HindawiPublishingCorporation TheScientificWorldJournal Volume2013,ArticleID752071,12pages http://dx.doi.org/10.1155/2013/752071 Review Article Influence of Physical Activity and Nutrition on Obesity-Related Immune Function Chun-JungHuang,1MichaelC.Zourdos,1EdwardJo,2,3andMichaelJ.Ormsbee3 1DepartmentofExerciseScienceandHealthPromotion,FloridaAtlanticUniversity,777GladesRoad,FH11A-126B, BocaRaton,FL33431,USA 2DepartmentofKinesiologyandHealthPromotion,CaliforniaStatePolytechnicUniversity,Pomona,Pomona,CA,USA 3DepartmentofNutrition,FoodandExerciseSciences,TheFloridaStateUniversity,Tallahassee,FL,USA CorrespondenceshouldbeaddressedtoChun-JungHuang;[email protected] Received31August2013;Accepted19September2013 AcademicEditors:F.D’AcquistoandA.A.Manfredi Copyright©2013Chun-JungHuangetal. This is an open access article distributed under the Creative Commons Attribution License,whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperly cited. Researchexaminingimmunefunctionduringobesitysuggeststhatexcessiveadiposityislinkedtoimpairedimmuneresponses leadingtopathology.Thedeleteriouseffectsofobesityonimmunityhavebeenassociatedwiththesystemicproinflammatoryprofile generatedbythesecretorymoleculesderivedfromadiposecells.Theseincludeinflammatorypeptides,suchasTNF-𝛼,CRP,and IL-6.Consequently,obesityisnowcharacterizedasastateofchroniclow-gradesystemicinflammation,aconditionconsiderably linkedtothedevelopmentofcomorbidity.Giventhecriticalroleofadiposetissueintheinflammatoryprocess,especiallyinobese individuals, it becomes an important clinical objective to identify lifestyle factors that may affect the obesity-immune system relationship.Forinstance,stress,physicalactivity,andnutritionhaveeachshowntobeasignificantlifestylefactorinfluencing theinflammatoryprofileassociatedwiththestateofobesity.Therefore,thepurposeofthisreviewistocomprehensivelyevaluate theimpactoflifestylefactors,inparticularpsychologicalstress,physicalactivity,andnutrition,onobesity-relatedimmunefunction withspecificfocusoninflammation. 1.Introduction immune functions [6–8]. The confirmed presence of secre- torymoleculesderivedfromadipocytes,suchasproinflam- The global epidemic of obesity is irrefutably a major public matorycytokines(e.g.,tumornecrosisfactor-alpha[TNF-𝛼] health issue largely because of its comorbidities, namely, and interleukin-6 [IL-6]), constitutes the unique endocrine cardiovascular disease, type II diabetes, and cancer. Never- functionofadiposeandprovidesvaluablepathophysiological theless,theprevalenceofobesityhasdrasticallyescalatedby insight regarding obesity and its comorbidities [7]. During nearly57%overtheprevioustwodecades[1,2].TheNational unhealthy weight gain, the influx and storage of excess HealthandNutritionExaminationSurvey(NHANES2009- lipids in adipocytes perturbs normal cell function, which 2010)reportedthat36%ofUSadultsarecurrentlyclassified consequentlyinducestheoverexpressionandhyper-secretion asobese (BMI ≥30kg/m2), while16% representincidences of inflammatory peptides into circulation [9]. As a result, of severe cases (BMI ≥ 35kg/m2) [2]. Based on projections obesity is now recognized as a state of low-grade systemic derivedfrompreviousNHANESdata,86%ofU.Sadultswill inflammation characterized by high circulating levels of beoverweight(BMI≥25kg/m2)orobese(obesityaccounting inflammatorymolecules,suchasTNF-𝛼,IL-6,andC-reactive for 51.1%) by 2030 if this epidemiological trend remains protein (CRP) [10, 11]. Due to the deleterious effects of unresolved[3–5]. systemicinflammationonmultipleorgantissues,unhealthy Overthepasttwodecades,adiposetissuehasbeenestab- weightgainisassociatedwithhighriskofdevelopingserious lished as a multifunctional organ playing a critical role healthconditions,suchastypeIIdiabetesandcardiovascular not only in lipid/energy storage but also in endocrine and disease [7, 12]. Given the involvement of adipose tissue in 2 TheScientificWorldJournal the inflammatory process, especially in excessive states, it In addition, our laboratory recently found that following a becomes an important clinical objective to identify lifestyle