
very rapid, acute IgE-mediated responses are equally, if not
more likely, to have evolved to protect against a broader diverse
range of environmental irritants, toxins, venoms, hematophagous
fluids (from ectoparasites, such as mosquitoes and ticks), and
idly expel or remove these threats, potentially explaining the ur-
gency of the response. These unpleasant symptoms also lead to
gens (plants, mites, venoms, antibiotics, animals, and fungi) that
invoke theTH2 armamentarium.73Similarly,thetissuebarrier en-
hancement and repair mechanisms that lead to scarring and fibro-
sis in asthmatic patients are part of normal mechanisms
transiently solicited to restrict penetration, prevent spread, and
Although changing patterns of gene-environment interaction
are responsible for the increase in rates of allergic disease and
many other inflammatory conditions, the mechanisms are not
fully clear. Environmental changes must be driving this pan-
demic, but genetic predisposition remains an important determi-
polymorphisms that have no functional disadvantage in tradi-
tional environments might predispose to disease under radically
altered ‘‘modern’’ conditions. There are many diverse pathways
and numerous examples of how the disease predisposition
conferred by genetic polymorphisms change significantly under
different environmental conditions. In the context of allergic
disease, the effects of a number of specific genes vary dramat-
ically in relation to changes in relevant exposures, such as
cigarette smoking74and microbial exposure.75Genetic polymor-
phisms in other functional pathways (eg, vitamin D,76folate,77
and v-3 PUFA78pathways) also modify the host response to the
corresponding environmental exposure.
Epigenetic mechanisms provide a clear explanation for
changes in gene expression induced by environmental changes.
Epigenetic adaption (reviewed in more detail elsewhere3,79) al-
lows plasticity of gene expression in response to changeable en-
vironmental conditions, and the greatest potential for adaptive
programming is in early life, when systems and responses are de-
veloping. Although these mechanisms might be intended to en-
sure survival in anticipation of a potentially hostile environment
(eg, fetal imprinting of metabolic responses that conserve energy
in a growth-restricted fetus), they can also prime for an increased
though it is less clear how this concept fits other diseases, such as
determinants of allergic disease, including environmental pollu-
tants,81,82microbial exposure,83and dietary nutrients,84-86have
been documented to mediate changes in phenotype through epi-
genetic modifications (as reviewed by Prescott and Saffery3
Martino and Prescott79).
Changingenvironmentalexposures canalso influencethelocal
tissue milieu during antigen encounter, which critically deter-
mines the pattern of effector responses and the efficacy of
regulatory mechanisms.87There is new evidence that T-cell re-
sponses (at any age) are in a state of regulated plasticity, such
that the T-cell phenotype can be modulated between effector
and regulatory states (rather than a fixed state of terminal differ-
ity allows adaption to local tissue conditions and is strongly
tal factors implicated in the rise of allergic disease are recognized
to alter tissue milieu, including dietary factors,89microbial pro-
ducts,90,91and pollutants (smoking).92Thus it is possible and
likely that environmental influences in early life could exert ef-
fects on the milieu invarious tissues to promote or protect against
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VOLUME 131, NUMBER 1
These biological perspectives add to our understanding of the
mechanisms and pathways, but the ultimate goal is to achieve
effective lifestyle interventions. In the wider context the disci-
pline of allergy and immunology has an important role to play in
on the immune system and how this contributes to many disease
THINKING BEYOND HEALTH TO FIND SOLUTIONS
Our current global health crisis is a major threat to social and
economic development worldwide, and it is increasingly impor-
tant that we (working in health) collaborate with other sectors in
finding solutions to the many global challenges facing humanity
and our planet. Human health is inexorably linked with the health
of our natural environment. Threats, including global warming,
decreasing biodiversity, and modern pollutants, have repercus-
sions for food, water, and energy security. Equally, the built
environment, social structures, and cultural systems are critical in
determining education, equity, and collective behavior, which
ultimately influence individuals’ opportunities to make healthy
choices. Unless we consider the wider social, cultural, and
economic determinants of health in this context, we cannot
hope to overcome thegrowing burden of allergy and other NCDs.
For this reason, more than ever, it is important that we move
toward more interdisciplinary collaboration and more multi-
sectorial engagement to understand and address the complex
strategies will be required to mitigate the growing burden of a
broad range of modern diseases, and we need to urgently develop
effective strategies to restore traditional dietary and lifestyle
patterns, which clearly have manyproperties that protect notonly
against allergic disease but also against cardiovascular disease,
obesity, diabetes, and many other NCDs.
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