Nutritional armor: Omega-3 for the Warfighter

Guest Editors Wayne B. Jonas, M.D. and Scott J. Montain, Ph.D.

NUTRITIONAL ARMOR:NUTRITIONAL ARMOR:Omega-3 for the WarfighterOmega-3 for the Warfighter

Special Issue | Supplement to Military Medicine, Volume 179, Number 11 l November 2014

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NUTRITIONAL ARMOR: Omega-3 for the Warfighter

Nutritional Armor: Omega-3 for the Warfighter 1Scott Montain, Wayne B. Jonas

The Effect of Omega-3 Fatty Acids on Biomarkers of Inflammation: A Rapid Evidence Assessment of the Literature 2Raheleh Khorsan, Cindy Crawford, John A. Ives, Avi R. Walter, Wayne B. Jonas

Nutritional Armor in Evolution: Docosahexaenoic Acid as a Determinant of Neural, Evolution and Hominid Brain Development 61

Michael A. Crawford, C. Leigh Broadhurst, Stephen Cunnane, David E. Marsh, Walter F. Schmidt, Annette Brand, Kebreab GhebremeskelDietary Omega-3 and Omega-6 Fatty Acids Compete in Producing Tissue Compositions and Tissue Responses 76

Bill LandsOmega-3 Fatty Acid Biochemistry: Perspectives From Human Nutrition 82

Sheila M. InnisNutritional Armor for the Injured Warfighter: Omega-3 Fatty Acids in Surgery, Trauma, and Intensive Care 88

Mary S. McCarthy, Brian B. Morgan, John T. Heineman, Robert G. MartindaleLong-Chain Omega-3 Fatty Acids and Optimization of Cognitive Performance 95

Matthew F. Muldoon, Christopher M. Ryan, Jeffrey K. Yao, Sarah M. Conklin, Stephen B. ManuckNeuroprotection by Docosahexaenoic Acid in Brain Injury 106

Hee-Yong KimThe Potential for DHA to Mitigate Mild Traumatic Brain Injury 112

Julian E. Bailes, Vimal PatelThe Potential for Military Diets to Reduce Depression, Suicide, and Impulsive Aggression: A Review of Current Evidence for Omega-3 and Omega-6 Fatty Acids 117

Joseph R. Hibbeln, Rachel V. GowOmega-3 Fatty Acids and Stress-Induced Immune Dysregulation: Implications for Wound Healing 129

Janice K. Kiecolt-Glaser, Ronald Glaser, Lisa M. ChristianThe Safety of Fish Oils for Those Whose Risk of Injury is High 134

Tomohito Hamazaki, Heather Colleran, Kei Hamazaki, Yutaka Matsuoka, Miho Itomura, Joseph HibbelnMetabolic Health Benefits of Long-Chain Omega-3 Polyunsaturated Fatty Acids 138

Peter Howe, Jon BuckleyOmega-3 Polyunsaturated Fatty Acids in the Optimization of Physical Performance 144

Ren-Jay Shei, Martin R. Lindley, Timothy D. MickleboroughConsiderations for Incorporating Eicosapentaenoic and Docosahexaenoic Omega-3 Fatty Acids into the Military Food Supply Chain 157

Adam Ismail, Harry B. RiceThe Challenges of Incorporation of Omega-3 Fatty Acids into Ration Components and Their Prevalence in Garrison Feeding 162

Betty A. Davis, Brian C. PrallUnderstanding Diet and Modeling Changes in the Omega-3 and Omega-6 Fatty Acid Composition of U.S. Garrison Foods for Active Duty Personnel 168

Bernadette P. Marriott, Karina Yu, Sharon Majchrzak-Hong, Jeremiah Johnson, Joseph R. HibbelnOmega-3 Fatty Acids: Nutritional Armor for the Warfighter and Historical Trends Behind Optimal Warrior Performance 176

Richard H. CarmonaSummary Comments From Workshop Day 1: Nutritional Armor for the WarfighterCan Omega-3 Fatty Acids Enhance Stress Resilience, Wellness, and Military Performance? 181

Rhonda L. CornumNutritional Armor for the Warfighter: Can Omega-3 Fatty Acids Enhance Stress Resilience, Wellness, and Military Performance? 185

Patricia DeusterThe Response of an Expert Panel to Nutritional Armor for the Warfighter: Can Omega-3 Fatty Acids Enhance Stress Resilience, Wellness, and Military Performance? 192

Ian D. Coulter

VOLUME 179 NOVEMBER 2014 SUPPLEMENT

MILITARY MEDICINE

The Association of Military Surgeons of the United States (AMSUS) should not be held responsible for statements made in its publication by contributors or advertisers. Therefore the articles reported in this supplement to MILITARY MEDICINE do not necessarily refl ect the endorsement, offi cial attitude, or position of AMSUS or the Editorial Board.