combinedphysicalandpsychologicalstress,NEarea-under- factorsthatmayaffecttheobesity-immunesystemdynamic. the-curve(AUC)wasnegativelycorrelatedwiththepercent- For instance, stress, physical activity, and nutrition have age of CD19+ B cells, and heart rate (HR) was negatively eachshowntobesignificantlifestylefactorsinfluencingthe associatedwiththepercentagechangeintheCD4/CD8ratio inflammatoryprofileassociatedwiththestateofobesity[13– [35]. These elevations in NE and HR simultaneously in 15].Ofparticularinterest,itiswelldocumentedthatchronic response to the dual challenge suggest greater sympathetic inflammationisalsohighlycorrelatedtonutritionalfactors activationthat,inturn,couldpossiblyexplainthealteration in the distribution of lymphocyte subsets, resulting in inef- suchasthetypeandamountofcarbohydrates,proteinsand fectivecell-mediatedimmuneresponses[36,37].Therefore, fats that are consumed in the diet [16–18]. Therefore, the these findings indicate that acute stress enhances innate purpose of this review is to comprehensively evaluate the immunity and possibly suppresses adaptive immunity, and impactoflifestylefactors,inparticularpsychologicalstress, thesealterationscanbelikelyenhancedathigherintensities physical activity, and nutrition, on obesity-related immune ofphysicalstress.Theappropriateredistributionofimmune functionwithspecialfocusoninflammation. cellsinresponsetoacutestressorsisimperativetoaneffective and efficient immune response in preparation for potential 2.StressandObesity invaders and injury [26, 38]. However, when exposed to chronic stress, immunoprotection can be suppressed by Stressinthebodyisestablishedthroughsometypeofstres- reducing immune cell number, function (cytotoxicity), and sor(s), either physical or psychological. When stimulated, proliferation, thereby promoting susceptibility to diseases the human body responds in a complex manner, incorpo- [39,40]. ratingtheintertwinedactivityoftheendocrineandnervous Obesityisconsideredachronicinflammatorycondition systems(hypothalamic-pituitary-adrenal[HPA]andsympa- that enhances the risk of numerous inflammatory diseases, thoadrenal[SA]axes).Stresshormonessuchascortisolfrom includingdiabetesandcardiovasculardisease(CVD).These HPAaxisandcatecholamines(epinephrine(EPI)andnore- obesity-attributableillnesseshavebeendiscoveredtohavea pinephrine(NE))fromtheSAaxishavebeenshowntoalter strongassociationwithinflammatoryparametersinplasma immunecellresponses,andthisimportantimmunesystem such as proinflammatory cytokines (TNF-𝛼 and IL-6) [41, responsecoordinatesanumberofthebody’sadaptationsto 42]. In addition to plasma inflammatory mediators, the thestressor.Notably,elevationsinstresshormones(cortisol circulating mononuclear cells in obese individuals may be andcatecholamines)arethoughttohavedetrimentaleffects morereadilystimulatedtoproduceinflammatorycytokines on the immune system, leading to an imbalance between [43]. Interestingly, along with physical illnesses, obesity is innate(immediateantigen-nonspecificdefense)andadaptive associatedwithjob-associatedstressandpsychosocialdisor- immunity (specific response to a particular foreign antigen derssuchasdepressionandchronicanxiety[44–46].These creatingimmunologicalmemory)viathereleaseofimmune stress-relateddisordershavebeenfoundtoleadtoincreased mediatorssuchascytokines[19].Inresponsetoacutestress, riskofCVDandmortalityinobesepatients[47]. the innate immune promptly prepares to provide immune Chronicstresshasbeenshowntobeassociatedwithdis- protectionfollowedbyadaptiveimmunitywhenexposedto turbancesoftheHAandSAaxesandislinkedtoabdominal repeatedorprolongedstress,whereaschronicstresscansup- adiposity [48]. In response to acute stress, elevated cortisol presstheseimmunedefenses.Thisstress-immuneinteraction levels are associated with high central adiposity [49–51]. isanimportantantiviraldefenseandfosterstheelimination Furthermore, studies have demonstrated an increase in SA ofinvadingmicroorganisms[20,21]. axis reactivity in obesity patients [52–54]. This occurrence Research has shown that stress induces changes in seemstobepivotaltounderstandhowstressmayupregulate immune cell distribution [22–25], which ensures that the