Food Science and Technology Research
Online ISSN : 1881-3984
Print ISSN : 1344-6606
ISSN-L : 1344-6606
Review
The antiallergy activity of docosahexaenoic acid: A brief review
Kosuke Nishi
Author information
JOURNAL OPEN ACCESS FULL-TEXT HTML

2023 Volume 29 Issue 5 Pages 357-364

Details
Abstract

The prevalence of allergic diseases has been increasing worldwide. Allergy is known to be linked to lifestyle and diet. Docosahexaenoic acid (DHA) is an n-3 long-chain polyunsaturated fatty acid found in oily fish and microalgae. DHA is of great interest due to its various beneficial effects on the well-being and health of humans. Furthermore, a number of studies indicate a link between DHA and allergy. This review aims to describe the involvement of DHA in allergy development and allergic responses. Evidence-based research in humans indicates a potential protective effect of DHA consumption on allergy development although it is still controversial. Additionally, DHA has been demonstrated to possess antiallergy activity in laboratory animals and cell-based assays. Recent mechanistic investigations have suggested that not only DHA but its metabolites can be promising agents to prevent the incidence of allergic disease and attenuate allergic symptoms in the near future.

Introduction

The prevalence of allergic diseases, including hay fever, atopic dermatitis (eczema), allergic rhinitis, asthma, and food allergy, has been sequentially increasing in post-hygiene societies (Platts-Mills, 2015). Allergy is a T helper 2 (Th2) cell-driven, noncommunicable disease and is known to be linked to lifestyle and diet (Willemsen, 2016). Studies have shown that increased consumption of processed foods, including fast foods, could be related to the elevation in asthma prevalence (Wickens et al., 2005; Ellwood et al., 2013), while the intake of fruits and vegetables exhibits a protective effect on asthma (Nagel et al., 2010; Barros et al., 2015).

(4Z,7Z,10Z,13Z,16Z,19Z)-Docosa-4,7,10,13,16,19-hexaenoic acid or DHA (Fig. 1) is an n-3 long-chain polyunsaturated fatty acid (LCPUFA) with 22 carbons and six double bonds in the acyl chain and is found abundantly in oily fish, such as salmon, mackerel, and sardine, and microalgae. DHA is of great interest due to its various beneficial effects on the well-being and health of humans (Li et al., 2021). DHA has a protective effect against cardiovascular disease (Innes and Calder, 2018). Furthermore, epidemiological studies suggest that an increase in the prevalence of allergic disease could be associated with decreased consumption of n-3 LCPUFAs including DHA (Blümer and Renz, 2007). DHA would be thus a natural nutraceutical with antiallergy potential. This review aims to describe the effects of DHA on allergy development and allergic reactions in vitro and in vivo with a focus on its mode of action.

Fig. 1.

Chemical structures of docosahexaenoic acid and its metabolites.

Preclinical Studies

The antiallergy effect of DHA has been demonstrated in cell-based assays and animal experiments. Bryan et al. (2006) showed that DHA treatment significantly suppresses tumor necrosis factor a-induced C-X-C motif chemokine ligand (CXCL) 8 production and histamine-induced production of CC motif chemokine ligand (CCL) 5 and prostaglandin (PG) E2 in human alveolar respiratory epithelial cell line A549 cells. Because the chemotactic factors CCL5 and CXCL8 produced in the respiratory airways induce activated granulocyte infiltration, DHA would diminish the number of migrated granulocytes in the airway and the resultant allergic inflammation. van den Elsen et al. (2013a) showed that DHA treatment inhibits the production of PGD2, interleukin (IL) 4, and IL-13, which are mediators involved in severe, uncontrolled asthma, in human mast cell lines LAD2 cells and HMC-1 cells stimulated with ionomycin/phorbol 12-myristate 13-acetate (PMA). They also demonstrated that the inhibitory effect of DHA on IL-13 production is enhanced by cotreatment with a mitogen-activated protein kinase p38 inhibitor or a c-Jun N-terminal kinase inhibitor. Park et al. (2013) reported that the production of Th2 cytokines IL-4, IL-5, and IL-13 by mouse bone marrow-derived mast cells stimulated with PMA and ionomycin is significantly reduced when the cells were pretreated with DHA. In addition, they examined an antiallergy effect of n-3 LCPUFAs in vivo using conventional NC/Nga mice treated with 2,4,6-trinitrochlorobenzene on the dorsal skin to induce dermatitis. They found that atopic dermatitis-like skin lesions are significantly attenuated and GATA1 expression in mast cells significantly increases in the NC/Nga mice orally administered with fish oil.

