Impact of fatty acid status on immune function of children in low-income countries

Impact of fatty acid status on immune function ofchildren in low-income countriesmcn_313 89..98

Andrew M. Prentice and Liandré van der MerweMRC International Nutrition Group, London School of Hygiene and Tropical Medicine, London, UK, and MRC Keneba, Keneba, The Gambia

Abstract

In vitro and animal studies point to numerous mechanisms by which fatty acids, especially long-chain polyun-saturated fatty acids (LCPUFA), can modulate the innate and adaptive arms of the immune system. These datastrongly suggest that improving the fatty acid supply of young children in low-income countries might haveimmune benefits. Unfortunately, there have been virtually no studies of fatty acid/immune interactions in suchsettings. Clinical trial registers list over 150 randomized controlled trials (RCTs) involving PUFAs, only one ina low-income setting (the Gambia). We summarize those results here. There was evidence for improved growthand nutritional status, but the primary end point of chronic environmental enteropathy showed no benefit,possibly because the infants were still substantially breastfed. In high-income settings, there have been RCTswith fatty acids (usually LCPUFAs) in relation to 18 disease end points, for some of which there have beennumerous trials (asthma, inflammatory bowel disease and rheumatoid arthritis). For these diseases, the evidenceis judged reasonable for risk reduction for childhood asthma (but not in adults), as yielding possible benefit inCrohn’s disease (insufficient evidence in ulcerative colitis) and for convincing evidence for rheumatoid arthritisat sufficient dose levels, though formal meta-analyses are not yet available. This analysis suggests that fatty acidinterventions could yield immune benefits in children in poor settings, especially in non-breastfed children andin relation to inflammatory conditions such as persistent enteropathy. Benefits might include improved responsesto enteric vaccines, which frequently perform poorly in low-income settings, and these questions merit random-ized trials.

Keywords: immunity, fatty acid, PUFA, low-income countries, children, enteropathy, growth.

Correspondence:Andrew M. Prentice, MRC International Nutrition Group, London School of Hygiene and Tropical Medicine, KeppelStreet, London WC1E 7HT, UK. E-mail: [email protected]

Background paper for: ‘Fatty acid status in early life in low-income countries: determinants & consequences’. Napa Valley Lodge, 22–24September 2010.

Introduction

The effects on immune function of fatty acids (FAs),and particularly of the long-chain polyunsaturatedFAs (LCPUFAs), have been intensively researchedover the past several decades, and numerous compre-hensive reviews are available (Grimble 2001; Harbige

2003; Calder 2008, 2009, 2010; Gottrand 2008; Galli &Calder 2009; Ganapathy 2009). This paper will notseek to replicate these reviews. Instead, it will attemptto extract from the myriad available data the ele-ments most relevant to the immune defences of youngchildren brought up in the nutritionally deprived andhighly infectious environment still typical of many

DOI: 10.1111/j.1740-8709.2011.00313.x

Review Article

89© 2011 Blackwell Publishing Ltd Maternal and Child Nutrition (2011), 7 (Suppl. 2), pp. 89–98

low-income countries. We will attempt to focus onwhat is known and to highlight the far greater numberof unknowns that arise from the fact that this is a mostunder-researched topic.

Our task is made easier by the accompanyingpapers reviewing the FA profiles of typical diets inless-developed countries (LDCs) (Michaelsen et al.2011), the physiological roles of the various FAsduring early life (German 2011), the genetics ofPUFA conversion (Glaser et al. 2011) and the transfermechanisms across the placenta and via breast milk(Lauritzen & Carlson 2011).

We have chosen to focus on immune functions asthey develop and mature through infancy and intochildhood in the belief that these are the criticalperiods at which interventions are most likely to beeffective.

The survival challenge facing childrenin low-income settings

Despite the numerous advances in medical knowl-edge, antibiotics, drug therapies and vaccines, infec-tions are still by far the largest contributor to the highlevels of infant and under-five mortality seen in manyLDCs because of shortfalls in health provision,hygiene and vector control. Nutritional deficienciesare estimated to account (directly and indirectly) forabout 35% of these deaths (Black et al. 2008), andcase-specific fatality rates are very strongly related tomeasures of undernutrition across diseases such asdiarrhoea, pneumonia and measles (Black et al. 2008).

