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.