Several animal studies have suggested the role of n-3 LCPUFA intake in allergic immune responses. de Matos et al. (2012) reported the effect of an n-3 LCPUFA-enriched diet containing 8 % DHA and 16 % eicosapentaenoic acid (EPA) in total oil in food allergy model mice, where mice were fed a regular diet containing fish oil starting three weeks before the first sensitization and continued during the whole sensitization period until sacrifice. They found that serum levels of allergen-specific immunoglobulin (Ig) E and IgG1 significantly decrease in the mice fed a fish oil diet. They also found that histological inflammatory parameters in jejunum are significantly attenuated in the n-3 LCPUFA group. van den Elsen et al. (2013b) reported the effects of an n-3 LCPUFA-enriched diet containing 4 % soybean oil and 6 % tuna oil (28 % DHA, 7 % EPA, 9 % other PUFAs, 29 % saturated fatty acids, 23 % monounsaturated fatty acids, and 4 % minor components) on effector immune cells and immune responses in food allergy model mice, in which mice were fed a tuna oil diet before and during oral sensitization with whey. They found that the tuna oil diet significantly decreases the acute allergic skin response induced by whey in sensitized mice. They also found that serum levels of anti-whey IgE, IgG1, and IgG2a are significantly decreased in whey-sensitized mice on a tuna oil diet. In addition, the tuna oil diet significantly decreased the percentage of activated Th2 cells in the spleen collected from whey-sensitized mice fed a tuna oil diet. They also reported in another paper the effects of DHA intake in an allergic animal model, where mice were fed a DHA-enriched diet before and during oral sensitization (van den Elsen et al., 2014). They found that acute allergic skin response induced by an allergen is significantly reduced in the DHA supplementation group. In addition, serum levels of mucosal mast cell protease 1 and anti-allergen-specific IgE and IgG1 significantly decreased in the DHA supplementation group. de Theije et al. (2015) reported the effects of n-3 LCPUFA intake in food allergy model mice, in which mice were fed an n-3 LCPUFA-enriched diet, which was the same composition as the one mentioned above (van den Elsen et al., 2013b), before and during the entire experiment. They found that the acute allergic skin response induced by an allergen is significantly reduced in the n-3 LCPUFA-supplemented group. These studies have revealed the antiallergy effects of DHA in laboratory animals.

Observational Studies

The first epidemiological evidence of the link between n-3 LCPUFA intake and allergic diseases was presented by Peat et al. (1992). Subjects of this study were children aged seven to eleven years, who had lived in New South Wales, Australia. Since then, several observational studies have suggested the association between prenatal fish consumption and allergy development in offspring. Cross-sectional studies conducted in Germany and Japan showed that there could be a link between the consumption of DHA and EPA and a decreased prevalence of allergic rhinitis (Hoff et al., 2005; Miyake et al., 2007). A Swedish longitudinal study showed that total n-3 LCPUFA (DHA, EPA, and docosapentaenoic acid) proportion in plasma phospholipids at age eight years is associated with a reduced risk of asthma, rhinitis, and allergen sensitization at age 16 years as well as with incidence of asthma between ages eight and sixteen years (Magnusson et al., 2018). A French longitudinal study of children showed that infants who had received DHA/EPA/arachidonic acid-enriched formula were given significantly reduced medications at the age of two months (Adjibade et al., 2022).