The neonate is born into such a dangerous worldwith a largely naive immune system. If it is unlucky, it

may already be carrying one of the infections that cancross the placenta or be acquired at birth, but in mostcases, it will arrive uninfected and with an essentiallyaseptic gut. In the early hours, days and months, it isprotected by its innate immunity, by maternal anti-bodies and (in an ideal world) by the many anti-microbial factors provided by breastfeeding. Butwithin minutes of birth, it must start the processes ofacquiring the micro-organisms that will colonize itsgut and start training its immune system to discrimi-nate between friend and foe at both the cellular level(symbionts vs. pathogens) and the molecular level(self and food antigens vs. toxins and molecules sig-nalling the presence of a pathogen). Despite the pro-tection of being swaddled close to its mother andreceiving nutrients directly from her, such infants willinevitably be exposed from their very first breath to awide array of micro-organisms – some of which couldbe potentially fatal. Appreciating the immense com-plexities of these developing processes is a first step intrying to untangle a possible modulating role for FAs.The transition from this typical LDC situation to themore sterile environment of the first world has alsobeen a strong driver of FA immune function researchas changes in FA intakes have had a hypothesizedrole in the aetiology of asthma and allergies (Raviv& Smith 2010) – immuno-regulatory diseases thatbecome more common as hygiene improves.

FAs and immune function – a verybasic summary

The human immune system has two arms: innate andadaptive. Innate immunity includes barrier defences,

Key messages

• There are multiple putative pathways through which fatty acids, especially long-chain polyunsaturated fattyacids (LCPUFAs), may modulate immune function.

• Evidence for these actions is derived mostly from in vitro and small animal studies.• Randomized controlled trials in affluent populations, mostly aimed at ameliorating inflammatory conditions,

have yielded fairly robust evidence for efficacy in a number of diseases.• Populations in low-income countries, particularly post-weaning children, are very likely to have deficient intakes

of LCPUFAs, which might affect immune function.• There have been almost no fatty acid or LCPUFA trials in low-income countries, and this represents an

important research gap.

A.M. Prentice and L. van der Merwe90

© 2011 Blackwell Publishing Ltd Maternal and Child Nutrition (2011), 7 (Suppl. 2), pp. 89–98

the complement system, numerous pathogen recogni-tion receptors, multiple chemical signalling systems,natural killer cells, macrophages, neutrophils, mastcells, eosinophils, basophils and dendritic cells. It isphylogenetically more ancient than the adaptivemechanisms, but this should not be taken to implysimplicity; each of these processes represents an enor-mously complex biological system that needs to workin concert with the others. Innate immunity has theadvantage that it responds to generic markers ofpotential pathogens that may never have beenencountered by a neonate. Its chief disadvantage isthat it is not perfect; for instance, maintaining aperfect epithelial barrier integrity over the numeroussquare metres of the intestinal and respiratory tractsis simply not possible, and numerous micro-organismshave evolved ways to evade innate immune defences.Some have evolved to actually colonize immunedefence cells; Mycobacteria tuberculosis, for instance,invades and replicates within the phagolysosome of

macrophages. In contrast, adaptive immunity relies onprior exposure to an organism and develops targetedstrategies of pathogen elimination involving T- andB-cells, and specific antibodies. Its advantage is that itsgreater specificity is usually successful in avoiding orameliorating the effects of a second exposure to apathogen. Its limitations include the fact that itrequires the infant to survive the first exposure(through the assistance of maternal antibodies andinnate defences) and that it sometimes mistakes selfantigens for foreign antigens and sets up a damagingautoimmune response.

Each of these cells and processes listed above, andthe far greater number not listed, could potentially bemodulated by FAs. Table 1 lists some generic mecha-nisms through which interactions may occur and forwhich there is some experimental evidence [see thenumerous reviews available (e.g. Calder 2008, 2009,2010; Galli & Calder 2009; Ganapathy 2009)]. It mustbe stressed that much of this evidence is quasi-

Table 1. Generic mechanisms by which fatty acids (FAs) may influence immune function

Immune component Variables known to be affected by FA Citation

Epithelial barriers Cell–cell interactionsMaintenance of patencyVulnerability to peroxidative damage

Calder et al. (2009)Calder et al. (2009)Roig-Pérez et al. (2010)

Antigen presentation Effects on MHC expressionAltered dendritic cell function

Hughes et al. (1996)Sanderson et al. (1997)Shaikh & Edidin (2007)Weatherill et al. (2005)