theinflammatoryconditionsinobeseindividuals.Recently, body’s immune response is efficient or elicits an effective studieshaveshownthatobesesubjectsexhibithigherproin- immunoprotection. An appropriate distribution of periph- flammatorycytokineproductionsuchasIL-6inplasmaand eral immune cells provides for the performance of surveil- ex vivo compared with normal-weight subjects in response lance and effector functions of the immune system [26]. toacutementalstress[50,55].Althoughchronicallyelevated The release of catecholamines and cortisol in response to cortisolisthoughttohavedeleteriouseffectsontheimmune stressors (physical or psychological) can mediate changes system, a suppressive effect of immune regulation has been in the immune cell distribution [27, 28]. In response to showninresponsetoacutestressors[56].Importantly,Wirtz acutestress,immuneresponseisprimarilyregulatedbycat- et al. [57] have revealed that individuals with higher body echolamines[24].Thisisfurthersupportedbyotherstudies mass index demonstrated lower glucocorticoid sensitivity, demonstratingtransientimmunecellredistributionviabeta- resulting in a diminished ability to inhibit production of adrenergic activation following acute mental stress [23, 27, TNF-𝛼followingacutementalstress. 29, 30]. Specifically in response to exercise, monocytes and Inaddition,𝛽-adrenergicreceptorshavebeenshownto NK cells (innate immunity) exhibit the greatest fluctuation mediate catecholamine-induced decreases in proinflamma- followedbyCD3+TcellsandCD19+Bcells(adaptiveimmu- tory cytokines [58, 59]. Stress has been demonstrated to nity) [31–33]. These alterations in immune cells have been downregulatebeta-adrenergicreceptorexpressionandfunc- showntocorrespondwiththereleaseofcatecholamines[34]. tionsonmonocytesandNKcells,resultingintheelevation TheScientificWorldJournal 3 of TNF-𝛼 and IL-6 [46]. These are key proinflammatory incidence of infection compared to inactive and sedentary cytokines involved in CVD, chronic anxiety, and depres- individuals [75, 76], suggesting that physical activity may sion [60]. Furthermore,previous studies demonstrated that improve the immune response. Moreover, these benefits to increasedtension-anxiety,asubscaleoftheProfileofMood immune function in relation to regular exercise include States (POMS), is correlated with the downregulation of 𝛽- decreased levels of proinflammatory cytokines TNF-𝛼 [77], adrenergic receptors [61]. Individuals with high life stress IL-6 [78], and CRP [79] along with an increase in the anti- and hostility have less lymphocyte 𝛽-adrenergic sensitivity inflammatory marker (IL-10) [78]. Additionally, exercise is [62].Takentogether,thesefindingssuggestthatobesitycould associatedwithdecreasedlevelsofdepression[80].Tofully diminish the inhibitory effect of 𝛽-adrenergic receptors in comprehend the positive benefits of exercise to immune response to acute stress, resulting in a greater release of function it is necessary to examine the stress and recovery proinflammatory cytokines [50, 55]. Thus far, it has been response to exercise. Additional insight into how exercise discoveredthatobeseindividualshavereduced𝛽-adrenergic affectsacuteandchronicinflammationisnecessarytounder- receptor density [63] and higher plasma NE and EPI con- stand the importance of exercise as an antagonist to the centrations [64]. Hence, the investigation of mechanisms currentobesityepidemic. of 𝛽-adrenergic receptor regulation to stress may provide insightintotheroleofpsychoneuroimmunologicalprocesses inobesepopulations’healthanddisease. 