Consumption of ω3-fatty acids during perinatal life: role in immuno-modulation and allergy...

J. Perinat. Med. 35 (2007) S12–S18 • Copyright � by Walter de Gruyter • Berlin • New York. DOI 10.1515/JPM.2007.031

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Consumption of v3-fatty acids during perinatal life: role inimmuno-modulation and allergy prevention

Nicole Blumer and Harald Renz*

Department of Clinical Chemistry and MolecularDiagnostics, Philipps University of Marburg, Germany

Abstract

Epidemiological data suggest that dietary factors mayhave a role in recent increases of the prevalence of aller-gic diseases. One food-related component might be thereduced consumption of v3-polyunsaturated fatty acidsobserved especially in the Western societies; yet, clinicaltrials supplementing v3-fatty acids to adults with estab-lished allergies and bronchial asthma have generallybeen disappointing. However, it is known that the imma-ture immune system is highly susceptible to immuno-modulatory environmental conditions particularly in thepre- and postnatal period. This review discusses theimmuno-modulatory effects of v3-fatty acids supple-mentation in the perinatal life phase on the immune sys-tem of the child. Evidence exists that perinatal v3-fattyacid exposure affects T-cells and antigen presenting cellsof the neonates likely due to altered eicosanoid meta-bolism. Although animal experiments strongly suggest arole of maternal v3-fatty acid intake on allergic immuneresponses in the offspring, the beneficial effect of v3-fatty acid supplementation has been studied in a smallnumber of clinical trials. In these studies perinatal sup-plementation had some positive effects on distinct clin-ical phenotypes of the atopic syndrome. However, morestudies are needed to fully explore the opportunity ofperinatal immuno-modulation.

Keywords: Allergy; immuno-modulation; perinatal lifephase; v3-fatty acids.

Introduction

Chronic inflammatory diseases, including allergies orautoimmune diseases are highly prevalent in Westernand industrialized countries. Enormous increase, in inci-dence and prevalence of these disorders were observed

*Corresponding author:Prof. Harald Renz, MDDepartment of Clinical Chemistry and Molecular Diagnostics35033 MarburgGermanyTel.: q49 64212866234Fax: q49 64212865594E-mail: [email protected]

during the last 2–4 decades. Among these diseases,allergies represent an immunologic disorder stronglyexemplifying the interaction between genetic and envi-ronmental conditions. Furthermore, especially the peri-natal environment seems to play a decisive role for theinitiation of allergic disorders. Epidemiological data indi-cate that several environmental changes could be asso-ciated with development of allergies w41x. However, nofirm cause-and-effect relationship between environmen-tal determinants and onset of chronic immunological dis-orders could be established. Therefore, there is in-creasing need to analyze in more detail the interplaybetween defined environmental changes and the devel-opment of allergic diseases with the aim to develop newand better preventive strategies.

One factor, among others, described to be associatedwith the increased prevalence of allergic disorders is thealtered dietary behavior, especially that related to con-sumption of v3- and v6-polyunsaturated fatty acids(PUFAs). In many Western and industrialized societies thedecreased consumption of v3-fatty acids paralleled anincreased intake of v6-fatty acids. Therefore, the ratio ofv6- to v3-fatty acids in Western diets is currently higheras compared to the past. It has been proposed that thehigh concentrations of v6-fatty acids in Western dietsfavor a TH2 differentiation of the immune system duringcritical early periods of ontogeny and development. Theperinatal period represents an important window to ini-tiate the development of allergic disorders. v3-fatty acidsare described to act predominantly as anti-inflammatorycomponents and have therefore generated great interestwith regard to modulating inflammatory immune re-sponse such as allergy (Table 1).

It has been recently recognized that the very early lifeperiod is highly susceptible to immuno-modulation.Exposure to distinct environmental components duringpregnancy and in the very early life period is consideredto influence subsequent patterns of the neonatal immunesystems, and this may contribute to the increase in aller-gic diseases. Therefore, a strong need exists to identifyperinatal factors associated with this immuno-modulat-ing capacity early in life. Accumulating evidence existsthat maternal dietary PUFA consumption has effects onneonatal immune function and inflammatory reactionsw5x.