Innate cell defences Cell membrane structure and functionCell signalling

Katagiri et al. (2001)Razzaq et al. (2004)Leite et al. (2005)Yaqoob & Calder (2007)

Tolerance development Immuno-tolerance modulated (differentially) by n-3 and n-6 PUFAs Harbige & Fisher (2001)

Adaptive cell defences Cell membrane structure and functionIntracellular and extracellular signallingLipid rafts and T-cell signalling

Katagiri et al. (2001)Horejsí (2003)Stulnig et al. (1998, 2001)Fan et al. (2003)Yaqoob & Calder (2007)

Cytokine-mediated signalling Pro- vs. anti-inflammatory effects Galli & Calder (2009)

Lipid mediators Prostaglandins, leukotrienes, lipoxins, resolvins, protectins, etc. Tilley et al. (2001)Vachier et al. (2002)Calder (2006)Serhan et al. (2004)Galli & Calder (2009)

MHC, major histocompatability complex; PUFA, polyunsaturated fatty acid.

Fatty acids and immunity 91


theoretical because it has been obtained from in vitro

culture systems for which, among the many limita-tions, the issue of judging physiological ‘dose’ levels ofFAs is very challenging. It is more than likely thatsome of these putative effects are of no significance inwhole body mammalian systems, though some havebeen re-validated in small animal studies.

How can we sift through these numerous theoreti-cal effects to determine which, if any, have a signifi-cant and potentially modifiable impact on immunefunction in children in LDCs? The usual answerwould be to interrogate clinical trials that test aggre-gate effects of changes in FA supply on functional andclinical outcomes. However, as explained below, therehave been virtually no such trials. In the absence ofthese, a very poor proxy can be obtained by reviewingthe numerous trials conducted on clinical end pointsof interest in affluent populations. Calder (2006) lists18 such disease end points, for some of which therehave been numerous trials (viz. asthma, inflammatorybowel disease and rheumatoid arthritis). Evidence ofbenefit for most of the end points studied is absent orat best equivocal. For those most studied (usually withLCPUFA supplements), the evidence is judged rea-sonable for childhood asthma (but not in adults), asyielding possible benefit in Crohn’s disease (insuffi-cient evidence in ulcerative colitis) and for convincingevidence for rheumatoid arthritis at sufficient doselevels (Galli & Calder 2009), though formal meta-analyses could not be found. All of these end pointswere in relation to chronic disease outcomes inpeople consuming high intakes of fats and possiblyexcessive intakes of n-6 FAs.

This is a disappointing outcome given the widerange of possible immuno-modulatory effects of FAsand that the outcomes most studied have a largeinflammatory component for which there is a strongtheoretical basis to expect effects. It cautions againstthe over-optimistic extrapolation of theoretical pro-cesses of disease mediation into clinical efficacy, butthere remains much to be done before reaching nihil-istic conclusions.

This may be especially so in low-income settingswhere very low levels of total fat intake and low levelsof dietary diversity can limit the intake of preformedLCPUFAs and of the precursors of the n-6 and n-3

series PUFAs (Michaelsen 2011). For example, Fig. 1shows estimates of a-linolenic and docosahexaenoicacid (DHA) in young rural Gambian children as theyprogress from early exclusive breastfeeding, throughpartial weaning as complementary foods are intro-duced at 3–4 months of age, to total weaning at 18–24months (Prentice & Paul 2000). These calculationsshowed that breast milk provided a more thanadequate source according to the Food and Agricul-ture Organization recommended intakes but that thevery poor supply from complementary and childhoodfoods leads to a situation of profoundly inadequateintakes in the absence of breast milk. Under such

0 6 12 18 24 30 360

10

20

30

40

50

60

FAO (1994) recommendation = 50 mg kg–1

FAO (1994) recommendation = 20 mg kg–1

70

00 6 12 18

Age (months)

Age (months)

22:6

(m

g kg

–1 b

ody

wei

ght)

18:3

(m

g kg

–1 b

ody

wei

ght)

24 30 36

10

20

30

40

Fig. 1. Intakes of the n-3 fatty acids a-linolenic acid (18:3; upper) andDHA (22:6; lower) in Gambian children from birth to 36 months. FromPrentice & Paul (2000). DHA, docosahexaenoic acid; FAO, Food andAgriculture Organization.



circumstances, there would be a greater rationale fortesting possible health-protecting and therapeuticeffects of LCPUFAs, and it is therefore surprising thatmore trials have not been undertaken.