3.1.ExerciseandtheStressResponse. Intenseexercisetraining places a stimulus on the body often resulting in myofiber Althoughtheunderlyingmechanismscontributingtothe damage, muscle soreness, and edema [81]. This damaging relationship of the stress response, obesity, and proinflam- effectparticularlyoccursinnovicetraineeswhoarestressed matorycytokinesremaintobedetermined,elevatedlevelsof by an unfamiliar stimulus. This initial fatigue in response leptinhaverecentlybeenimplicatedasacontributingfactor to a new stimulus is described in Hans Seyle’s landmark thatlinksacutestresstoinflammation.Leptin,anadipocyte- work, the general adaptations syndrome (GAS) [74], as the derived hormone, plays an important role in metabolism, “alarmreactionstage.”Followingtheinitialalarmresponse, adiposity,andvascularinflammationandhasbeenimplicated theGASexplainsthatoncerecoverytakesplace,anindividual in the development of coronary heart disease [65]. In vitro enters the stage of resistance, indicating the capability of stimulation of cultured human endothelial cells with leptin undertakingfurtherstress.Theonsetofthestageofresistance has induced an increased accumulation of levels of proin- signifies the adaptation to the initial stress realized in the flammatorymediator(e.g.,monocytechemotacticprotein-1) alarm stage. This concept of initial fatigue and recovery is via activation of nuclear factor-kappa B [66]. Interestingly, similar to the repeated bout effect (RBE), which states that recent research has shown that people who undergo acute performingthesameexercisestimuluswithin6monthsofthe mentalstressdemonstrateincreasesinleptinlevels,andthese initialboutresultsinanattenuatedlevelofmyofiberdamage increases are positively correlated with waist circumference [81].Consequently,theincurredadaptationisspecifictothe [67, 68]. Brydon et al. [68] also showed that a positivecor- task performed in the initial exercise bout. This concept of relation between basal circulating leptin and IL-6 exists specificity is otherwise known as the specific adaptations in response to mental stress. These findings suggest that to imposed demands (SAID) principle, which states that leptin may partially contribute to inflammatory response individualsadapttothespecificstressorplaceduponthemto followingacutestress.Futureinvestigationshouldattemptto becomemorefit forlivingconditions[82]. Althoughinitial understandthemechanismscontributingtotherelationship fatigue leads to long-term adaptation without programmed betweenobesityandproinflammatoryreactivitytostress.In restandvariationtoexercise-trainingvolumeandintensity, turn, an understanding of how the mind and body interact tissue repair may not fully transpire and overtraining syn- and impact health can directly influence how we develop drome may develop [83]. Moreover, lack of ample recovery targetedtreatments,suchasexercise-trainingandweightloss fortissuerepairmayresultinchronicinflammationandcen- programs,astherapeuticinterventionsforobesity-associated tralfatiguepotentiallyhavingdeleteriouseffectsonexercise cardiovascular, chronic infectious, and inflammatory neu- performance.Furthermore,astateofchronicinflammation, ropsychiatricdiseases. which impairs immune function, may contribute to an increasedprobabilityofobesity,CVD,anddiabetes. 3.PhysicalActivityandImmuneFunction 3.2. Acute and Chronic Inflammation. When dissecting the Physicalactivityhaslongbeenassociatedwithimprovements subsequenteffectsoftheinflammatoryresponse,itisneces- in aerobic capacity [69], strength [70], muscle growth [71], sarytounderstandthatinflammationcanbebothacuteand and body composition [70]. However, it is now widely chronicinnature[84].Acuteinflammationisanimmediate accepted that chronic physical activity enhances immune response to stress and may not necessarily be indicative of function and attenuates the likelihood of chronic disease, long-term adaptations. To illustrate, acute stress hormone such as CVD, diabetes, and obesity [72, 73]. Initially, unac- response, such as cortisol, has increased significantly in customed exercise places a stressor on the body resulting response to high-volume resistance training [85]. However, in fatigue [74]; however, once the recovery process occurs, long-term exercise training of two years in length has beneficial adaptations are the result. In fact, fit individuals resulted in decreased resting cortisol concentrations [86]. (thosewhopartakeinregularphysicalactivity)havealower Thus, chronic exercise training appears to reduce resting 4 TheScientificWorldJournal cortisollevels.Therefore,acuteelevationsinmarkersofstress 3.5.Summary. Obesityisachronicinflammatorycondition, signify an immediate stress response; however, long-term