Tryptophan metabolism is altered in many allergic conditions and the IDO pathway plays a central role. Higher serum tryptophan concentrations are found in patients with seasonal AR
[64][34] and asthmatic children
[65][35]. Higher tryptophan and kynurenine levels are found in children with asthma and AR
[26][22]. Low IDO activity has been found in asthma and AR patients
[26,66][22][36]. IDO activity is induced by IFN-γ and is considered a Th1 cell activation marker
[67][37]. During Th2 allergic inflammation, an elevated level of nitric oxide inhibits IDO activity by binding to the heme group of the enzyme. Therefore, the rationale of antioxidants as an anti-allergic therapy lies in their ability to block inducible nitric oxide synthase
[67][37] and rescue the IDO activity which is essential to generate Tregs.
L-glutamine is another amino acid that plays a critical role in immune cell function. Although not an essential amino acid, L-glutamine is the primary fuel for immune cells and is essential for basic immune cell functions such as lymphocyte proliferation and cytokine production
[68][38].
3.2. Dietary Lipids
The amount of dietary lipids and type of fatty acids influence allergic inflammation. High total fat, animal fat, saturated fatty acids (SFAs), cholesterol,
n-6 polyunsaturated fatty acids (PUFAs), and medium-chain fatty acids (MCFs) are risk factors, whereas monounsaturated fatty acids (MUFAs) and
n-3 PUFAs have protective properties. High animal fat and SFAs are associated with allergic rhinitis in human adults while high MUFA intake is associated with a lower risk for asthma
[46,59][26][29].
A high-fat diet (60% Kcal from saturated fat) has been shown to increase serum TSLP in C57BL/6 mice and exacerbate dermatitis in mice through upregulation of TSLP in NC/Nga mice that develop AD spontaneously
[18][39]. The high-fat diet increased TSLP in dorsal skin, infiltration of inflammatory cells, and epidermal thickening in NC/Nga mice compared with a low-fat diet. Dermatitis score was much lower in high-fat-fed NC-TSLP-KO mice, suggesting TSLP mediates a high-fat-diet-induced increase in dorsal skin inflammation
[18][39]. Long-term feeding (10 months since weaning) of a Western diet (21.2% fat, 34% sucrose, and 0.2% cholesterol) also substantially increased spontaneously developed dermatitis in aged C57BL/6 mice, as compared with a control diet (5.2% fat, 12% sucrose, and 0.01% cholesterol)
[71][40]. The Western diet-fed mice had increased epidermal thickness in their dorsal skin and much more epidermal hyperplasia in the lesion skin, with hypergranulosis and spongiosis typical of AD
[71][40]. The Western diet leads to increased total bile acids, altered bile acid profiles, and elevated bile acid signaling through two bile acid receptors TGR5 (transmembrane G-protein-coupled receptor-5) and S1PR2 (sphingosine-1-phosphate receptor-2) in the lesion skin
[71][40]. Lowering serum cholesterol with a bile acid sequestrant cholestyramine reduced epidermal hyperplasia and decreased Th2 and Th17 cytokines
[71][40].
Besides saturated fatty acids and cholesterol, medium-chain fatty acids (MCFs) contained in coconut oil or palm oil also prove to be a dietary risk factor for allergy
[5]. In a mouse model of peanut allergy, compared with
n-6 PUFAs from peanut oil, MCFs decreased dietary peanut or OVA antigen absorption into the circulation and increased antigen in the Peyer’s patches, which resulted in a significant increase in activated DC cells
[72][41].
The phospholipids isolated from asparagus (
Asparagus officinalis L.) are demonstrated to have anti-allergic properties. Oral administration of these phospholipids suppressed serum total IgE and OVA-specific IgE in OVA-challenged mice and ameliorated clinical scores of AD induced by picryl chloride in NC/Nga mice
[73][42]. Phospholipid and glycolipid fractions from asparagus also potently inhibited β-hexosaminidase release from cultured RBL-2H3 (rat basophilic leukemia-histamine-releasing cell line) cells, indicating a direct effect on degranulation in allergic responses
[73][42].
Although conflicting results are generated from human studies about the effects of long-chain PUFA supplementation on asthma, AR, and AD
[74][43], animal studies provide clear evidence of the protection of dietary
n-3 PUFA in these allergic conditions. Dietary
n-3 fatty acid α-linolenic acid shows beneficial effects in allergic inflammation by improving skin barrier function in AD mice
[75][44] and attenuating symptoms in OVA-induced AR in mice, as compared with
n-6 fatty acid linoleic acid
[76][45]. Dietary linseed oil (enriched with α-linolenic acid) increases EPA-derived metabolite 15-HEPE (hydroxyeicosapentaenoic acid in eosinophils) in eosinophils in the nasal passage, which inhibits mast cell degranulation by binding to PPAR (peroxisome proliferator-activated receptor) γ
[76][45].