Local interactions between FAdepots and immune tissues

The work of Caroline Pond has revealed that mam-malian lymph nodes are usually in close proximity toadipose depots, and there is evidence of functionallinks between the two (Mattacks et al. 2004; Pond2005). Lymph node lymphocytes and local dendriticcells obtain their FAs from local adipocytes. Dendriticcells that permeate the adipose tissue stimulatelipolysis especially after local immune stimulation,and inflammation alters dendritic cell FA composi-tion as well as that of lymph node-containing adiposetissue, thus counteracting the effects of dietary lipidsand emancipating the immune system from fluctua-tions in lipid supply and type (Pond 2005). Sucheffects might be particularly important in childrensuffering a nutritional challenge at the same time asan infectious one, as is so commonly the case in devel-oping countries. Furthermore, the issue of why illnessprovokes appetite suppression (often to a profounddegree) is not well resolved, and, although highlyspeculative, it is possible that mobilization of endog-enous FAs pre-stored with a favourable immuno-stimulatory profile might be a contributory factor.This would be an interesting thesis amenable to study.

These paracrine interactions between adipose andlymphoid tissues are also stimulated by n-6 andattenuated by the n-3 series fats.

What are the implications of these findings forimmune function in children in LDCs? They mayimply that the composition of lymphoid-associatedadipose tissue is under regulatory control that enablesit to harvest a desirable FA profile from circulatinglipids in readiness for a specific immune response, thusgiving some freedom from the constraints of day-to-day dietary supplies and allowing adequate functiondespite marginal supplies of the LCPUFAs. However,a corollary of this is that a neonate’s endowment ofFAs may have a crucial role in determining its earlyimmune responses and that intervention trials seeking

to influence immune function may need to be of longduration (and may need to start in pregnancy) becausethe turnover of body fat stores is generally slow(though it should be noted that the turnover of peri-nodal adipose depots could be much faster).

FA intervention studies inlow-income countries

There have been astonishingly few attempts to studythe biological effects of LCPUFAs by means of con-trolled supplementation studies in low-income coun-tries, and so far as we can tell, there have been nopublished trials addressing immune outcomes.

Given that growth in infancy and young childhoodin LDCs is strongly linked to infectious load, inter-vention studies with growth as the primary outcomewould be potentially informative, but even this simpleoutcome has not been studied. In affluent settings,meta-analyses of n-3 PUFA interventions in termbabies have shown no benefit to growth (Makrideset al. 2005; Horvath et al. 2007; Simmer et al. 2008a;Rosenfeld et al. 2009), and those in preterm infantshave shown mixed and inconclusive results (Simmeret al. 2008b). Elsewhere in this supplement, Makrideset al. (2011) conclude that marine oil supplementationin pregnancy increases mean birthweight by 50 g andmean birth length by 0.48cm, and that these effectsmay be mediated by extending the length of gestationby approximately 2.5 days because there was no sig-nificant reduction in the proportion of small-for-datesbabies. All of these trials were conducted in first-world countries.

It has been speculated that essential FA deficiencymay play a role in the pathophysiology of protein–energy malnutrition (Smit et al. 2004), but only asingle trial in 10 malnourished Pakistani infants hasbeen reported (Smit et al. 2000), and the onlyoutcome studied was the change in erythrocyte FAprofiles (which were significantly altered by DHAsupplementation).

A search on the term ‘PUFA’ in the ClinicalTrials.gov (143 trials) and International Standard ran-domised Controlled Trial Numbers (ISRCTN) (10trials) registers reveals only a single PUFA trial in adeveloping country.This trial (ISRCTN66645725) has



recently been completed by our group in ruralGambia (van der Merwe 2009). The aim of the trialwas to examine whether daily high-dose PUFAsupplements could help prevent the gut damage(chronic environmental enteropathy) that occurs inalmost all children raised in the typically unhygienicconditions of low-income countries. The enteropathyis characterized by villous atrophy, crypt hyperplasia,inflammatory cell invasion of the lamina propria anddamage to tight junctions, resulting in a leaky gut thatallows translocation of bacteria and potentially toxicor allergenic substances (Lunn et al. 1991; Campbellet al. 2004). Enteropathy generally starts early in life,coinciding with the first exposures to complementaryfoods, and has been strongly implicated as a driver ofgrowth faltering (Lunn et al. 1991; Goto et al. 2009).Intestinal biopsy studies have revealed that a keyfeature of this chronic enteropathy is the presence ofa fulminant, unresolving inflammation with some par-allels to other inflammatory bowel diseases (Sullivan2002; Campbell et al. 2003). Paradoxically, the inflam-mation is seen even in severely malnourished childrenwho might be expected to be immunosuppressed.Therationale for our trial was that the long-chain n-3series PUFAs DHA and eicosapentaenoic acid (EPA)may help to prevent and/or resolve this chronicinflammation through both topical and systemicroutes, and hence allow the gut to heal. We reasonedthat the intervention should start at the time when theenteropathy usually gains its first footholds (i.e. ataround 3 months post-partum).