MILITARY MEDICINE, 179, 11:1, 2014

Nutritional Armor: Omega-3 for the Warfighter

Scott Montain, PhD*; Wayne B. Jonas, MD

Nutritional Armor: Omega-3 for the Warfighter is a

special issue of Military Medicine containing peer-reviewedarticles, panel summaries, and expert commentaries about

omega-3 and omega-6 essential fatty acids, in dietary and

supplement protocols, and their relationship to health, brain

function, response to injury and trauma, and the enhancement

of performance. Much of this research was originally pre-

sented in 2009 at the Nutritional Armor for the Warfighter

Conference, jointly hosted by the Samueli Institute through

its Metabolic Defense Program and National Institute on

Alcohol Abuse and Alcoholism. At the conference, experts

in nutritional science, biochemistry, physiology and clinical

applications, as well as doctors and high-ranking military

personnel presented the latest research on essential fatty

acids. Subsequently, participants prepared manuscripts sum-

marizing their research and presented material. Updates on

these articles were obtained over the last year and peer

reviewed. Of particular interest was gathering evidence to

determine whether omega-3 and omega-6 intake should be

changed in the military and, if so, in what populations, pro-

portions, and through which methods.

Manuscripts in this special issue include information from

the following categories: (1) cellular and whole-body func-

tions of omega-3 and omega-6 and their potential to modulate

health; (2) nutritional sources, requirements, and conse-

quences of fatty acid balance, including nutritional modeling

of garrison feeding programs; and (3) how service members

and veterans can optimize health, fitness, and recovery

through nutritional protocols that incorporate omega-3-rich

foods or supplements into daily intake.

Although no final recommendations were sought, nor can

be made from the research presented in this issue, the articles

demonstrate an urgent need to examine the ratio of fatty

acid intake. Increasing evidence demonstrates a balance of

omega-3 and omega-6 is critical to mental and physical

health. Research reveals the possibility that modern western-

ized diets poor in omega-3 and rich in omega-6 fatty acids

may increase chronic diseases and diminish optimal function-

ing. These diets contain 80+% of their polyunsaturated fattyacids (PUFA) as omega-6 linoleic acid (LA) and are low in

omega-3 fatty acids compared to Paleolithic and more bal-

anced diets with similar proportions of LA to a-linoleic acid(ALA), and eicosapentaenoic acid (EPA) and docosahexaenoic

acid (DHA). Studies document that excessive consumption

and tissue levels of omega-6 compared to omega-3 may

adversely affect health in areas such as cardiovascular disease,

metabolic syndrome, depression, increased suicidal risk, sur-

gical recovery, immune function, wound healing, proper

inflammatory response, and other conditions. In addition,

adding omega-3 supplements under certain conditions can

enhance recovery.

It is our hope that the content in this special issue ele-

vates awareness about essential fatty acids and the potential

they offer in terms of providing nutritional armor for the

warfighter and veteran to promote health and well-being.

We urge scientists, clinicians, and military and veteran

leaders to increase their focus on improving our knowledge

about the optimal omega-3 and omega-6 intake and use. Our

country needs it and our service members and veterans

deserve it.

The Samueli Institute would like to thank the following

individuals for their role as Conference Organizers: CAPT

Joeseph R. Hibbeln, MDActing Chief, Section on Nutri-

tional Neurosciences LMBB, NIAAA, NIH. Dr. Bernadette

P. MarriottProfessor, Division of Gastroenterology and

Hepatology, Department of Medicine, and Military Division,

Department of Psychiatry and Behavioral Sciences, Medical

University of South Carolina.

*Military Nutrition Division, U.S. Army Research Institute of Environ-

mental Medicine, Building 42, Kansas Street, Natick, MA 01760-5007.

Samueli Institute, 1737 King Street, Suite 600, Alexandria, VA 22314.

doi: 10.7205/MILMED-D-14-00452

MILITARY MEDICINE, Vol. 179, November Supplement 2014 1

MILITARY MEDICINE, 179, 11:2, 2014

The Effect of Omega-3 Fatty Acids on Biomarkers of Inflammation:A Rapid Evidence Assessment of the Literature

Raheleh Khorsan, PhDc*; Cindy Crawford, BA; John A. Ives, PhD;Avi R. Walter, MSc; Wayne B. Jonas, MD

ABSTRACT Introduction: Previous studies of omega-3 fatty acids report improved outcomes where inflammation isa key factor. The objective of this systematic review is to evaluate effects of omega-3s on inflammatory biomarkers.Methods: Randomized clinical studies that measured the influence of omega-3 fatty acids on inflammatory biomarkerswere identified using a comprehensive search. Eligible studies were rated with the American Dietetic AssociationEvidence Analysis Manual and Grading of Recommendations, Assessment, Development and Evaluation (GRADE)process to examine study quality and risk/benefit. Results: 112 studies were included. Over 65% reported statisticallysignificant effects. The majority were scored as low risk of bias (high quality) and scored strong (cardiac populationsand critically ill) to weak (Alzheimers Disease, hypertriglyceridemia/diabetes, and obesity) on the risk/benefit ratioevidence for modulation of inflammatory biomarkers. There was inadequate data to determine a GRADE for inflamma-tory biomarker studies for some conditions (healthy individuals, rheumatoid arthritis, metabolic syndrome, renaldisease, pregnancy, or children). Conclusion: Clinical literature on the effects of omega-3 fatty acids on inflammatorybiomarkers contains mostly small sample sizes, is neutral to high quality, and report mixed effects. Larger studiesexamining dose and delivery are needed.