3.3. Dietary Fiber
Recent animal studies show that dietary fiber protects against AD or allergic asthma through its bacterial metabolites short-chain fatty acids, particularly butyrate
[14,82,83][14][46][47]. Gut microbiota fermentation of dietary fiber into SCFAs is the key to the gut–skin axis or gut–lung regulation of allergic reactions in the skin and lungs. Consistent with animal studies, dysbiosis characterized by the enrichment of
Faecalibacterium prausnitzii and a reduced capacity for butyrate fermentation in the human gut microbiome has been found in patients with AD
[84][48]. Gut microbiota-derived butyrate has been found to be inversely associated with mite-specific IgE levels in childhood asthma
[85][49].
Short-chain fatty acids, particularly butyrate, regulate type 2 inflammation mainly through the inhibition of HDAC (histone deacetylase) on various immune cells and structural cells. Vancomycin treatment in mice results in dramatic alterations in the gut microbiome characterized by decreased richness, diversity, and decreased abundance of butyrate-producing families, leading to increased susceptibility to allergic inflammation
[83][47]. A supplement of SCFA in drinking water attenuated OVA or papain-induced allergic asthma by suppression of DC activation and trafficking, therefore restraining Th2 cell development in Peyer’s patches
[83][47]. Butyrate also directly regulates ILC2 cells by suppressing IL-33-induced IL-13 and IL-5 production in cultured ILC2 lung cells from Rag2
−/− (recombination-activating gene 2 deficient) mice who lack T cells
[24][50]. When administered either through drinking water or through an intranasal route, butyrate ameliorated ILC2 cell-driven lung inflammation. The inhibitory effect of butyrate on ILC2 cell proliferation was due to histone deacetylase (HDAC) inhibition
[24][50].
3.4. Dietary Flavonoids and Other Phytochemicals
Flavonoids are a major type of phytochemicals in the diet and are naturally occurring phenolic compounds which are commonly found in fruits, vegetables, herbs and spices, legumes, tea, and vinegar
[96,97][51][52]. There are six subclasses of dietary flavonoids based on their chemical structures, namely flavanols, flavones, isoflavones, flavanones, flavonols, and anthocyanidin
[96,97][51][52]. Accumulating evidence has shown the anti-allergic effect of dietary flavonoids.
As a major dietary flavonol-type flavonoid, quercetin is found in many fruits and vegetables including onions, shallots, apples, berries, tea, tomatoes, grapes, nuts, and seeds. The anti-inflammatory effect of quercetin is well documented in various animal models of allergy
[98][53]. Quercetin is effective in reducing allergic symptoms by decreasing serum IgE and Th2-related cytokines, reducing eosinophil, neutrophil, and mast cell infiltration into local tissue, reducing epithelial thickness in the lung and hyperkeratosis, and suppressing epithelial cell-derived cytokines IL-25, IL-33, and TSLP
[98][53]. However, in most in vivo animal studies, quercetin is administered through i.p. injection. As quercetin is a glycone (namely, carbohydrate conjugate), how dietary quercetin is metabolized by the gut microbiota and the subsequent effects on allergic inflammation remain to be explored. In a recent study, oral administration of quercetin was shown to attenuate nasal symptoms of OVA-induced AR in BALB/c (Halsey J Bagg albino mice strain c) mice by suppressing angiogenic factors and proinflammatory cytokines TNF-α, IL-6, and IL-8 in nasal lavage fluids
[99][54]. The minimum effective dose for the above in vivo inhibition is similar to the maximum daily recommended dosage for dietary quercetin supplements.
Kaempferol, another flavonol-type flavonoid found in many fruits, vegetables, herbs, teas, and medicinal plants, also exhibits anti-inflammatory, antioxidant, and anti-allergic properties. In cultured lung epithelial BEAS-2B (human broncho-epithelial-alveolar stem cell-derived cells) cells, nontoxic kaempferol suppresses LPS (lipopolysaccharide)-induced TGF-β production, TGF-β-induced myofibroblast formation, LPS-induced collagen, and MT1-MMP, suggesting its ability to suppress the epithelial-to-mesenchymal transition and fibrosis. In a mouse model of asthma, orally administered kaempferol not only suppressed eosinophil infiltration and airway inflammation but also inhibited the airway epithelial-to-mesenchymal transition (EMT) and fibrosis
[53][55]. As fibrotic airway remodeling is characteristic of asthma, leading to lung function deterioration, and is not treated by current drug therapy, kaempferol may be a potential therapy for asthma-related airway construction and is worthy of further clinical studies. Kaempferol also protects mice against AD by suppressing T cell activation though interaction with MRP-1
[101][56].