The trial randomized 183 children at 3 months toreceive daily capsules with 2 g of purified fish oil con-taining 200 mg DHA and 300 mg EPA, or 2 g of oliveoil as placebo, for 24 weeks (i.e. until 9 months of age).Ninety-four per cent (172 infants) completed the trial.Primary outcomes were growth and gut integrity(assessed by the lactulose–mannitol dual-sugar per-meability test). Secondary outcomes were plasmaFA status, cognitive development (assessed by theWillatt’s two-step means–end problem-solving test at12 months and attention assessment), intestinal andsystemic inflammation, and morbidities assessed byactive surveillance. As anticipated, the interventionsignificantly altered the infants’ plasma phospholipidFA profiles with increases in DHA (4.87 vs. 4.44% of

total FA, P < 0.001) and EPA (2.13 vs. 1.34% of totalFA, P < 0.001) with no change in the n-6 series arachi-donic acid. The trial revealed no excess of adverseevents in either group so the intervention was judgedsafe.

In general, the results were somewhat disappoint-ing with little evidence of benefit in terms of gutpermeability, systemic or intestinal inflammation,morbidity or weight growth. Linear growth showedevidence of benefit with a substantial effect size butwith wide confidence intervals (CIs), and the differ-ence was not significant (+0.79 Z s-score; 95% CI-0.27 to 0.90, P = 0.084). Most of the measuresshowed a small trend towards benefit in the interven-tion group, but they were generally quite far fromsignificance even with the reasonable sample size of80+ per group. At 9 months, there was a significantincrease in mid-upper arm circumference (MUAC) infavour of the PUFA group.This could be explained asa multiple testing artefact, but when the groups werereassessed at 12 months (3 months after the end ofintervention), the PUFA group showed significantlygreater change in MUAC, triceps, biceps and sub-scapular skinfold thicknesses from the 3-month base-line, indicating an increased adiposity.

The dose levels used in this trial were as high as weconsidered reasonable, following consultation withexperts in the field and noting that high doses ofPUFAs might have theoretical adverse side effectsincluding immunosuppression, anticoagulation andlipid peroxidation. The daily supplements wereadministered under direct observation by field staff,compliance was very high and plasma FA profileschanged as expected. Therefore, the null resultscannot be attributed to inadequate dose or non-compliance.There is a high degree of variability in thelactulose–mannitol and fecal calprotectin assays(both methodological and biological), and hence, theresult could be a type II error that has failed to detecta real effect. The persistent advantage in terms ofadiposity at 12 months might support this view. Alter-natively, it could be that the FA status of these breast-fed infants at 3 months was already adequate, assuggested by the plasma analysis and the fact thatthese were not very greatly altered (likely because ofthe fact that all infants were at least partially breast-



fed), and that interventions for this age group are notrequired. Figure 1 suggests that later interventions,after complete weaning, might have a greater effecton PUFA status and growth, but by this stage, thechronic enteropathy that was the primary target ofour trial is well entrenched.

Research gaps in relation to FAsand immunity

In addressing the research gaps in relation to FAs andimmunity, we return to the issue of the immense com-plexity of the developing immune system and its inter-actions with a child’s nutritional status. Figure 2represents just a very basic overview of the variables.