This review focuses on immuno-modulatory effects ofv3-fatty acids on the developing neonatal immune sys-tem with special interest in allergic disorders, and itspotential role in allergy protection. Secondly, it addresses

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Table 1 v3-fatty acids and allergic disorders.

Study/observation Outcome Author

Randomized, placebo Reduced sensitization to egg; less Dunstan et al., 2003, Clin Exp Allergycontrolled, prospective trial; severe atopic dermatitis, but Dunstan et al., 2003, J Allergy Clin ImmunolSupplementation of pregnant unchanged IgE levels at age of onewomen with fish oil (ns98) year

Randomized, placebo No effect on IgE levels and asthma, Mihrshahi et al., 2004, Pediatr Allergy Immunolcontrolled, prospective trial; reduced prevalence to develop Peat et al., 2004, J Allergy Clin Immunolv3-supplementation of wheeze at age of 18 months;pregnant women and their reduced risk to develop atopicchildren (ns616 women) cough at age of three years

Case control, retrospective Development of autoimmune Stene et al., 2000, Diabetologiastudy; v3-rich diet during diseases (diabetes type 1) until agepregnancy (ns85) of 15 years

Prospective cohort study; Reduced risk to develop allergic Nafstad et al., 2003, J AsthmaSupplementation of children rhinitis at age of four yearswith fish oil during the firstyear of life (ns2531)

the question how v3-fatty acid effects are being trans-ferred from the mother to the child, either during preg-nancy or during lactation.

Effects of v3-fatty acids on immune functions

v3-fatty acids cannot be synthesized by man and are,therefore, essential components of the diet. They arefound primarily in fatty fishes with high oil content. Twobiologically very active fatty acids of the v3 family aredocosahexeanoic acid (DHA) and eicosapentaenoic acid(EPA). These fatty acids seem to carry major immuno-modulatory functions. They might influence immune cellfunction for a variety of reasons: First, the fluidity of cellmembranes is important in the function of all cell types,including immune cells. Membranes of most immunecells contain large amounts of the v6-fatty acid arachi-donic acid (AA). High intake of v3-fatty acids decreasesthe proportion of AA in immune cell membranes and,consequently, the proportion of v3-fatty acids and, sub-sequently, cell responsiveness to exogenous stimuli.

Second, after mobilization of AA from cell membranes,this fatty acid acts as a substrate for the production ofeicosanoids, namely the two-series of the prostanglan-dins (e.g., PGE2) and the four-series of the leukotriens(e.g., LTB4). These eicosanoids have different, partiallyopposing immuno-modulatory activities: PGE2 is knownto promote IgE production, whereas LTB4 favors theexpression of many pro-inflammatory cytokines includingTNF-a, IL-1, IL-6 and IL-2. Overall, these eicosanoids arepredicted to be involved in maintenance of allergicinflammatory reactions, and to induce bronchoconstric-tion in asthmatic patients w42x. The v3-fatty acids EPAand DHA competitively inhibit the metabolism of AA,resulting in a reduced production of the ‘‘pro-allergic’’

four-series of the leukotriens and the two-series of pros-taglandins. Metabolism products of the v3-fatty acidsare immunologically less active and are less potent inmaintaining allergic reactions w27x.

Third, v3-fatty acids are known to inhibit the activationof pro-inflammatory cell signals like the NF-kB signaltransduction cascade w28, 29x, the production of pro-inflammatory cytokines including IL-1b, TNF-a, IL-6 andIL-2 and the proliferation of lymphocytes as well as ofNK cells w4x.