INTRODUCTION

Omega-3 Fatty Acids

In 1946, the first major study of essential fatty acids (EFA)

identified vitamin-like properties of linoleic acid (18:2n-6)

(omega-6) and linolenic acid (18:3n-3) (omega-3) in human

infants.1 Today, there is much debate over assisting the

public in identifying and preventing the current imbalanced

intakes of omega-3 and omega-6 nutrients that cause pre-

ventable clinical disorders and continue escalating healthcare

costs.2 Indeed, studies continue to assess the importance

of the omega-6/omega-3 fatty acid ratio in cardiovascular

disease and other chronic diseases.3 Current studies advo-

cate lower intake of omega-6 compared to greater intake

of omega-3 fatty acids in reducing the risk of some of

the chronic diseases of high prevalence that are associated

with inflammation.1,3

Omega-3 fatty acids (also known as n-3 or w-3) includea-linolenic acid (ALA), eicosapentaenoic acid (EPA), doco-sahexaenoic acid (DHA), and docosapentaenoic acid (DPA).

Among fatty acids (FAs), long-chain omega-3 polyunsatu-

rated FAs (PUFAs) possess the most potent immunomodu-

latory activity,4 and among the omega-3 PUFAs, those from

fish oil (FO) are rich sources of the bioactive long-chain n-3

including EPA and DHA. The majority of DHA and EPA

are found in diets containing cold-water fatty fish, FOs, flax,

range-fed poultry, eggs and farm animals, and in supple-

ments and prescription formulations. Other less biologically

potent FAs include plant-based ALA with n-3 PUFA.4 The

major plant omega-3 ALA is found in walnuts, soybean,

canola oil, and flaxseed.

Epidemiological and experimental studies on the benefits

of FOs and omega-3 FA consumption has increased over

the past few decades.5 Diets enriched with high amounts of

both plant- and marine-derived omega-3 PUFAs seem to

be associated with a lower incidence of coronary heart dis-

ease (CHD)6,7 and a reduction in cardiovascular events.8

In addition, both animal and clinical studies support the use

of omega-3 FAs for inflammatory9 and autoimmune disease

management.10 There have been a number of clinical trials

assessing the benefits of dietary supplementation with FOs

in treating several inflammatory and autoimmune diseases

among humans,4 including rheumatoid arthritis (RA),11,12

Crohns disease,13,14 inflammatory bowel disease,13,1517 as

well as other inflammatory conditions.18,19 Many of the

placebo-controlled trials of FO with chronic inflammatory dis-

eases report significant benefit, including decreased disease

activity and a lowered use of anti-inflammatory drugs.4,20

In 2012, a systematic review (SR) of randomized con-

trolled trials (RCTs) on omega-3 FAs and inflammatory bio-

markers in healthy and clinical populations was conducted

utilizing PubMed and LILACS databases.21 This study

selected 26 RCTs published over the preceding 10 years

and written in the English language that evaluated omega-3

diet supplementation or dietary manipulation. Studies were

excluded if a supplement was administered that could poten-

tially confound the effects of omega-3 FAs or if there was

*Samueli Institute, 2101 East Coast Highway, Suite 300, Corona del

Mar, CA 92625.

Department of Planning, Policy and Design, School of Social Ecology,

University of California Irvine, Irvine, CA 92697.

Samueli Institute, 1737 King Street, Suite 600, Alexandria, VA 22314.

The views opinions and/or findings contained in this work are those of the

author(s) and should not be construed as an official Department of the Army

position, policy, or decision unless so designated by other documentation.

doi: 10.7205/MILMED-D-14-00339

MILITARY MEDICINE, Vol. 179, November Supplement 20142

no ethical approval. Specifically, they excluded five studies

in which arginine and omega-3 FA were used together as

supplement sources. Twenty-six articles2246 met their inclu-

sion criteria. The quality of each publication was determined

by using the JADAD scale and the CONSORT checklist, and

combining the results to come up with an aggregate total

score. The outcome of the SR was that omega-3 supplemen-

tation may be beneficial for lowering levels of inflammation

and endothelial activation in cardiovascular disease and other

chronic and acute diseases, including chronic renal disease,

sepsis, and acute pancreatitis.21 However, numerous studies

evaluating the effects of omega-3 in which inflammatory bio-

markers were considered as outcomes were omitted from their

review. Moreover, in the interim, there have been additional

clinical studies published.

The SR reported here builds on the Rangel-Huerta et al

SR21 and reviews the potential of omega-3 FAs to amelio-

rate inflammatory conditions, especially those of military rele-

vance. In support of a conference in 2009, titled Nutritional

Armor for the Warfighter Workshop,47 speakers noted that

omega-3 FAs have the potential to ameliorate inflammatory

conditions in warfighters. As a consequence of a conference

where speakers discussed the pros and cons for omega supple-

mentation in warfighters, the authors were asked to evaluate

the effects of omega-3 FAs on biomarkers of inflammation

in clinical studies. The purpose of this report is to provide

an updated and more extensive analysis of the available

evidence on markers of inflammation, clinical efficacy, and

safety of n-3 PUFA in healthy and clinically ill humans, as

compared to standard (non n-3 enriched) care.