These can be conceptualized as a multidimensionalknowledge matrix that needs to be filled before wewould have a complete operator’s manual that couldguide the precise design of preventative and thera-peutic interventions. It will quickly be appreciatedthat this matrix contains tens of thousands of indi-vidual cells, most of which are currently empty. Forinstance, we might wish to know how a singleLCPUFA, say DHA, alters dendritic cell function inthe inflamed gut of a young infant and how this affectsits response to enteric vaccines and hence, forinstance, the infant’s susceptibility to diarrhoeal dis-eases. Any attempt to fill even this single cell in theoverall knowledge matrix would require numerousseparate studies in vitro, in animals and in humans,

Fig. 2. Schematic representation of some of the complexities involved in understanding nutrient–immune function relationships. APR, acute phaseresponse; BCG, Bacillus Calmette-Guérin; DTP, diptheria, tetanus and pertussis; PUFA, polyunsaturated fatty acid.



and would still not capture the myriad of potentialinteractions with numerous other variables includingthe child’s genetic background. From this example, itcan easily be appreciated that the full matrix willnever be completed in such piecemeal fashion. Analternative approach is needed. This becomes thedomain of the new systems biology approaches inwhich the application of modern high-throughput andwide spectrum analytical ‘omics’ tools together withpowerful bio-informatic interrogative methods seemto promise a way forward.

Elsewhere, we have argued that the design of newand effective nutritional interventions for children inlow-income countries would benefit from the redirec-tion of some of the large funds spent on purelyempirical trials towards more basic studies designedto fill crucial knowledge gaps regarding the mecha-nisms of action of nutrients. In the case of FAs, thisargument might be reversed because there is a wealthof theoretical mechanisms of action and an astonish-ing absence of experimental (small-sample proof-of-principle studies) or clinical trials in low-incomecountries. Our failure to identify relevant trials wouldsuggest that there is room for a series of carefullydesigned studies in populations with evidence eitherof FA deficiencies or of clinical syndromes putativelylinked to defects in FA metabolism.

Conflicts of interest

LVDM is now employed by Danone Research, theNetherlands. AMP has research collaborations withValid Nutrition.

References

Black R.E., Allen L.H., Bhutta Z.A., Caulfield L.E., deOnis M., Ezzati M., Mathers C., Rivera J., for the Mater-nal and Child Undernutrition Study Group. (2008)Maternal and child undernutrition: global and regionalexposures and health consequences. Lancet 371, 243–60.

Calder P.C. (2006) n-3 polyunsaturated fatty acids, inflam-mation, and inflammatory diseases. American Journal ofClinical Nutrition 83 (6 Suppl.), 1505S–1519S.

Calder P.C. (2008) The relationship between the fatty acidcomposition of immune cells and their function. Prostag-landins, Leukotrienes, and Essential Fatty Acids 79,101–108.

Calder P.C. (2009) Fatty acids and immune function: rel-evance to inflammatory bowel diseases. InternationalReviews of Immunology 28, 506–534.

Calder P.C. (2010) Does early exposure to long chain poly-unsaturated fatty acids provide immune benefits?Journal of Pediatrics 156, 869–871.

Calder P.C., Albers R., Antoine J.M., Blum S., Bourdet-Sicard R., Ferns G.A. et al. (2009) Inflammatory diseaseprocesses and interactions with nutrition. British Journalof Nutrition 101 (Suppl. 1), S1–S45.

Campbell D.I., McPhail G., Lunn P.G., Elia M. & JeffriesD.J. (2004) Intestinal inflammation measured by fecalneopterin in Gambian children with enteropathy: asso-ciation with growth failure, Giardia lamblia, and intesti-nal permeability. Journal of Pediatric Gastroenterologyand Nutrition 39, 153–157.

Campbell D.I., Murch S.H., Elia M., Sullivan P.B., SanyangM.S., Jobarteh B. et al. (2003) Chronic T cell-mediatedenteropathy in rural west African children: relationshipwith nutritional status and small bowel function. Pediat-ric Research 54, 306–311.

Fan Y.Y., McMurray D.N., Ly L.H. & Chapkin R.S. (2003)Dietary (n-3) polyunsaturated fatty acids remodelmouse T-cell lipid rafts. Journal of Nutrition133, 1913–1920.

FAO (1994) Fats and oils in human nutrition: report of ajoint expert consultation, FAO Food and NutritionPaper No. 57. Food & Agriculture Organisation:Rome.

Galli C. & Calder P.C. (2009) Effects of fat and fatty acidintake on inflammatory and immune responses: a criticalreview. Annals of Nutrition and Metabolism 55, 123–139.

Ganapathy S. (2009) Long chain polyunsaturated fattyacids and immunity in infants. Indian Pediatrics 46,785–790.

German J.B. (2011) Dietary lipids from an evolutionaryperspective: sources, structures and functions. Maternaland Child Nutrition 7 (Suppl. 2), 2–16.