The postulated anti-inflammatory role of v3-fatty acidson immune responses implies a relationship between theintake of fatty acids and the suppression of inflammatorydiseases including allergy. Indeed, a reduced intake ofv3-fatty acids, mainly DHA, has been observed duringthe period of increasing asthma prevalence w2x. Takentogether, these observations resulted in the new conceptof v3-fatty acids as ‘‘allergy preventing factors’’. Whetherv3-fatty acid exposure in the perinatal life phase modu-lates the neonatal immune response, and if so, by whichmechanisms, is of major interest.

v3-fatty acids in cord blood and thedevelopment of immunological disorders

There are several studies associating cord blood fattyacid concentrations and the subsequent development ofimmunologic disorders such as allergic diseases. In thiscontext, Yu et al. w49x observed that v3-fatty acid con-centrations of maternal and fetal serum correlate only inchildren who did not develop allergic diseases within thefirst six years of life. They conclude that an abnormalmetabolic relationship exists between mothers and chil-dren at risk of atopic disease. An impairment of cordblood v6-fatty acid composition was associated with the



S14 Blumer and Renz, v3-fatty acids and immuno-modulation


development of allergic diseases w15x. In contrast, Yuet al. w49x detected increased levels of v6- and v3-fattyacids in cord blood and this was associated with thedevelopment of allergic diseases, whereas Beck et al. w1xfound no differences in cord blood levels of v3-fattyacids between children who did or did not develop aller-gies. Thus, results concerning the associations betweenconcentrations of v3-fatty acids in cord blood and aller-gies in later life seem to be controversial and require fur-ther investigation. Recently, Gold et al. w16x evaluatedwhether levels of v3- and v6-fatty acids in cord bloodare related to neonatal immune response. They showedthat higher v3-fatty acid levels in cord blood are asso-ciated with reduced lymphocyte proliferation andreduced IFN-g production after antigen-specific (dustmite, cockroach) stimulation. Whether these observa-tions have any clinical implications remains to be eluci-dated. However, several investigators found reducedneonatal IFN-g levels to be associated with increasedrisks to develop allergic disorders later in life w36, 43x.

Interventional studies

Because of the immuno-modulatory potential of v3-fattyacids and their metabolites, these fatty acids were oftenused for therapy aiming to ameliorate allergic diseases.Consequently, several clinical trials using v3-PUFA sup-plementation in adults or children with established bron-chial asthma were performed w47x. The aim of these trialswas to determine the effect of v3-fatty acid supplemen-tation in asthma. A Cochrane review compared nine ran-domized controlled trials conducted between 1986 and2001. In all of these studies the intervention period tookat least four weeks. All study participants suffered frombronchial asthma. Seven of these studies were conduct-ed in adults, whereas two were conducted in children.Eight studies compared fish oil with placebo and onecompared high dose versus low dose of v3-fatty acidsupplementation. In summary, there was no consistenteffect on the analyzed outcomes such as lung function,asthma symptoms, asthma medication use, or bronchialhyperreactivity. Authors concluded that at least in adults,v3-fatty acid supplementation does not lead to animprovement of their asthmatic symptoms. Furthermore,there are no sufficient data to make a final judgmentabout supplementation on established asthma in youngatopic children.

In the meantime, more studies have been conductedregarding the prevention of allergic disease by using v3-fatty acid supplementation in the perinatal life phase. Inone randomized controlled trial in 98 atopic women whoreceived either fish oil or placebo from 20 weeks’ ges-tation until delivery w9x, infants within the fish oil grouphad a reduced prevalence to develop sensitizationagainst hen eggs at the age of one year. Furthermore,

these children developed less severe atopic dermatitis incomparison to children of the control group, although theprevalence of atopic dermatitis was not reduced. Therewas no difference in IgE-levels between study groupsw10x.

Mihrshahi and co-workers w32x have also used v3- fat-ty acids to prevent the development of allergic diseases.In this study, 616 pregnant women with a family historyof atopic diseases were recruited and asked to preparemeals containing high levels of v3-fatty acids. After birth,children received a diet containing high levels of v3-fattyacids from the age of six months onwards, and were ana-lyzed at 18 months and 3 years of age. The control fam-ilies consumed food with a high content of v6-fatty acidsand children received placebo supplements. The v3-intervention diet had no effect on neonatal serum IgE lev-els, atopy (assessed by skin prick testing) or bronchialasthma (diagnosed by the physician) at 18 months ofage. However, the prevalence of wheezing was reducedsignificantly in the v3-supplemented study group. At theage of three years children had a clinical assessment foreczema, serum IgE levels and skin prick testing againstingested and inhaled allergens w35x. Children of the v3-supplementation group showed a reduced risk to devel-op atopic cough, whereas no changes were observed forIgE levels or skin prick testing. This suggests an immunemodulating activity of v3-fatty acid supplementation inairway inflammation rather than allergic sensitization.