whichenhancestheriskofCVDandisassociatedwithvari- adaptations to physical activity appear to favor parasympa- ousinflammatorycytokines(TNF-𝛼andIL-6).Whenintro- theticdominance. ducedasanewstressor,exerciseacutelyincreasescatabolic responses [85], resulting in muscle fatigue [74]. However, researchindicatesthatregularparticipationinexerciseleads 3.3. Exercise and Acute Inflammation. A typical acute to decreased systemic inflammation [93]. Indeed, Colbert response to an infection, stressor, or immune system stim- et al. [72] related higher levels of physical activity to lower ulatorlipopolysaccharide(LPS)istheelevationoftheproin- levels of IL-6 and CRP. Furthermore, exercise is beneficial flammatorycytokineTNF-𝛼[87].Inratsthatwereexercised during the aging process to decrease catabolic hormone to exhaustion (an average of 102 minutes), an attenuated responses[100].Consequently,exerciseseemstoprovidesig- TNF-𝛼 response was measured compared to the response nificantbenefitsthatenhanceimmunefunctionanddecrease in nonexercised rats when administered with LPS for up inflammation.Thus,exerciseisrecommendedasaneffective to 6 hours [87]. In agreement, in human data, healthy strategytopositivelyalterobesity-relatedimmunefunction. men who performed aerobic exercise to exhaustion prior to the infusion of LPS exhibited lower levels of TNF-𝛼 comparedtoanon-exercisinggroup[77].Likewise,Nosaka 4.NutritionandInflammation and Clarkson [88] reported no increase in plasma levels of TNF-𝛼 following a bout of damaging resistance training 4.1.Macronutrients:QualityandQuantity of the elbow flexors. Interestingly, TNF-𝛼 levels have been reportedtobesignificantlyelevatedinobesepopulations[89, 4.1.1.EnergyContent. Chronicinflammationisinfluencedby 90].Indeed,TNF-𝛼hasbeenestablishedtobeassociatedwith energybalance.Acuteoverconsumptionofenergyhasconsis- insulin resistance, leading to obesity [91]. Ultimately, both tentlyresultedinincreasesinmarkersofinflammation[101]. aerobicandresistanceexercisemaybeeffectiveinattenuating Theseincreasesoccurwithorwithoutweightgain,suggesting acuteinflammatoryresponses,whichmighthavesignificant thatchronicinflammationinoverweightorobeseindividuals implicationstopreventingobesity. maybestronglyinfluencedbycaloricloadandnotnecessarily theprimaryresultofincreasedadiposity.Thismayalsohelp to explain the prevalence of chronic disease in the Western 3.4. Exercise and Chronic Inflammation. Numerous studies world where diets often include calorie-dense foods (e.g., have been conducted on the relationship between exercise “fastfood”).Conversely,caloricrestrictionand/orfastingcan and concentrations of CRP [79, 92, 93]. These studies all alsoresultinincreasesininflammation[102].Thesefindings demonstrate an inverse relationship between CRP concen- suggestmaintenanceofenergybalanceasanimportantfactor trations and physical activity [92]. Further, physical fitness in the prevention of systemic inflammation. Interestingly, measured by maximal oxygen consumption (VO2 max) is outsideofenergybalance,thetypeofmacronutrientsthatwe alsoinverselyrelatedtoCRPconcentrations[94].Dataalso consumealsoplaysapivotalroleinwhole-bodyinflamma- indicates that active older men (i.e., exercising 4 days/wk) tion. have lower levels of IL-6 and greater levels of IL-10 when compared to older men who perform a low amount of physicalactivity(i.e.,notactivemostdaysoftheweek)[78]. 4.1.2. Carbohydrates. Carbohydrates (CHO) can dramati- Moreover, multiple studies show that lifestyle interven- callyinfluencewhole-bodyinflammation.Inaddition,there tions with exercise impact the inflammatory response [95– are many factors that affect the inflammatory potential of 98]. Balagopal et al. [95] reported that obese adolescents CHO intake including glycemic index (GI), glycemic load whounderwenta3-monthlifestyleinterventionofenhanced (GL),anddietaryfiber.ThedegreetowhichaCHOincreases physicalactivityandnutritionhabitshaddecreasedbodyfat the blood sugar response (high-GI equals greater increases percentage, insulin resistance, CRP, and IL-6. Additionally, in blood sugar) will influence the inflammatory response. ninemonthsofendurancetrainingin14individualsprepar- In