Objective

The purpose of this review is to examine the quality and quan-

tity of clinical research using the REAL SR approach4851

and to assess the evidence for the effects of omega-3

FA interventions on inflammatory biomarkers for clinical

conditions associated with inflammation and in studies of

healthy humans.

The specific objectives of this review were to (1) survey

the available literature on omega-3 FAs for conditions related

to inflammation in the human population using a REAL;(2) assess the literature for quantity, quality, and effective-

ness of omega-3 FAs on inflammatory biomarkers that used

RCTs study design; and (3) identify gap areas and suggest

next steps for the research field.

METHODSThe following databases were searched from inception

through February 2014: Pubmed, CINAHL, PsycINFO, all

of Cochrane EBM Databases, and the National Agricultural

Library Online. The initial search terms were EPA, DHA,

omega-3 PUFA, or Omega, coupled with inflammation terms

or those conditions known as inflammatory conditions (i.e.,

RA, etc.). Medical subject headings vocabulary was uti-

lized in relevant databases where applicable. The search

was restricted to only English language, peer-reviewed

published literature, and experiments involving human sub-

jects. Reference lists were pearled of all relevant studies to

capture additional reports not found through traditional

searching of databases, as well as conversing with subject

matter experts (SMEs).

Eligibility Criteria

Articles were included in this REAL if they met thefollowing criteria: (1) an inflammatory condition and/or

inflammation itself was being assessed; (2) the interven-

tion involved omega-3 FA supplementation; (3) a control/

comparator intervention was assessed at same time; and

(4) the outcome assessed inflammatory biomarkers as pri-

mary or secondary outcomes, and the study design was a

RCT or SR published in the English language.

Articles were excluded if the report was on a combina-

tion treatment, such as omega-3 FAs plus Vitamin E or the

nutritional package included omega-3 FAs as one of the

components where the effect of omega-3 FAs alone could

not be directly assessed, or if the study was unable to

control for confounding effects of the add-on therapy; how-

ever, studies that administered combination treatments of

FAs only, such as omega-3 FAs and omega-6 FAs or if the

effect of omega-3 FAs alone could be directly assessed

were included. Any study not assessing inflammatory bio-

markers was excluded.

Three investigators (CC, ARW, and RK) independently

screened titles and abstracts for relevance based on the

inclusion criteria. Any disagreements about including a study

were resolved through discussion and consensus with the

review team, or by SMEs (JAI and WBJ).

Quality Assessment and Data Extraction

Methodological quality of the included studies was assessed

independently by three reviewers (CC, RK, and AW). The

individual studies were all RCTs and were evaluated for

study quality and bias using Section 1 and 2 of the American

Dietetic Association (ADA) Evidence Analysis Manual

Quality Criteria Checklist for Primary Research.52 This

checklist was developed to conduct evidence analysis on

nutrition and dietary supplement topics of research and is

well-accepted in the field.53 Each study, once assessed,

received a score of positive/high (+), neutral (0), or negative/low () according to the quality criteria for ADA. Data

extraction was conducted to describe each study included

by population, whether a power calculation was conducted

and achieved, the intervention (diet, supplement, etc.), dose

of the omega-3 FA product, nature of controls, dropout rates

among groups, relevant outcomes and results for the inflam-

matory biomarkers assessed, authors main conclusions, and

any related adverse events reported. Once the quality assess-

ment of the individual studies was completed, the SMEs with

the reviewers conducted a quality assessment of the overall


Omega-3 and Inflammatory Biomarkers REAL

literature pool for each condition using a modification of

the international standard for Grading of Recommenda-

tions Assessment, Development and Evaluation (GRADE)

approach.54 The modified GRADE evaluates (1) the confi-

dence in the estimate of the effect; (2) the magnitude of

the effect size; and (3) safety; to be able to assess an

overall recommendation for the intervention. All screeners,

reviewers, as well as SMEs were fully trained in the meth-

odologies employed and were able to attain a consistent

Kappa above 90%.

Study Selection

Conditions and Populations

Eligible studies included participants of all ages, either

healthy or with acute or chronic disease. There was no restric-

tion on the basis of gender, ethnicity, study setting, or other

clinical characteristics. This SR grouped the studies included

in the analysis into the following categories that emerged

from the literature: (1) healthy populations; (2) cardiac

patients; (3) RA patients; (4) functional conditions, which

includes populations with an active inflammatory process

that impacts ongoing function including asthma, bone

marrow transplant patients, Crohns disease, metabolic syn-

drome (MetS), periodontitis, and ulcerative colitis patients;

(5) long-term organic conditions, which captures those

populations with AD, hypertriglyceridemia and diabetes, obe-

sity, peripheral arterial occlusive disease, and renal disease;

(6) emulsion, which mainly included critically ill patients,

primarily those with septic shock patients; (7) children; and

(8) pregnant women.