The study of Nafstad and colleagues w33x, based on2531 children, showed that fish oil supplementation dur-ing the first year of life was negatively associated withthe risk to develop allergic rhinitis. A negative associationwith the development of allergic asthma was observedexclusively in children of non-atopic mothers.

A retrospective study underlined that supplementationwith a diet rich in v3-fatty acids during pregnancy w38xand in the first year of life w39x seems to reduce the riskof TH1 mediated diseases like type-1 diabetes.

Although these studies are highly encouraging, anurgent need exists for more controlled studies examiningthe efficiency of fish oil supplementation in prevention ofdisease related to immunological disorders. This mightlead to more safe and natural intervention strategies.Some published recommendations concerning the intakeof v3-fatty acids during pregnancy and lactation are list-ed and summarized in Table 2.

Animal studies

Epidemiological studies provide the basis for the devel-opment of new hypotheses which then undergo testingin in-vitro and in-vivo systems. Until now only few animalstudies were published analyzing the effect of maternalexposure to certain fatty acids on the developing neo-natal immune system. One study was performed by





Table 2 Recommended dosage intake of v3-fatty acids.

References Recommended daily dosage/type Populationof v3 fatty acid

Mele MC, Miggiano GAC, 2003 DHA: 100 mg/day (q50–60 mg/day Pregnant womenin the third trimester)

Dietary Reference Intakes, 2000 a-linolenic acid: Pregnant and lactating1.4 g/day pregnant women women1.3 g/day lactating women

Makrides M, Gibson RA, 2000 v3 PUFA: Pregnant women200–400 mg/day

Simopoulus AP, 1999–2000 DHA: 300 mg/day Pregnant and lactatingwomen

European Food Saftey DHA: 250 mg/day Pregnant and lactatingAuthority (EFSA) women

Scientific Advisory EPA and DHA: 250 mg/day Pregnant and lactatingCommittee on Nutrition (SACN) women

Korotkova and co-workers, examining whether maternalintake of dietary fatty acids influences the induction oforal tolerance to the food allergen ovalbumin (OVA) inneonatal rats w24, 25x. In addition, serum leptin levels inthese neonates were assessed w23x. Leptin is known tobe an immune-modulating hormone modifying T-cellresponses in favor of a TH1 biased direction w30x. In thisexperiment rats were fed during late gestation andthroughout lactation with the following diets: a PUFAsdeficient diet, diet rich in v6-fatty acids, a diet rich in v3-fatty acids, or a specific combination of v6- to v3-fattyacids, respectively. Offspring of all groups were supple-mented with OVA via breast milk and immunized eitherto OVA or to the heterologous antigen human serumalbumin (HSA) at an age of three weeks. Breast milk anal-ysis revealed a significantly different composition of fattyacids depending on maternal diet. Offspring of motherstreated with a diet deficient in PUFAs developed a sup-pressed antibody response against OVA, indicating aninduction of tolerance against OVA. Maternal exposure toa diet rich in v3-fatty acid resulted in a suppressedimmune response against OVA as well as against theunrelated antigen HSA, a mechanism known as bystand-er suppression. A maternal diet rich in v6-fatty acids ledto OVA-specific tolerance induction in the offspring, butthe immune response against the HSA-antigen was notinhibited. The underlying mechanism still remains to beelucidated, but antigen-specific T-cell unresponsivenessmay be part of it. Maternal supplementation with a dietcontaining a specific v6/v3-ratio did not lead to thedevelopment of oral tolerance in the offspring. Theseresults suggest that the induction of the immunologicalmechanism of oral tolerance is dependent on the con-centration of v6- and v3-fatty acids in the maternal diet.