Glaser C., Lattka E., Rzehak P., Steer C. & Koletzko B.(2011) Genetic variation in polyunsaturated fatty acidmetabolism and its potential relevance for humandevelopment and health. Maternal and Child Nutrition 7(Suppl. 2), 27–40.

Goto R., Mascie-Taylor C.G. & Lunn P.G. (2009) Impactof intestinal permeability, inflammation status andparasitic infections on infant growth faltering in ruralBangladesh. British Journal of Nutrition 101, 1509–1516.

Gottrand F. (2008) Long-chain polyunsaturated fatty acidsinfluence the immune system of infants. Journal ofNutrition 138, 1807S–1812S.

Grimble R.F. (2001) Nutritional modulation of immunefunction. Proceedings of the Nutrition Society60, 389–397.



Harbige L.S. (2003) Fatty acids, the immune response, andautoimmunity: a question of n-6 essentiality and thebalance between n-6 and n-3. Lipids 38, 323–341.

Harbige L.S. & Fisher B.A. (2001) Dietary fatty acidmodulation of mucosally-induced tolerogenic immuneresponses. Proceedings of the Nutrition Society60, 449–456.

Horejsí V. (2003) The roles of membrane microdomains(rafts) in T cell activation. Immunological Reviews191, 148–164.

Horvath A., Koletzko B. & Szajewska H. (2007) Effect ofsupplementation of women in high-risk pregnancies withlong-chain polyunsaturated fatty acids on pregnancyoutcomes and growth measures at birth: a meta-analysisof randomized controlled trials. British Journal of Nutri-tion 98, 253–259.

Hughes D.A., Pinder A.C., Piper Z., Johnson I.T. & LundE.K. (1996) Fish oil supplementation inhibits the expres-sion of major histocompatibility complex class II mol-ecules and adhesion molecules on human monocytes.American Journal of Clinical Nutrition 63, 267–272.

Katagiri Y.U., Kiyokawa N. & Fujimoto J. (2001) A rolefor lipid rafts in immune cell signaling. MicrobiolImmunol 45, 1–8.

Lauritzen L. & Carlson S.E. (2011) Maternal fatty acidstatus during pregnancy and lactation and relation tonewborn and infant status. Maternal and Child Nutrition7 (Suppl. 2), 41–58.

Leite M.S., Pacheco P., Gomes R.N., Guedes A.T.,Castro-Faria-Neto H.C., Bozza P.T. & Koatz V.L.(2005) Mechanisms of increased survival afterlipopolysaccharide-induced endotoxic shock in miceconsuming olive oil-enriched diet. Shock 23, 173–8.

Lunn P.G., Northrop-Clewes C.A. & Downes R.M. (1991)Intestinal permeability, mucosal injury, and growth fal-tering in Gambian infants. Lancet 338, 907–910.

Makrides M., Collins C.T. & Gibson R.A. (2011) Impact offatty acid status on growth and neurobehavioural devel-opment in humans. Maternal and Child Nutrition7 (Suppl. 2), 80–88.

Makrides M., Gibson R.A., Udell T., Ried K. &International LCPUFA Investigators (2005) Supplemen-tation of infant formula with long-chain polyunsaturatedfatty acids does not influence the growth of term infants.American Journal of Clinical Nutrition 81, 1094–1101.

Mattacks C.A., Sadler D. & Pond C.M. (2004) Site-specificdifferences in fatty acid composition of dendritic cellsand associated adipose tissue in popliteal depot, mesen-tery, and omentum and their modulation by chronicinflammation and dietary lipids. Lymphatic Research andBiology 2, 107–129.

Michaelsen K.F., Dewey K.G., Perez-Exposito A.B.,Nurhasan M., Lauritzen L. & Roos N. (2011) Foodsources and intake of n-6 and n-3 fatty acids in low-

income countries with emphasis on infants, youngchildren (6–24 months), and pregnant and lactatingwomen. Maternal and Child Nutrition 7 (Suppl. 2), 124–139.

van der Merwe L. (2009) Long-chain omega-3 polyunsatu-rated fatty acids in relation to gut integrity, growth, andcognitive development of rural African children. PhDThesis, University of London.

Pond C.M. (2005) Adipose tissue and the immune system.Prostaglandins, Leukotrienes, and Essential Fatty Acids73, 17–30.

Prentice A.M. & Paul A.A. (2000) Fat and energy needsof children in developing countries. American Journal ofClinical Nutrition 72 (5 Suppl.), 1253S–1265S.