Proinflammatory vs. Anti-Inflammatory Markersas Outcomes

Inflammation is characterized by interplay between pro- and

anti-inflammatory cytokines. Major anti-inflammatory cyto-

kines include interleukin (IL)-1 receptor antagonist, IL-4,

IL-6, IL-10, IL-11, IL-13, and alpha-interferon (IFN-a).Tumor necrosis factor-alpha (TNF-a), gamma-interferon(IFN-g), IL-12, IL-18, and granulocyte-macrophage colony-stimulating factor (GM-CSF) are well characterized as pro-

inflammatory cytokines.55,56 Also, a number of biomarkers

can be either pro- or anti-inflammatory depending on their

dose, location of action, and the conditions of the system.

For example, endothelial nitric oxide synthase plays a

role in inflammation and can regulate the expression of

the proinflammatory molecules factor- kB (NF-kB) andcyclooxygenase-2.57 Alternatively, proinflammatory cyto-

kines can modulate the expression of endothelial nitric

oxide synthase.

Molecules of this sort can be classified as inflammation

modulators. Any and all pro- or anti-inflammatory biomarkers

were of interest to this SR and included for analysis. The

majority of inflammatory biomarkers included in this SR

review were (1) the cytokines including chemokines (CCL2,

CCL3, CCL5, CCL11), interferons (IFN-a and IFN-b), ILs(IL-1a, IL-1b, IL-8, IL-10, IL-12, IL-13), lymphokines(IL-2, IL-3, IL-4, IL-5, IL-6, GM-CSF, IFN-g), tumornecrosis factor (TNF-a, TNF-b), transforming growthfactor; (2) acute phase reactant proteins; (3) eicosanoids

(PGE1, PGE2, LTB4, F2-isoprostanes); (4) adhesion mole-

cules (sVCAM-1, sICAM-1, sE-selectin, sP-selectin); and

(5) related biofactors (sIL-1RII; sIL-6R, sTNF-Rs 1 and 2,

CD11b, CD18, CD49, CCR2 and CCR5, MMP-7, MMP-9,

MMP-12, TIMP-2, a1-ntichymotrypsin, fibrinogen, PAI-1,

orosomucoid AGP).21

RESULTS

Included Studies

From the total of 355 articles screened according to eligi-

bility criteria, a total of 112 articles2238,4042,4446,58146

were included in the present analysis. These included arti-

cles were cross-checked against the previous 2012 SR

discussed above.21 Two articles,39,43 which were included

and scored for bias in the Rangel-Huerta et al21 SR were

excluded from this review as we were unable to (1) locate

an inflammatory biomarker in the Engler et al39 study or

(2) confirm the Perunicic-Pekovic et al43 was a RCT design

(Fig. 1).

Healthy Populations

Twenty-one studies2228,38,45,5869 included in the REALSR analysis were on healthy populations where omega-3

FAs were introduced and inflammatory biomarkers were

assessed (Table I). Most of the subjects were given capsules

containing omega-3 FAs, but in some studies, they were

provided as part of their diets.58,61 Two studies tested

omega-3 fortified drink while continuing to consume their

usual diet.25,68 Three studies were emulsion studies admin-

istering omega-3 via infusion (intravenously) to healthy

FIGURE 1. Flow chart.



participants and are presented in the emulsion section

(Table II).36,126,127

Of the twenty-one studies included, fourteen were scored

as high quality (+) with primarily mixed results or no effect.Six studies scored a neutral quality, of which two showed

statistically significant results.22,67 The remaining study scored

low quality (), which showed an effect in favor of

omega-3.61 The doses provided, the duration of adminis-

tration, and age range of participants varied widely across

studies (Table I). In addition, most studies had more male

participants (about 71% male participants completed) com-

pared to female participants. In fact, eight studies included

only male participants.12,22,24,60,61,6769

Cardiac Patients

Twelve studies24,30,32,41,7077 examined cardiac populations

of which eight were scored as high quality (+), six ofwhich (75%) were statistically significant in favor of

omega-3 in reducing inflammation across all biomarkers

assessed such as ICAM, sV-CAM-1, CRP, TNF, IL-6, or

IL-18,30,41,71,74,76,77 with the remaining having at least

one biomarker showing favorable reduction in inflamma-

tion. Four studies scored as neutral quality (0), with pri-

marily conflicting results across these studies (Table III).

There were no poor quality studies in this category. Simi-

lar to healthy subjects, most of the cardiac study subjects

were given capsules containing omega-3 FAs, but in some

studies, diet was manipulated.71,76 Dose for omega-3, EPA,

and DHA varied across studies. Also like in the healthy

subject studies, the majority of cardiac studies reported out-

comes based on male subjects. In total, cardiac studies had

about 78% of male participants complete the intervention.