Decreased serum leptin levels could be found in off-spring of mice supplemented with v3-fatty acids. Leptinis believed to play an important role in the induction ofinflammatory cell responses, suggesting a potential rolein allergic reactions. Overall, the use of animal models

underlines the effects of v3-fatty acids on the developingneonatal immune system. However, further studies areneeded in this field to fully appreciate the mechanismsof allergy prevention.

Potential immuno-regulatory mechanism ofv3-fatty acids during pregnancy

In-vitro analysis, as well as animal and human in-vivostudies, indicate that v3-fatty acid supplementationsomehow primes the development of the very youngimmune system, especially in the perinatal period. Inorder to develop effective prevention strategies it isimportant to uncover how these effects are transferredfrom mother to child.

Prior to birth, all of the v3-fatty acids accumulated bythe fetus originate from the maternal circulation via pla-cental transfer. After birth, transfer of the fatty acidsoccurs via breast milk. Several authors described thatfree fatty acids can pass the placenta selectively w13x. Inaddition, evidence now exists that cellular uptake of thefree fatty acids occurs through a membrane translocationprocess involving a fatty acid binding protein. The pref-erentially transferred fatty acid in human is the v3-fattyacid DHA. Furthermore, fatty acids cross the placenta inthe form of lipoproteins w18x via placental lipoproteinreceptors. The levels of PUFAs in the fetus and in moth-ers are usually closely related w14x. Accordingly, v3-PUFAsupplementation during pregnancy increases the neo-natal composition of v3-PUFAs in cord blood detectedin plasma and erythrocyte phospholipids w34x. Interest-ingly, Yu et al. w49x postulated that the correlationbetween the maternal fatty acid composition and thoseof the child was only found in non-allergic mothers, indi-cating a disturbed fatty acid metabolism in allergicmother. However, De Vriese and colleagues w7x observedthat high fatty acid intake during the first and third tri-





mesters of pregnancy does not alter DHA concentrationin cord plasma phospholipids.

Dunstan et al. w11x showed that fish oil supplementa-tion during pregnancy enhances the DHA-composition ofthe phospholipid fractions of neonatal cell membranes,whereas levels of the v6-fatty acid AA were reduced. Asdescribed above, altered fatty acid composition of cellmembranes might be causative for changes in immuneresponses. v3-fatty acid treatment during pregnancy isalso described to effect cytokine expression patterns ofneonatal cord blood cells. IL-13 levels in cord plasmawere significantly reduced in prenatal fish oil supple-mented children in comparison to those from placebo-supplemented mothers w10x. The predictive value ofneonatal IL-13 levels concerning the risk to develop aller-gic diseases is controversial and, therefore, unclear w46x.However, lower IL-13 levels might shift immune re-sponses in favor of a TH1 direction which is counterbal-ancing allergy-driven TH2 immune responses.Furthermore, Dunstan et al. w9x found a tendency ofreduced expression levels of several neonatal cytokinesas well as an inhibited lymphoproliferative immuneresponse in children exposed to v3-fatty acids beforebirth.

Among other characteristic features, allergic diseasesexhibit an accumulation of eosinophils paralleled by high-ly active differentiation process of these inflammatorycells. CD34 is a cell surface marker expressed by mye-loid progenitor cells including eosinophilic progenitors.This marker is expressed differently in cord blood of neo-nates at risk to develop allergic diseases in comparisonto healthy controls w44x. Denburg et al. w6x demonstratedthat the percentage of CD34 positive cells in cord bloodwas higher in children from v3-fatty acid supplementedmothers. Furthermore, these cells showed an enhancedresponsiveness to IL-5. Overall, this study shows thatmaternal dietary supplementation with v3-fatty acids sig-nificantly affects CD34q progenitor populations in cordblood.