Raviv S. & Smith L.J. (2010) Diet and asthma. CurrentOpinion in Pulmonary Medicine 16, 71–76.

Razzaq T.M., Ozegbe P., Jury E.C., Sembi P., BlackwellN.M. & Kabouridis P.S. (2004) Regulation of T-cellreceptor signalling by membrane microdomains.Immunology 113, 413–426.

Roig-Pérez S., Cortadellas N., Moretó M. & Ferrer R.(2010) Intracellular mechanisms involved in docosa-hexaenoic acid-induced increases in tight junction per-meability in caco-2 cell monolayers. Journal of Nutrition140, 1557–1563.

Rosenfeld E., Beyerlein A., Hadders-Algra M., KennedyK., Singhal A., Fewtrell M. et al. (2009) IPD meta-analysis shows no effect of LC-PUFA supplementationon infant growth at 18 months. Acta Paediatrica 98,91–97.

Sanderson P., MacPherson G.G., Jenkins C.H. & CalderP.C. (1997) Dietary fish oil diminishes the antigen pre-sentation activity of rat dendritic cells. Journal of Leuko-cyte Biology 62, 771–777.

Serhan C.N., Arita M., Hong S. & Gotlinger K. (2004)Resolvins, docosatrienes, and neuroprotectins, novelomega-3-derived mediators, and their endogenousaspirin-triggered epimers. Lipids 39, 1125–1132.

Shaikh S.R. & Edidin M. (2007) Immunosuppressiveeffects of polyunsaturated fatty acids on antigen presen-tation by human leukocyte antigen class I molecules.Journal of Lipid Research 48, 127–138.

Simmer K., Patole S.K. & Rao S.C. (2008a) Longchainpolyunsaturated fatty acid supplementation in infantsborn at term. Cochrane Database of Systematic Reviews,CD000376.

Simmer K., Schulzke S.M. & Patole S. (2008b) Longchainpolyunsaturated fatty acid supplementation in preterminfants. Cochrane Database of Systematic Reviews,CD000375.

Smit E.N., Muskiet F.A. & Boersma E.R. (2004) The pos-sible role of essential fatty acids in the pathophysiologyof malnutrition: a review. Prostaglandins, Leukotrienes,and Essential Fatty Acids 71, 241–250.



Smit E.N., Oelen E.A., Seerat E., Boersma E.R. &Muskiet F.A. (2000) Fish oil supplementationimproves docosahexaenoic acid status ofmalnourished infants. Archives of Disease inChildhood 82, 366–369.

Stulnig T.M., Berger M., Sigmund T., Raederstorff D.,Stockinger H. & Waldhäusl W. (1998) Polyunsaturatedfatty acids inhibit T cell signal transduction bymodification of detergent-insoluble membrane domains.Journal of Cell Biology 143, 637–644.

Stulnig T.M., Huber J., Leitinger N., Imre E.M., AngelisovaP., Nowotny P. et al. (2001) Polyunsaturated eicosapen-taenoic acid displaces proteins from membrane rafts byaltering raft lipid composition. Journal of BiologicalChemistry 276, 37335–37340.

Sullivan P.B. (2002) Studies of the small intestine in persis-tent diarrhea and malnutrition: the Gambian experience.Journal of Pediatric Gastroenterology and Nutrition34 (Suppl. 1), S11–S13.

Tilley S.L., Coffman T.M. & Koller B.H. (2001) Mixedmessages: modulation of inflammation and immuneresponses by prostaglandins and thromboxanes. Journalof Clinical Investigation 108, 15–23.

Vachier I., Chanez P., Bonnans C., Godard P., Bousquet J.& Chavis C. (2002) Endogenous anti-inflammatorymediators from arachidonate in human neutrophils. Bio-chemical and Biophysical Research Communications290, 219–224.

Weatherill A.R., Lee J.Y., Zhao L., Lemay D.G., Youn H.S.& Hwang D.H. (2005) Saturated and polyunsaturatedfatty acids reciprocally modulate dendritic cell functionsmediated through TLR4. Journal of Immunology174, 5390–5397.

Yaqoob P. & Calder P.C. (2007) Fatty acids and immunefunction: new insights into mechanisms. British Journalof Nutrition 98 (Suppl. 1), S41–S45.



Documents

Impact of fatty acid status on immune function of children in low-income countries