fact, GI has consistently shown a positive correlation ingforamarathonresultedindecreasedlevelsofCRP[92]. with biomarkers of whole-body inflammation. Specifically, Likewise, an exercise intervention of 3 years, which gave markersofinflammationincreaseacutelyfollowingahighGI detailed advice in regard to physical activity, in 60 obese meal[103].Ofnote,markersofinflammationeitherdecline women resulted in weight loss along with decreased levels or remain unchanged following low-GI meals [104]. This ofTNF-𝛼[99].Infact,an8-weekexercise-trainingprogram discrepancymaybeafunctionofGL,theproductofdietary consistingof4days/wkofcyclingbetween40and50%VO2 GI,andquantityofCHOactuallyeaten,asconsumptionof peak did not affect insulin sensitivity or CRP levels despite alargequantityoflow-GIfoodhasbeenshowntoincrease improvements in aerobic fitness and endothelial function markers of inflammation to a similar degree as to the con- [96]. One possible explanation for these conflicting results sumptionofasmallquantityofhigh-GIfood[105].However, isthattheinterventiondurationof8weekswastooshortto data on the relationship between GL and inflammation are elicitchangesininsulinsensitivityandCRPlevels.Ultimately, conflicting. Although some studies have shown a positive itseemsthatlong-termexerciseinterventions(greaterthan8 correlationbetweendietaryGLandmarkersofinflammation weeks)areeffectiveinreducetheinflammationresponseand (i.e., C-reactive protein, CRP) [106, 107], others have failed improvephysicalfitness. toreportasignificantassociation[108].Thisdivergencemay TheScientificWorldJournal 5 be due to differences in energy content of the diets in GL noninflammatory effects have been reported with omega-6 studies, which, as discussed above, has been shown to have consumption [122]. Indeed, the effectiveness of PUFAs in a strong relationship with inflammation [109]. Many GL reducing markers of inflammation may lie in the ratio studiescomparevaryingdietaryCHOamountswhilesimul- between omega-3 and omega-6 PUFAs. It has also been taneouslylimitingcaloriesto encourageweight loss. There- suggested that a higher ratio of omega-3 to omega-6 PFAs fore,thesealterationsmaygoagainsteachotherandpossibly increasestheanti-inflammatorypotentialofthesefats[123]. explaintheconfoundingresults. MUFAsalsoappeartobeanti-inflammatoryasseveralstudies Increased consumption of refined carbohydrates in the [124, 125], but not all [118], have reported an inverse rela- modern diet has not only led to increased consumption of tionship between MUFA levels and inflammatory markers. high-GIdietsbutalsoreducedintakeofdietaryfiber.Thislow Strongerevidenceforthisinverserelationshipisfoundspecif- fiberintakemayexplaintheincreasedprevalenceofchronic ically between olive oil consumption, which contains high inflammationanddiseaseasnumerousstudieshavereported levelsofMUFAs,andsystemicinflammatorymarkers[126]. an inverse relationship between fiber intake and CRP [110]. Of interest, the anti-inflammatory effects of fiber appear to 4.1.4.Protein. Theeffectsofproteinsoninflammationseem holdtrueforbothdietaryfiberandfibersupplements[111]. to vary depending on the source of the protein. Red meat Moreover,thisrelationshipmayalsoholdtrueforinsoluble istypicallyconsideredasproinflammatory.Thisislikelydue fibers, which have been shown to positively affect immune totheassociationbetweenhighdietaryredmeatintakeand function[112].Dietaryfibermayalsoinfluenceinflammation bothcoronaryheartdisease[127]andtypeIIdiabetes[128]. through its mediating effects on glycemia. In one lifestyle However,evidencefromstudiesonleanredmeathasfailed intervention study on a representative sample of Italian toshowanyincreaseinmarkersofinflammation[129].This adults, blood CRP concentrations were lowered along with suggeststhatthequalityofthemeatmaybemoreindicative fasting blood glucose in response to increased fiber intake, independentofweightloss[113].Thus,perhapsbymediating ofitsinflammatorypotential.Indeed,consumingprocessed theabsorptionofnutrientsandmodulatingchangesinblood meat(e.g.,bacon,hamburger,andsausage)seemstoincrease