Intervention Studies

Many papers have shown a link between the intake of DHA by pregnant women and the development of allergic diseases in infants. Koch et al. (2008) reported the result of a randomized, double-blind, placebo-controlled trial conducted in Germany, in which 53 patients (18–10 years old) with atopic eczema received either DHA (5.4 g) or control capsules every day for eight weeks. They found that the clinical outcome assessed as a severity scoring of atopic dermatitis index is significantly improved in the DHA group at week 8. Additionally, they found that IgE production is significantly inhibited in peripheral blood mononuclear cells stimulated with IL-4 and an anti-human CD40 monoclonal antibody, which were collected from the patients of the DHA group. Furuhjelm et al. (2009) reported a randomized, double-blind, placebo-controlled trial conducted in Sweden, where 145 pregnant women were given n-3 LCPUFA (1.6 g EPA and 1. 1 g DHA) supplementation or placebo from the 25th gestational week and continuing through 15 weeks of lactation. They found that the incidence of food allergy and IgE-related eczema is significantly lower in the n-3 LCPUFA group than in the placebo group. Additionally, they reported the two-year follow-up of infants in another paper and found that the cumulative incidence of IgE-related disease is significantly lower in the n-3 LCPUFA group than in the placebo group (Furuhjelm et al., 2011). Palmer et al. (2012) reported the follow-up of 706 infants at high risk of developing allergic disease, whose mothers had participated in a randomized, double-blind, placebo-controlled trial conducted in Australia. In the trial, the mothers were given 900 mg of n-3 LCPUFAs or a placebo per day from the 21st week of gestation until birth. The result showed that the prevalence of infants with atopic eczema tends to be lower in the n-3 LCPUFA group than in the placebo group at one year of age. The study also showed that sensitization to a food allergen tends to be less frequent in the n-3 LCPUFA group. Warstedt et al. (2016) reported the result of an intervention study conducted in Sweden. In the study, a daily supplementation (2.7 g) of DHA and EPA to pregnant women at risk of having an allergic infant from gestational week 25 until three months of lactation increased the concentrations of DHA and EPA in breast milk. Additionally, they showed that higher proportions of DHA and EPA in breast milk are associated with an absence of IgE-associated disease in infants.

A Th2-skewed immune response is associated with the development of allergic disease. Dunstan et al. (2003) reported the result of a randomized, placebo-controlled trial conducted in Australia. In the study, IL-10 production was significantly suppressed in cat hair allergen-stimulated cord blood mononuclear cells collected at delivery from atopic, pregnant women received fish oil (3.7 g, mainly composed of DHA and EPA) every day from the 20th week of gestation until delivery. They also observed that infants in the fish oil group have a positive skin prick test to egg three times less than those in the placebo group at one year of age. Krauss-Etschmann et al. (2008) reported the result of a randomized, double-blind, placebo-controlled trial conducted in Spain, Hungary, and Germany. In the study, 311 pregnant women received either 0.5 g of DHA and 0.15 g of EPA or a placebo every day from the 22nd gestational week. The transcription of Th1/Th2-related cytokine/chemokine genes was analyzed in 197 maternal and 195 cord blood samples. The data showed that n-3 LCPUFA supplementation is significantly associated with decreased transcription of IL-1 and interferon (IFN) γ genes in maternal blood samples. Additionally, they showed that the transcription of the transforming growth factor (TGF) β gene significantly increases, while the transcription of IL-4, IL-13, and CCR4 genes significantly decreases in cord blood samples by maternal n-3 LCPUFA supplementation. D'Vaz et al. (2012a) reported the result of a randomized, double-blind, placebo-controlled trial conducted in Australia. In the study, 150 infants at high atopic risk were given fish oil containing 280 mg of DHA and 110 mg of EPA or a placebo every day from birth to six months. Blood from 120 infants was collected at six months of age, and cytokine responses of lymphocytes stimulated with an allergen or with an agonist of Toll-like receptors were determined. The result revealed that the production of IL-13 and IL-10 tends to be lower in the fish oil group than in the placebo group. They also reported that the increased plasma levels of DHA and total n-3 LCPUFAs of the same subjects at the age of six months are significantly associated with decreased risk of recurrent wheezing (D'Vaz et al., 2012b). Lee et al. (2013) found a link between the methylation levels in the promoter regions of IFN-γ and IL-13 genes and n-3 LCPUFA supplementation (P = 0.06) in an intervention study conducted in Mexico. Subjects of the study were pregnant women in gestation weeks 18–22 and were randomly assigned to receive daily either 400 mg DHA or a placebo. The result suggests that maternal n-3 LCPUFA supplementation during pregnancy may modulate the Th1/Th2 balance in infants. These studies described above indicate that maternal perinatal consumption of DHA and EPA would play a role in preventing the development of allergic disease in infants.

Pooled and Meta-Analyses

Stratakis et al. (2018) reported the result of a pooled analysis of prospective birth cohorts. In the study, the authors pooled individual data from two cohorts conducted in the Netherlands and Greece. Subjects of the Dutch cohort were pregnant women with gestational age <16 weeks, and 1008 women provided umbilical cord blood samples. A follow-up evaluation was conducted when the children were seven years of age. Subjects of the Greek cohort were pregnant women at 10–13 weeks of gestation. Fatty acid levels of 500 umbilical cord blood samples were measured. A follow-up evaluation was conducted when the children were six years of age. The authors found that higher concentrations of DHA and EPA and a higher ratio of total n-3:n-6 LCPUFAs in cord blood, which reflects fetal exposure in late pregnancy, are linked with reduced risk of wheezing and asthma symptoms in children aged 6–7 years. Best et al. (2016) reported the result of a meta-analysis of randomized controlled trials. In the study, the authors combined three randomized controlled trials conducted in Australia and Sweden and found that the incidence of atopic eczema in the offspring at one year of age is significantly reduced in the maternal n-3 LCPUFA supplementation group. In addition, they found that a positive result in a skin-prick test and sensitization to any food in the offspring at one year of age are significantly reduced in the maternal n-3 LCPUFA supplementation group.