Oral administration of naringenin, a flavanone mostly found in citrus peel, was shown to significantly reduce nasal scratching score in rats with OVA-induced AR with improved histology in the nasal epithelium and decreased serum IgE, IL-4, and IL-5
[103][57]. In addition, naringenin inhibited TSLP production in PMA/Ionophore-activated human mast cells (HMC-1 cells) through inhibition of NF-κB and TSLP-induced mRNA expressions of IL-13, TNF-α, IL-17 receptors, and TSLP receptors in these cells
[102][58].
The gut microbiota-derived metabolites are critical for the anti-allergic function of some flavonoids. For example, the flavone glycoside diosmin and its aglycone form diometin were shown to diminish DNCB-induced AD symptoms in SKH-1 hairless mice, such as increased trans-epidermal water loss and hydration, epidermal thickness, and infiltration of mast cells
[103][57]. Decreased serum IgE and IL-4 in these mice were observed for both diosmin and diometin; however, in cultured RBL-2H3 cells, only diosmetin and not diosmin showed inhibitory effects on IL-4 production.
Some dietary phytochemicals other than flavonoids also exhibit strong anti-allergic properties. Licoricidin, a component isolated from licorice (
Glycyrrhiza uralensis) root which is a commonly used herb in traditional medicine, shows protection against mouse AD by suppression of T cell activation through regulating PTPN1 activity
[105][59]. Resveratrol, the best-studied polyphenol, inhibits mast cell activation and shows potential in treating allergic conditions
[107][60].
3.5. Vitamins and Minerals
Vitamins and minerals have long been known for their immunomodulatory roles. Vitamins A, D, and E, and trace elements zinc and iron, are particularly important dietary factors, influencing allergic inflammation and the development of allergic diseases. Sufficient intake of Vitamins A, D, and E is required to control asthma
[5]. Supplementation with vitamins E and D alone or in combination improves symptom management of AD
[116][61]. Serum vitamin D level is a determining factor in remission with standard therapy for AD. A serum level of 1, 25(OH)
2VD
3 higher than 20 ng/mL plus standard therapy is sufficient to reduce the severity of AD
[115][62]. In a randomized, double-blind, placebo-controlled clinical study, an oral supplement of 5000 IU/day vitamin D
3 in patients with AD significantly increases the serum level of 1, 25(OH)
2VD
3 to a much higher level than the placebo group, and this dosage achieved sufficiency in 100% of the patients
[115][62]. Vitamin D also shows potential in managing airway remodeling in asthma, based on a number of in vitro studies showing the inhibitory effects of vitamin D on bronchial smooth muscle cells, human airway smooth muscle cells, human asthmatic bronchial fibroblasts, and human bronchial fibroblasts
[54][63].
The trace element zinc is essential for immune function. Zinc deficiency is often linked to allergies. A zinc supplement is shown to be effective in relieving asthma but not beneficial to AD
[50,57][27][64]. In an animal asthma model, zinc deficiency is related to greater airway hyper-responsiveness compared with normal zinc intake, whereas zinc supplementation reduces inflammatory cell infiltration and improves clinical symptoms
[120][65]. At the cellular level, the beneficial impact of zinc on allergic immune reactions mainly includes T cell differentiation and antigen-specific T cell proliferation. In cultured human PBMCs (peripheral blood mononuclear cells), zinc deficiency increases Th17 differentiation
[121][66]. On the other hand, the zinc supplement in the cell culture of allergen-stimulated PBMCs alters the Th1/Th2 ratio and decreases the proportion of Th17
[122][67]. Zinc supplementation also enhances Treg differentiation either in allergen-stimulated PBMCs from atopic patients
[37][68] or in TGF-β treated PBMCs and mixed lymphocyte cultures
[36][69].
Iron is another trace element that has been linked to the etiology of atopic diseases
[123][70]. As the most common nutritional disorder, iron deficiency is associated with half anemia which affects about a third of the world’s population
[124][71]. Iron deficiency can be present either as low hemoglobin levels in the blood or with low levels of metabolically active iron despite normal ferritin iron storage in the body
[123][70]. While the majority of the iron requirement in the human body is met by recycling from senescent red blood cells by splenic macrophages and redistribution to other cells, dietary intake of iron provides only about one-tenth of the daily requirement
[123][70]. Therefore, the macrophage regulation of the iron pool and metabolism is highly important, which determines the activation state of the immune system.