sugar,fibereffectivelyreducesinflammation. theriskoftypeIIdiabetes,whichisassociatedwithincreased whole-bodyinflammation[130]. Inflammation from protein ingestion may also vary 4.1.3.Fats. Theinflammatorypotentialoffatisafunctionof between meat-based, plant-based, and milk-based proteins. thetypeoffatbeingconsumed.Numerousstudieshaveimpli- InastudyfromDenmark,obeseparticipantswerefedasingle cated saturated fats (SFAs) as inflammatory agents. SFAs, high-fat meal containing 4 different sources of protein: fish whicharecommonlyfoundinprocessedmeat,refinedgrain, (cod),wheyisolate,gluten,orcasein.Serumlevelsofinflam- and/orfriedfoods,havebeenshowntoincreasemarkersof matorycytokinesweremonitoredinthe4hoursfollowingthe inflammation such as CRP, IL-6, and E-selectin, a vascular adhesionmolecule[114].AstrongcorrelationbetweenSFAs meal.Codproteinandglutenresultedinabluntedincreasein andCRPcanbefoundintheNationalHealthandNutrition markersofinflammationversusthewheymealbutwerenot Education Survey (NHANES 99-00) [115]. Furthermore, different from the casein meal [131]. Therefore, consuming Aryaetal.[116]reportedthatamongotherdietarynutrients, cod protein and/or plant-based protein may be beneficial SFAlevelswerethemostimportantpredictorofCRPlevels. for whole-body inflammation relative to some milk-based However,itshouldbenotedthatsomestudieshavefailedto proteins(whey).Evidencealsoexiststosupporttheuseofsoy showacorrelation[117]or,insomecases,haveevenshowna proteintobluntinflammation.Infact,reductionsinmarkers slightnegativecorrelationbetweenSFAandCRPlevels[118]. ofinflammationhavebeenshownwithconsumptionofsoy Thisdiscrepancymaybeduetothepopulationstudiedand [132], soybean oil [133], and soy nuts [134]. More data is confounding variables such as other nutrients included in needed,however,beforeadefinitiveconclusioncanbemade thediet,physicalactivity,andthepopulationstudied.Trans forwhichtypesofproteinsmayworkbesttoreducewhole- fats (TFA), fatty acids containing one double bond created bodyinflammation. viahydrogenationofvegetableoils,whicharefoundinfoods such as butter, margarine, milk fat, and fried foods, may alsoincreasemarkersofinflammation.IntheNurses’Health 4.2.Micronutrients/Antioxidants Study,astrongcorrelationwasshownbetweenTFAlevelsand 4.2.1. Flavonoids. Flavonoids, naturally occurring antioxi- inflammatorybiomarkersofCRP,IL-6,andE-selectin[119]. dant, commonly found in foods such as onions, apples, ThismayexplainthestrongconnectionbetweenserumTFA grapes, berries, and cocoa, are anti-inflammatory agents. levelsandcoronaryheartdisease[120]. Commonflavonoidssuchasquercetin,kaempferol,malvidin, Conversely, monounsaturated fatty acids (MUFAs) and peonidin,daidzein,andgenisteinhavebeenreportedtohave polyunsaturated fatty acids (PUFAs) have an inverse rela- aninverserelationshipwithCRP[135]. tionshipwiththeinflammatorybiomarkers.Levelsofcertain PUFAs such as omega-3 fatty acids, common in cold-water fish, are consistently found to have an inverse relationship 4.2.2.Carotenoids. Carotenoidsarethenaturalpigmentsthat with IL-6 [121]. The effects of other common PUFAs such givemanyfruitsandvegetablestheirdistinctivebrightcolors. as omega-6 fatty acids are less clear. Inflammatory and These are found in abundance in oranges, sweet potatoes, 6 TheScientificWorldJournal kale,andspinach.Carotenoidssuchasalpha-carotene,beta- the potential of anthcyanins to inhibit cancer formation in carotene,andluteinseemtohaveanti-inflammatorypoten- rodents [147]. This finding could be the result of reported tial.Infact,participantsofonestudywiththehighestserum anti-inflammatorypropertiesofanthocyanins.Arecentstudy levelsofalpha-caroteneweresignificantlylesslikelytohave on participants with high blood cholesterol levels reported highlevelsofIL-6.Interestingly,theoppositewasalsofound thatconsumptionofananthocyaninsupplementtwicedaily tobetruewherelowlevelsofvariouscarotenoidsintheblood for24weeksresultedinreductionsinCRPandothermarkers wereassociatedwithincreasedlevelsofIL-6[136].Further- ofsystemicinflammation[148]. more,anotherstudyreportedapotentiallyprotectiveeffectof Bromelain is a proteolytic enzyme found primarily in luteinandlycopeneagainstatherosclerosis,whichtheauthors