Three studies did not report gender as a demographic.32,71,72

Rheumatoid Arthritis (RA) Patients

Eleven studies7888 examined RA patients. Four scored

high quality (+) with primarily conflicting results acrossstudies.7981,83 The other two studies showed nonsignifi-

cant effects on C-reactive protein (CRP) when given

FO supplements.79,83 There were five neutral quality (0)

studies,78,84,8688 with one showing positive effects across

biomarkers,84 three with at least one biomarker with an

effect in favor of omega-3,78,86,87 and one showing no effect

across any biomarkers assessed.88 In addition, there were

two low quality () studies showing a reduction across

at least one of the several proinflammatory biomarkers

assessed82,84 (Table IV). Again, like most of the cardiac

study subjects, RA patients were given capsules con-

taining omega-3 FAs rather than a fatty fish diet. In

one study, patients received FO as part of their diets

intravenously.79 This single study is discussed both in

this section of the review as well as the emulsion sec-

tion (Table II). Unlike the healthy participants and car-

diac patient omega-3 studies, RA patients were primarily

female (about 78% females completed interventions). Two

studies did not describe gender.82,86

Functional and Other Conditions

Eleven studies42,59,8997 of varying conditions (asthma, Crohns

disease, MetS, periodontitis, ulcerative colitis) were included

in our functional category (Table V). Seven studies (64%)

scored high quality (+) and four studies (36%) scored neutralin quality (0) according to ADA criteria. Forty-two percent

(42%) of the completed participants in the functional con-

dition group were male. A few studies involved dietary

interventions of omega-392,94 compared to omega-3 sup-

plement capsules. Two studies administered omega-3 via

powder drinks.91,92

Asthma

Two studies89,90 involving asthmatic patients with statisti-

cally significant results scored as high quality (+). Thefirst study involved 60 patients with atopic asthma who

received lipid extract of New Zealand green-lipped mussel

or a matching placebo for a period of 8 weeks and reported

a significant decrease in daytime wheeze and the con-

centration of exhaled H2O2.89 The second study involved

23 dust mite allergic asthmatics receiving PUFA-enriched

fat blend or placebo for 5 weeks and reported significantly

lower exhaled NO (eNO) levels in the omega3 PUFA-

supplemented group.90 These two studies measured what

we are terming modulators and not necessarily pro or

anti-inflammatory biomarkers.

Crohns Disease

Two studies91,92 examined Crohns disease, one scoring

high quality (+) and the other neutral (0). One of thesestudies involved 31 patients who received either omega-3

or omega-6 Impact Powder (IP) and showed a significant

difference in concentration of IL-1b and in concentration

of monocyte chemoattractant protein (MCP-1) in week 9

for omega-3 supplementation.92 The second study was

neutral in quality (0) and had nonstatistically significant

results. These patients were provided with omega-3 or

omega-6 IP and both groups showed a decrease in CRP;

however, there was no statistically significant difference

between the two groups.91

Metabolic Syndrome

Four studies42,9395 included patients with MetS, two of

which scored high quality94,95 and two scored neutral in

quality (0).42,93 Of those studies that were high quality (+),one study94 examined the effect of four different diets

(including omega-3) on inflammation, reporting no statis-

tically significant dietary effects between the pre and post-

intervention on inflammatory status in fasting MCP-1, IL-6,

or IL-1b. The other high-quality score study,95 a four-armresearch design, found statistically significant decreases



between treatment groups ( p < 0.05) in DBP in the kinakogroup after 90 days when compared to the results obtained

from the FO and kinako groups. Both studies, which scored

neutral in quality (0), did not find significant differences

between groups.42,93

Periodontitis

Two studies59,96 on periodontitis populations assessed modu-

lators as their inflammatory biomarkers instead of pro- or

anti-inflammatory biomarkers. One study involved partici-

pants who were asked to stop brushing their teeth for a

period of time and then provided with omega-3 PUFA or

olive oil (OO) for 8 days. This study scored high quality

according to ADA and showed a tendency toward improve-

ment in plaque and gingival index (GI), but no statistically

significant between-group differences were found.59 The other

study involved participants taking borage oil, EPA, or a com-

bination of both or a placebo oil where the use of borage oil

showed better results than EPA for plaque index (PI) and

GI,96 and received a neutral ADA score.

Ulcerative Colitis

The final study in this category included 18 patients with

ulcerative colitis who received FO capsules or a vegetable

oil placebo for 4 months. This study scored high quality (+)and reported statistically significant results for reductions in

rectal dialysate leukotriene B4 levels, improvements in his-

tologic findings, and weight gain for the FO group.97

Long-Term Organic Conditions

We categorized twenty-seven studies29,31,3335,46,98118 as

long-term organic conditions (Table VI). These conditions

included AD, hypertriglyceridemia and diabetes, overweight

and obesity, peripheral arterial occlusive disease, renal disease,

and cancer and bone marrow transplant. Nineteen studies

(70%) scored high quality (+) and eight studies (30%) scoredneutral in quality (0) according to ADA criteria. Fifty-four

percent (54%) of the participants in the long-term organic

conditions were male participants.