Other potential mechanisms explaining the immuno-logic activity of v3-supplementation during the perinatalphase are still being discussed. There is evidence thatprostaglandin E2 (PGE2) synthesis in the neonate is sup-pressed by maternal v3-fatty acid supplementation w37x.PGE2 is suggested to be involved in maintenance of aller-gic reactions, mainly bronchoconstriction and IgE syn-thesis w42x. It was also described that v3-fatty acidsinduce a state of tolerance at the materno-fetal interfaceby suppressing MHC class II expression w22x.

Potential immuno-regulatory mechanisms ofv3-fatty acids during lactation

v3-fatty acids affect the neonatal immune system notonly via the placenta, but also via breast milk. Many com-

ponents present in breast milk have pro- or anti-inflam-matory functions and, thus, the potential to affect thedevelopment of allergic diseases. v3-fatty acids partici-pate in this regard. The PUFA composition of human milkis, at least partially, determined by the PUFA content ofmaternal diet w3, 31x. Concentrations of the v3-fatty acidDHA seem to be very tightly regulated by maternal intakew19x. Furthermore, breast milk concentrations of v3-fattyacids were related to infant plasma and erythrocytephosholipid DHA concentrations w26x. There are oppos-ing publications concerning the predictive value of v3-and v6-fatty acids in breast milk and the developmentof atopic diseases. Stoney et al. w40x reported that higherDHA contents of breast milk was associated with anincreased risk to develop atopic disorders. In contrast,Duchen and co-workers w8x postulated that low v3-fattyacid concentrations in breast milk favor the developmentof atopic diseases.

The immuno-modulatory components of breast milkact at a first instance on the gastrointestinal tract of theneonate. Early events in the intestine are believed to playan important role in the development of immune toler-ance mechanisms. Supplementation of pregnant moth-ers with v3-fatty acids enhances levels of IgA andsoluble CD14 in breast milk w12x. There are studies show-ing that high levels of IgA in breast milk are associatedwith a reduced risk to develop cow’s milk allergy in chil-dren w20x. IgA antibodies may bind antigens present inthe neonatal intestine and, therefore, reduce antigen-presentation and development of pro-inflammatory reac-tions, contributing to tolerance inducing effects. SolubleCD14 (sCD14) is also known to affect immune responsesin the infant’s intestine. This factor has been shown tostimulate intestinal cells to release immuno-modulatorycytokines w45x. Accordingly, sCD14 in breast milk wasidentified as a protective factor for the development ofallergies in the child w21x.

In line with other studies, Hawkes et al. w17x reportedthat supplementation of lactating women with a v3-fattyacid diet rich in DHA increases DHA concentrations inmaternal plasma as well as breast milk. Nevertheless,levels of the pro-inflammatory cytokines IL-6, IL-1 b andTNF-a as well as of the tolerance inducing cytokine TGF-b were not elevated in breast milk. This study suggeststhat immunologic effects of v3-fatty acid supplementa-tion were probably not transmitted via cytokines of thebreast milk from mother to child (potential immuno-reg-ulatory mechanisms are summarized in Figure 1).

Conclusion

Animal as well as human studies indicate that supple-mentation with v3-polyunsaturated fatty acid in the veryearly life phase has the capacity to influence neonatalimmune functions. Therefore, the concept to prevent or





Figure 1 Summary of potential mechanisms of fatty acid action in the perinatal time phase.

at least to modify the development of allergic diseasesby supplementing with v3-polyunsaturated fatty acids ina very early phase of life seems to be a promisingapproach. So far, only a limited number of studies dealwith this allergy-preventing strategy. No clear observa-tions indicate beneficial effects of a perinatal v3-fattyacid supplementation on the onset of bronchial asthmaand IgE sensitization. Nevertheless, there is evidencethat a perinatal v3-fatty acid supplementation has anti-allergic effects on disease-related symptoms like allergicrhinitis, wheeze or atopic cough. Therefore, v3-fatty acidsupplementation during the very early life phase mightbe a promising strategy in the field of allergy prevention.There is a strong need for further research in this area tosupport this clinical approach.

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Consumption of ω3-fatty acids during perinatal life: role in immuno-modulation and allergy...

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