Dietary factors
The obvious dietary factor relevant to the establishment of oral
tolerance (and susceptibility to FA) is food allergens . Oral
tolerance is the active maintenance of both mucosal and systemic
non-responsiveness to ingested food
allergens.113 The
induction of tolerance to dietary antigen is a multistep
process;114dietary vitamin A plays a critical role in its regulation.
CD103+ dendritic cells (DC) in the gut associated
lymphoid tissue (GALT) express elevated levels of retinal dehydrogenase
(RALDH) enzymes which enhance their ability to metabolize dietary
vitamin A. Antigen-loaded CD103+ DC migrate to the
mesenteric lymph node (MLN) from the intestinal lamina propria (LP).
Retinoic acid (RA) produced by these DC and by stromal cells in the MLN
induce the expression of the gut homing receptors CCR9 and α4β7 favoring
TGF-β dependent conversion of Foxp3+ regulatory T
cells (Tregs). 115-117Committed Tregs then home back to LP, expanding under the influence of
IL-10 produced by CX3CR1hi macrophages. Some Tregs
exit the mucosa via the lymph or bloodstream to promote systemic
tolerance. 114 Elegant
studies in germ-free mice on an antigen-free diet showed that, in the
small intestine, Foxp3+ Tregs are induced by exposure
to dietary antigen.118In the large intestine, however, Foxp3+ Tregs are
induced by a subset of the mucosa-associated bacteria which comprise the
intestinal microbiota.119
The increasing prevalence of FA parallels increases in other
non-communicable diseases and can be explained, in part, by alterations
in the composition and function of the commensal microbiome.
21st century lifestyle practices including increased
antibiotic use, low fiber/high fat diets, reduced exposure to infectious
diseases, Caesarean birth and formula feeding have collectively depleted
populations of bacteria beneficial to
health.120-122 In
addition to dietary antigen induced Foxp3+ Tregs, a
bacteria-induced barrier protective response is required to prevent
allergic sensitization to food.123,124Clostridia-induced IL-22 production by type 3 innate lymphoid cells
(ILC3) is necessary and sufficient to reduce intestinal epithelial
permeability to dietary
allergen.123 IL-22
protects the intestinal epithelial barrier by regulating epithelial
proliferation and the production of mucus and anti-microbial
peptides.124 The
mechanisms by which intestinal bacteria, particularly those in the
Clostridia class, regulate mucosal immunity and allergic disease are
increasingly understood. Prominent among these is their ability to
ferment short chain fatty acids (SCFAs) from dietary fiber. SCFAs have
potent immunomodulatory effects correlated with host health125 including
induction of colonic Tregs126 and improvement of
allergy symptoms in a mouse
model.127 Butyrate, in
particular, is an important energy source for colonic epithelial cells.128 Butyrate drives
oxygen consumption by colonocytes through β-oxidation, which maintains a
locally hypoxic niche for butyrate-producing obligate anaerobes
.129 Early dysbiosis
characterized by an impaired capacity to produce butyrate may be a
common feature of allergic
diseases.130Tryptophan metabolites , from both dietary and bacterial
sources, also play a central role in regulating tolerance in the gut.
Catabolism of tryptophan to indole derivatives produces ligands which
bind to the aryl hydrocarbon receptor on innate lymphoid cells (ILC3)
and stimulate the production of IL-22 to regulate epithelial barrier
permeability. 131Finally commensal bacteria can metabolize bile acids to produce
bioactive mediators which regulate T cell differentiation in the
intestinal lamina propria (Figure 6).132
From the evidence from mouse models that food allergen exposure was
necessary for the development of tolerance, observational studies in
humans linking allergen avoidance in the first few years of life with
the development of FA further supported the dual allergen-exposure
hypothesis. Specifically, a cross-sectional study showed that peanut
consumption in Israel early in life was associated with a lower
prevalence of peanut allergy than a population with a similar ancestry
in the UK, where peanut was typically avoided in the first few years of
life.133 Whereas
avoidance of food allergens in an infant’s diet was standard advice in
many countries, advice has changed, and oral tolerance induction is
being used as a strategy to prevent peanut and other FA by introducing
peanuts and other food allergens early into the diet of young
infants.17 The LEAP
study showed that the rate of peanut allergy could be reduced by 86% in
non-sensitised children and the LEAP-On study confirmed that this
protection against peanut allergy remained one year after complete
subsequent avoidance at five years of age in the children’s
diet.134 The impact of
early peanut introduction in LEAP was peanut specific and did not
protect against other
FA.135 The EAT study
(a lower risk, exclusively breastfed population) showed similar results
for peanut in a per protocol
analysis.136 It also
showed that consuming cooked egg in infancy was associated with a
reduction in egg allergy. Since, subsequent studies and a meta-analysis
have confirmed the efficacy of this
approach,133,137-139and a recent Japanese study has shown that early introduction of cow’s
milk in early infancy protects against the development of milk
allergy.140Introducing multiple foods early and continuing to eat them regularly
proved challenging for most families in the EAT study. The study
identified several factors associated with reduced adherence to this
strategy: increasing maternal age, feeding difficulties in the neonate,
and non-Caucasian ethnicity. This could help identify families who might
benefit from further support to encourage early
weaning. 141-143
Many other dietary factors have been studied for their association with
FA and/or AD. Observational studies have been summarized in a number of
systematic reviews focusing on the maternal and infant diet144,145or the maternal diet during pregnancy alone.144,146Collectively over a hundred papers from observational studies have been
identified reporting dietary patterns, diet diversity, fruit and
vegetable intake, fat and fatty acid intake, vitamin and mineral intake,
and a wide range of other dietary exposures, including alcohol, tea or
coffee intake. Summarizing these studies using meta-analysis is limited
as study exposures and outcome definitions are highly heterogeneous. A
comprehensive review by the UK Food Standards Agency focusing on
maternal and infant dietary intake concludes that there is no consistent
evidence for associations between dietary exposures and allergy outcomes
based on observational
studies.144 Other
systematic reviews have, however, attempted to summarize findings from
these studies.