Alzheimers Disease

Three studies34,35,98 assessed AD patients, all of which scored

high quality (+). One of these studies showed statisticallysignificant results with DHA-rich omega-3 FAs supplementa-

tion, which increased plasma concentrations of DHA (and

EPA), and were associated with reduced release of IL-1, IL-6,

and granulocyte colony-stimulating factor (G-CSF) from

peripheral blood mononuclear cells (PBMCs) for patients

receiving omega-3 FAs vs. placebo oil capsules.35 This is one

of the few studies with a relatively large sample size (N = 361)and that measured blood levels of FA. In the other two studies,

patients received DHA and EPA or a placebo oil capsules

for 6 months, and showed no influence on inflammatory or

other measured biomarkers in CSF or plasma.34,98

Hypertriglyceridemia and Diabetes

There were eight studies on hypertriglyceridemia33,99102 or

diabetes.31,103,104 Most of the studies (75%)31,99,101104 in this

group scored high quality (+) according to ADA criteria. Ofthe six studies that scored high quality, most reported reduc-

tions in inflammatory markers.99101 Of the two studies33,100

that scored neutral (0) according to ADA criteria, one study

examined subjects with hypertriglyceridemia that were other-

wise healthy individuals and showed statistically significant

results with DHA supplementation in the absence of EPA,

which resulted in a reduction in the number of circulating

neutrophils and serum CRP and GM-CSF and an increase

in the concentration of matrix metalloproteinase (MMP-2)

according to ADA criteria.100 The other study compared two

different doses of DHA plus EPA and found that neither dose

statistically improved inflammatory markers (IL-1b, IL-6,TNF-a, and high-sensitivity CRP) or the expression of inflam-matory cytokine genes in isolated lymphocytes.33

There were three studies scoring high quality (+) involv-ing patients with type 2 diabetes with or without hypertension

consuming EPA, DHA, or placebo capsules.31,103,104 Although

the serum IL-2 and TNF-a levels were reduced in the treatmentgroup serum, CRP levels varied across these studies.31,103,104

Overweight and Obesity

There were ten studies29,105112,115 on overweight/obesity

patients, five scoring high quality (+) and five scoring neu-tral quality (0). For the five high-quality studies, four (80%)

reported nonsignificant statistical results for TNF, IL-6, and

CRP inflammatory biomarkers in patients receiving omega-3

or a placebo29,108110 (Table VI). For the neutral quality

studies, one showed statistically significant results across

various inflammatory biomarkers when patients consumed

flaxseed flour vs. a placebo.106 The other neutral quality studies

showed nonsignificant results for inflammatory biomarkers

when patients consumed omega-3 long-chain PUFA-enriched

versions of typical processed foods or placebo.105,111,112

Peripheral Arterial Occlusive Disease

One study addressed patients with peripheral arterial occlu-

sive disease where participants received canola oil or

sunflower oil, as placebo, added to their usual diets for

8 weeks. This study was scored as high quality and there

were no significant differences for either group for CRP

inflammatory biomarkers.116

Renal Disease

Three studies assessed omega-3 among patients with renal

disease.46,113,114 Two of the three studies (67%) scored high

quality (+) according to ADA criteria.46,113 For all threestudies, patients received pills of omega-3 FA or placebo

pills. The two high-quality studies concluded that consum-

ing omega-3 FA lowers CRP and IL-1b significantly morethan placebo.46,113



Cancer and Bone Marrow Transplant

Two studies reported on omega-3 interventions for cancer

and bone marrow transplant patients.117,118 Both studies

scored as high quality (+) according ADA criteria. The firststudy where 16 patients underwent allergic bone marrow

transplant received EPA orally and showed significantly

lower levels of TNF-a, IFN-g, and IL-10 compared withthe non-EPA group.117 The second study investigated the

effects of an oral nutritional supplement containing n-3

PUFAs on nutritional status and inflammatory markers

where the EPA plus DHA group had greater weight loss

and lower IL-6 production after 5 week, though not statisti-

cally significant (B = 227.9; p = 0.08).

Parenteral Omega-3 (Emulsion Studies)

Our SR retrieved twenty-seven studies36,37,40,44,79,119140 on

parenteral nutrition (PN) of omega-3 on participants to

reduce inflammation. Nineteen (68%) of these studies were

published since 2004. Twenty-three studies (85%) scored

high quality (+) and four studies (15%) scored neutral inquality (0) according to ADA criteria. Emulsion studies were

done for healthy participants, patients with RA, and critically

ill patients. Four studies were categorized as healthy partici-

pants and patients with RA. The three healthy participant

emulsion studies are referenced in Table II and of the single

RA emulsion study is referenced in Tables II and IV. The

majority of the studies (n = 23) were on critically ill patientsor surgical patients. In fact, 16 of the 27 studies (59%) were

surgery-related studies and six studies (22%) included patients

in intensive care units (ICUs).

Studies of Parenteral Omega-3 in Healthy and RA Patients

Four studies, all assessed as high quality (+),36,79,126,127

addressed inflammatory responses and the composition of

platelets in healthy subjects and patients with RA given FO

intravenously or with usual treatment (soybean oil lipid emul-

sion). These studies reported that the use of omega-3-enriched

emulsions increases the serum concentration of alpha-

tocopherol and the percentage content of EPA and DHA

from start of study to end of study. In addition, these studies

also reported that omega-3 emulsion resulted in a greater

reduction in IL-6 and TNF-a, though most of these findingwere not significant.

Studies of Parenteral Omega-3 in Critically Ill Patients

Twenty-three studies (85%) were included in our critical

illness population category receiving PN (Table II). Six

studies that met our inclusion criteria involved patients in

the ICU and three with systemic inflammatory response

syndrome (SIRS). Nineteen (83%) of these studies were

scored high quality (+) according to ADA criteria. Four(17%) scored natural (0) according to ADA criteria.