These studies suggested that maternal n-3 LCPUFA supplementation could be a preferred intervention to exert a protective effect on the incidence of allergic disease in the offspring. From the studies shown above, maternal DHA supplementation during pregnancy would have an allergy-preventive benefit for the offspring. However, the anti-allergy effect of DHA is still controversial. Several papers reporting the result of a randomized controlled trial showed that n-3 LCPUFA supplementation does not significantly alter the incidence of IgE-associated allergic disease (Palmer et al., 2013; Best et al., 2018; Decsi et al., 2022). Some of these studies showed the tendency of an anti-allergy effect of DHA supplementation although it was not statistically significant. Some follow-up studies showed little effect on the incidence of allergic disease in infants delivered from mothers supplemented with n-3 LCPUFA. It thus seems to be important to continuously consume enough amount of DHA to receive its beneficial anti-allergy effect. More studies are required to find the appropriate dose of DHA intake and conclude the anti-allergy effect of DHA.

Mechanistic Studies

A number of studies on potential mechanisms underlying the antiallergy activity of DHA have been reported. Eicosanoids are lipid mediators with 20 carbons, including PGs, leukotrienes, and thromboxanes, biosynthesized by lipoxygenase (LOX) and cyclooxygenase (COX). Arachidonic acid-derived eicosanoids induce inflammatory responses and sensitization to allergens (Shek et al., 2012). N-3 LCPUFAs, including DHA, exert antiallergy activity by competing with arachidonic acid as substrates for LOX and COX; n-3 LCPUFA-derived LOX and COX products possess anti-inflammatory activity. In addition, n-3 LCPUFAs modulate the plasma membrane fluidity due to a high number of unsaturated bonds and change the components of lipid rafts, microdomains rich in sphingolipids and cholesterols with concentrated molecules required for intracellular signaling associated with the cellular function, in immune cells, which leads to the antiallergy activity by altering the intracellular signaling and thus suppressing proinflammatory mediator production (Shek et al., 2012; Wang and Kulka, 2015). Recently, Fussbroich et al. (2020) showed an effect of n-3 LCPUFA supplementation on microRNA expression in allergic asthma model mice. In the study, mice were sensitized with an extract from house dust mites and then received an n-3 LCPUFA supplementation daily for 24 days. For the last three days of supplementation, the mice were challenged, and then the lung tissue was collected for the analysis of microRNA expression. As a result, 62 microRNAs were significantly dysregulated in allergic asthma mice, of which 21 microRNAs, including miRNA-146a-5p, were restored by n-3 LCPUFA supplementation. They also showed that upregulated miRNA-146a-5p expression is associated with reduced activities of COX-2 and 5-LOX, which produce chemical mediators in inflammation.

The antiallergy activity of DHA metabolites in addition to DHA itself has attracted attention these days. 17S-Hydroperoxy-docosa-4Z,7Z,10Z,13Z,15E,19Z-hexaenoic acid is synthesized from DHA by 15-LOX. It is next transformed to specialized pro-resolving mediators resolvin D1 and D2 (Fig. 1) by 5-LOX via 7S(8)-epoxide intermediate (Bannenberg and Serhan, 2010). Rogerio et al. (2012) reported the impact of resolvin D1 in allergic asthma model mice. Sensitized mice were intravenously injected with resolvin D1 before or after the aerosol challenge. The authors demonstrated that resolvin D1 significantly reduces airway eosinophilia, mucus metaplasia, IL-5 level in bronchoalveolar lavage fluid, and IKBa degradation in the lung. Yang et al. (2022) found that the histamine-induced increase in intracellular calcium concentration and mucous secretion, which are observed in ocular allergy, is significantly low in resolvin D1-treated conjunctival goblet cells collected from humans and rats. Puzzovio et al. (2023) proposed that resolvin D1 released from activated mast cells contributes to the resolution of allergic inflammation. In the study, they showed that pretreatment with DHA significantly enhances resolvin D1 production by mouse bone marrow-derived mast cells, human LAD2 mast cells, human cord blood-derived mast cells, foreskin-derived mast cells, and nasal polyp-derived mast cells after IgE-mediated activation. In addition, they found a trend of reduced inflammation in a mouse model of allergic peritonitis accompanied by increased resolvin D1 release. 17-Hydroxydocosahexaenoic acid is a precursor of D-series resolvins. Kim et al. (2016) reported that resolvin D1 and 17-hydroxydocosahexaenoic acid inhibit IgE production by human peripheral blood B cells collected from healthy donors. They proposed that resolvin D1 blocks class switching to IgE in human B cells by stabilizing the Bcl-6 expression.