pineapples. Among many other therapeutic benefits (e.g., report to be likely a result of a reduction in inflammatory improved endothelial function, enhanced absorption of markers[137]. antibioticdrugs,andinhibitionoftumorcellgrowth),brome- lain is an effective anti-inflammatory agent [149]. These 4.2.3. Magnesium. Magnesium, found typically in whole anti-inflammatory properties have been observed in vitro grain,greenleafyvegetables,nuts,andlegumes,maybeone viaitsmodulatingeffectoncertaininflammatorycytokines ofthemosteffectiveagentsforcombattingchronicinflamma- [150]. The benefits are also apparent in clinical trials which tion.Numerousstudieshavereportedtheinverserelationship report the effectiveness of bromelain for treating certain betweenmagnesiumintakeandCRPandIL-6[119,138],in inflammation-deriveddiseases/conditions(e.g.,osteoarthri- somecasesinadose-dependentmanner[138]. tis)[151]. 4.2.4. Vitamins. Vitamins, found commonly in fruits and 4.4.Beverages vegetables, are essentialto immunefunctionandare thusa necessaryimpedimenttoexcessiveinflammation.Numerous 4.4.1. Tea/Coffee. Tea consumption is associated with vitamins such as vitamins C, E, A, B6, and riboflavin each reduced markers of inflammation. In fact, after 6 weeks of havebeenassociatedwithreducedcytokineproduction(e.g., blackteaconsumptioninhealthymen,therewasareduction IL-6)[139]. in CRP and platelet aggregation [152]. Green tea may have similarpropertiesasithasbeenindicatedtobeaneffective antioxidantinvitro[153].However,theeffectivenessofgreen 4.3.WholeUnprocessedFoods teaatreducingmarkersofinflammationlikeCRPinclinical trials is less clear. Studies examining 1-month to green tea 4.3.1. Fish. In general, consumption of fish has been linked consumptiononhealthymales[154]andmalesmokers[155] to various health benefits, particularly heart health [140]. havefailedtoreportaneffectonCRPlevels. Some of these health benefits may be due to reductions in markers of inflammation [141]. This seems likely as certain The effects of coffee consumption on inflammation are fish, particularly cold-water fish like salmon and mackerel, equivocal. Some studies have reported anti-inflammatory containhighlevelsofPUFAslikeomega-3fattyacids,which effects[156],whileothershavereportednoeffectsatall[157]. as discussed above, likely have anti-inflammatory effects. Thiscouldbeduetogeneticfactorsasarecentstudyrevealed Indeed, the anti-inflammatory nature of fish seems to be a a genetic polymorphism affecting one’s responsiveness to direct result of PUFA content as numerous studies on fish caffeine[158].Becausecaffeinemayhaveanti-inflammatory oil supplements (high in omega-3 PUFAs) have reported properties [159], the effectiveness of coffee as an anti- reductions in markers of whole-body inflammation [142, inflammatoryagentmaybemediatedbyone’sresponsiveness 143]. In agreement, using salmon fed 3 different diets to tocaffeine.Whilespeculative,theimpactofphysicalactivity manipulate the omega-3 fatty acid content of the fish, it and other lifestyle factors likely plays a critical role in the was found that only the participants consuming salmon overallanti-inflammatoryresponsetothesenutrients. containingthehighestlevelsofomega-3ssawreductionsin IL-6[144]. 4.4.2. Alcohol. The effectiveness of alcohol at reducing or preventing inflammation seems to depend on the amount 4.3.2. Fruits and Vegetables. A large body of research exists consumed.Whileexcessiveconsumptionand/orbingedrink- documenting the many health benefits of consuming fruits ingisknowntohavemanyadversehealthoutcomesincluding andvegetables[140].Moreover,theanti-inflammatoryeffects increasedinflammation[160],moderateintake(e.g.,∼150mL ofconsumingfruitandvegetablesarewelldocumented[145, of wine per day) of alcohol seems to reduce markers of 146].Thisisnosurpriseconsideringthatfruitsandvegetables inflammation in various populations [161]. The degree to contain high concentrations of dietary fiber, flavonoids, whichthesemarkersarereducedmaydependonthesource carotenoids, and vitamins, which have all been associated of alcohol. 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