Of those that scored high quality (+), one high-qualitystudy demonstrated nonsignificant effects for the inflamma-

tory biomarker assessed (IL-6), showing that supplementa-

tion with FO did not affect this inflammatory biomarker.121

Two other high-quality studies on septic patients who were

given enteral nutrition received a standard soybean oil-based

emulsion or an emulsion containing FO (Omegaven) for540 or 10131 days. Within 2 days of FO infusion, free n-3

FAs increased, and the n-3/n-6 ratio was reversed and the

generation of proinflammatory cytokines by mononuclear

leukocytes was markedly elevated during n-6 and was sup-

pressed during n-3 lipid application.40 The authors reported

that both these studies establish that infusion of long-chain

n-3 PUFA for patients with sepsis can modulate inflam-

matory mediator production and related inflammatory pro-

cesses.147 Of the four studies that scored neutral in quality

(0) according to ADA criteria, two studies compared the

effects of a medium- and long-chain triglyceride fat infu-

sion on systemic inflammation and hepatic steatosis in ICU

patients. The first study44 found that plasma cytokine, PGE2,

LTB4, IL-1b, IL-6, IL-10, and TNF-a concentrationsdecreased over time in both groups ( p < 0.05). The secondstudy included sepsis and SIRS patients who received PN

employing the MCT/LCT fat infusion or the FO-based fat

infusion over 7 days in the ICU. Groups receiving the

MCT/LCT PN had higher proinflammatory cytokine (TNF-a,IL-1, and IL-6) values and lower anti-inflammatory cytokine

(IL-10) values than patients fed with FO, but statistical sig-

nificance was seen only at the middle and end of the study

periods in the septic groups. The results of this study may

support that FO could be more effective than MCT/LCT fat

emulsion, especially in patients with infectious conditions.136

Taken together, these studies indicate that inclusion of FO

in PN regimens for critically ill and surgical patients modu-

lates the generation of inflammatory eicosanoids and cytokines.

It seems there is a shift in the generation of leukotrienes

toward the leukotriene-5 series and an ameliorated LTB5:

LTB4 ratio, thereby reducing the incidence of systemic inflam-

matory response.148 Furthermore, the inclusion of FO in PN

regimens, may help to counter the surgery-induced decline in

antigen presenting cell activity139 and T-lymphocyte cytokine

production.135 Importantly, these studies do not reveal any

deleterious effects of FO infusion in these patients.147(p567)

Pediatric Populations

This review retrieved four studies128,141143 on the effect on

omega-3 FAs in children. Two scored high quality (+) andtwo studies scored neutral in quality (0) according to ADA

criteria. One study, neutral in quality, was unable to find

significant effect on biomarkers for inflammation for DHA

supplementation compared to corn and soy oil (control).141

The other remaining three studies reported mixed results.

A study on lipid omega-3 emulsion was administered

in infants for days 1 to 4 before open-heart surgery, and

10 days after surgery found that the plasma TNF-a con-centration was significantly lower ( p = 0.003) in the treat-ment compared to the control group. In infants without



sepsis, plasma TNF-a did not differ according to treat-ment; however, when sepsis developed, mean plasma TNF-awas significantly lower in treatment compared to control

( p = 0.0007).128 The two remaining studies in this groupof studies reported similar findings. In neonates that have

undergone surgery and are fed omega-3 FAs through a

nasogastric tube, it was found that although decreases of

cytokines during hospitalization were similar in both groups,

there was a greater decrease of IL-1b in the DHA group than in

the OO group after adjusting for confounders (p = 0.028)142

(Table VII).

Pregnant Women

The role of omega-3 on inflammation during pregnancy and

fetal development is not well studied. We retrieved three

studies on the effect of these EFAs on pregnancy inflam-

mation outcomes. During pregnancy, the immune tolerance

between the fetus and the mother is mediated by a number of

complex processes at the maternofetal interface.149 Omega-3

FAs may play a part in a number of these pathways. Two

studies scored high quality (+) and one scored neutral inquality (0) according to ADA criteria. Of the two high-

quality studies, one study145 on pregnant women (100). In total, there were twenty-one studies and 1,191 participants in this group. Therefore,

we believe that further research is very unlikely to change

our confidence in the estimate of effect. Thus, we are unable

to recommend omega-3 to reduce inflammation in healthy par-

ticipants. In contrast, most high-quality studies in patients with

established cardiovascular disease had improved inflammatory

status (lower proinflammatory and higher anti-inflammatory)

biomarkers compared to controls. Three studies in this group

had a large number of participants (>100). In total, there were12 studies and 1,121 participants in this group. This category

was dominated by one study with a large sample size and good

score.77 In this study, levels of IL-18 were decreased by diet

(10.5% vs. baseline, p = 0.012 compared with no diet) andby omega-3 PUFA supplementation (9.9% vs. baseline, p =0.008 compared with placebo). Levels of IL-18 were also

significantly reduced in each treatment group compared

with the control group ( p = 0.021 for both), with a poten-tially additive effect of the 2 intervention principles ( p > ]>> setdistillerparams> setpagedevice

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Nutritional armor: Omega-3 for the Warfighter

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Transcript of Nutritional armor: Omega-3 for the Warfighter