Protectin D1 (Fig. 1) is generated from DHA by 15-LOX via 16(17)S-epoxide-docosa-4Z,7Z,10Z,12E,14E,19Z-hexaenoic acid intermediate (Bannenberg and Serhan, 2010). Bilal et al. (2011) demonstrated a protective effect of n-3 LCPUFAs in allergic airway responses using Fat-1 transgenic mice that produce markedly high levels of DHA and EPA. The authors found a significant decrease in the number of eosinophils and in the concentrations of IL-1α, IL-2, IL-5, IL-9, IL-13, granulocyte-colony stimulating factor, CXCL1, and CCL5 in bronchoalveolar lavage fluid collected from Fat-1 transgenic mice sensitized in the lung. They also found significantly increased concentrations of protectin D1 and resolvin E1, which are biosynthesized from DHA and EPA, respectively, in the lung of Fat-1 transgenic mice.

Maresin-2 (Fig. 1) is generated from DHA by 12-LOX and soluble epoxide hydrolase via 13S,14S-epoxy-maresin intermediate (Deng et al., 2014). Yu et al. (2022) reported an antiallergy activity of maresin-2. They found a significant reduction in mucus secretion and inflammation in lung tissue, the number of inflammatory cells and Th2 cytokine levels in bronchoalveolar alveolar lavage fluid, and the total and allergen-specific serum IgE in allergic bronchial asthma mice intravenously injected with maresin-2 before inhalation challenge.

Docosahexaenoyl ethanolamide (Fig. 1) is also one of the DHA metabolites, and its antiallergy activity in vitro and in vivo was reported (Nishi et al., 2019). The authors found that docosahexaenoyl ethanolamide significantly inhibits the degranulation of both rat basophilic leukemia RBL-2H3 cells and mouse bone marrow-derived mast cells, suppresses IgE-mediated passive cutaneous anaphylaxis reaction in mice, and lessens an allergic symptom in pollinosis model mice. Docosahexaenoyl ethanolamide also altered the production of IgE and Th2-associated cytokines in splenocytes collected from the pollinosis mice. Ethanolamides of various long-chain fatty acids were further evaluated. The authors found that ethanolamides of n-3 LCPUFAs (α-linolenic acid and EPA) in addition to docosahexaenoyl ethanolamide exert a promising antiallergy effect, whereas free fatty acids and ethanolamides of fatty acids other than n-3 LCPUFAs show no or weak activity (Kim et al., 2019). The studies shown above indicate that DHA metabolites could be a promising agent for the prevention and attenuation of IgE-associated allergic diseases.

Conclusion

A number of observational and intervention studies have indicated an association between maternal DHA intake during pregnancy and the development of allergic disease in infants. However, the potential protective role of DHA in allergy development is still controversial; further detailed studies are required to establish the robustness of these findings. DHA has also been demonstrated to possess the potential to modify immune function as well as inflammatory processes in laboratory animals and cell-based assays although its molecular target and the underlying mechanisms of action are still not completely clear. Additionally, the antiallergy activity of DHA metabolites has attracted attention. DHA metabolites and their derivatives can be promising agents to prevent the incidence of allergic disease and attenuate allergic symptoms in the near future.

Acknowledgements This work was supported in part by Nipponham Foundation for the Future of Food and Grant-in-aid for Scientific Research (C) (JSPS KAKENHI Grant Numbers JP17K07792 and JP20K05891).

Conflict of interest There are no conflicts of interest to declare.

References
 
© 2023 by Japanese Society for Food Science and Technology

This article is licensed under a Creative Commons [Attribution-NonCommercial-ShareAlike 4.0 International] license.
https://creativecommons.org/licenses/by-nc-sa/4.0/
feedback
Top