Copper is closely related to iron metabolism. The copper-containing ferroxidase ceruloplasmin is involved with iron mobilization during acute inflammation, and its elevation indicates iron deficiency
[117,123][70][72]. A recent clinical study in Japan showed that multiple nutritional and gut microbial factors are associated with AR
[48][73]. Four nutrients (retinol, vitamin A, cryptoxanthin, and copper) were negatively associated with AR
[48][73]. In a cohort study in Poland (
n = 80), the plasma level of Cu was found to be associated with AR in children aged 9–12
[125][74].
Selenium is an essential trace element that is very important for optimal immune function. Populations from China, the UK, and Scandinavia generally tend to have reduced Se levels
[126][75]. While Se deficiency leads to impaired immune responses, Se supplements boost immune competence. Selenium is an essential component of glutathione peroxidase (GSH-Px), a key antioxidant enzyme that functions to reduce peroxides, therefore protecting against inflammation-induced, excessive oxidative stress-related membrane damage
[127][76]. While a lower serum level of selenium is reported to be associated with an increased risk of asthma in human studies
[128[77][78],
129], an animal study demonstrated that a lower level of selenium is associated with a lower asthma outcome. Although adequate dietary intake of selenium does not protect against the development of allergic asthma in mice, dietary selenium supplements have a synergistic anti-asthma effect with vitamin E in reducing airway inflammation and Th2-related cytokines
[118][79].
4. Obesity and Allergy
Dietary interventions producing weight loss in obese patients have been shown to be effective in improving asthma control [137][80]. Randomized controlled trials on dietary intervention showed that weight loss through restrictive diets with low energy is effective in improving asthma outcomes [138][81] and reducing airway inflammation in obese patients [139][82]. Even a normal caloric diet with a reduced content of fat, particularly saturated fat, was associated with reduced body weight and improvement of asthma-related quality of life in obese pubertal adolescents [140][83]. Although there are very limited studies, weight loss is associated with improved symptoms in atopic dermatitis.
Plant-based diets are effective for weight loss [143,144,145][84][85][86] and can be an effective strategy for weight control, as well as in the treatment of obesity [145][86]. A plant-based vegan diet excludes all animal products, mainly consisting of grains, legumes, and vegetables and fruits; while in comparison, a vegetarian diet does not eliminate all animal products but emphasizes the consumption of fruits, vegetables, and nuts [145][86]. The weight reduction effect of such diets may be attributed to reduced calories and low fat intake [145][86]. Plant protein, as part of a plant-based diet, has recently been shown to be a contributing factor for weight control in overweight individuals [143][84]. An increased intake of protein and a decreased intake of animal protein are associated with a decrease in body fat mass. Plant-based diets are nutritionally adequate if planned well [144][85]. However, nutrient intake in the long term can be a concern, as revealed in a study of the weight-loss effects of a vegan diet in overweight postmenopausal women. The adoption of a low-fat vegan diet for 14 weeks leads to changes in macronutrients such as decreased intake of total fat, saturated fat and cholesterol, protein, and increased carbohydrate and fiber intake [144][85]. In terms of micronutrients, the vegan diet increased intakes of total vitamin A, β-carotene, thiamine, vitamin B6, folic acid, vitamin C, magnesium, and potassium, but decreased intakes of vitamin D, vitamin B12, calcium, phosphorous, selenium, and zinc [144][85]. Fortified food or supplements may help those following a vegan diet to meet the requirements of micronutrient intakes.
5. Conclusions
In conclusion, diet and nutrition play a key role in the development and severity of allergic diseases by regulating tissue and immune homeostasis. Excessive calories, high intake of protein and saturated fatty acids, or lack of dietary fiber and micronutrients can trigger the defense mechanism in the immune system and prime the host for allergic reactions. Therefore, calorie restriction, coupled with sufficient dietary fiber and adequate macronutrient intake, will be essential for maintaining immune tolerance to allergens. The plant-based diets, which emphasize the high consumption of fruits and vegetables, grains, and legumes while avoiding or reducing animal foods, are associated with the reduction of inflammation and weight loss. Further dietary intervention studies are warranted to explore the potential beneficial effects of plant-based diets and the specific nutrients related to such diets on allergic outcomes. As basic research efforts identify more novel dietary components with anti-allergic properties, randomized placebo-controlled trials are also needed to verify their efficacy in human patients. Nutritional therapy holds great promise in reducing allergy symptoms, either as primary therapy and treatment or in support of drug therapy. Assessment of nutritional status and anthropometric characteristics of the patients, and analysis of host and gut microbiota by the multi-omics approach, will be important in future clinical trials to identify novel mechanisms linking nutrition and allergy.