David C.Nieman *,Laurel M.Wentz

a Human Performance Laboratory,Appalachian State University,North Carolina Research Campus,Kannapolis,NC 28081,USA

b Department of Nutrition and Health Care Management,Appalachian State University,Boone,NC 28608,USA

Abstract Thisreview summarizes research discoverieswithin 4 areasof exercise immunology that havereceived themost attention from investigators:(1)acuteand chronic effectsof exerciseon theimmunesystem,(2)clinical benef itsof theexercise-immunerelationship,(3)nutritional inf luences on the immune response to exercise,and(4)the effect of exercise on immunosenescence.These scientif ic discoveries can be organized into distinctive time periods:1900-1979,which focused on exercise-induced changes in basic immune cell counts and function;1980-1989,during which seminal papers were published with evidence that heavy exertion was associated with transient immune dysfunction,elevated inf lammatory biomarkers,and increased risk of upper respiratory tract infections;1990-2009,when additional focusareaswere added to the f ield of exercise immunology including the interactive effect of nutrition,effects on the aging immune system,and inf lammatory cytokines;and 2010 to the present,when technological advancesin massspectrometry allowed system biology approaches(i.e.,metabolomics,proteomics,lipidomics,and microbiome characterization)to be applied to exercise immunology studies.The future of exercise immunology will take advantage of these technologies to provide new insights on the interactions between exercise,nutrition,and immune function,with application down to the personalized level.Additionally,these methodologies will improve mechanistic understanding of how exercise-induced immune perturbations reduce the risk of common chronic diseases.2095-2546/?2019 Published by Elsevier B.V.on behalf of Shanghai University of Sport.This is an open access article under the CCBY-NC-ND license.(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Keywords:Aging;Exercise;Immunology;Infection;Inf lammation;Mass Spectrometry;Nutrition

1.Introduction to exerciseimmunology

Although exercise immunology is considered a relatively new area of scientif ic endeavor with 90%of papers published after 1990,1some of the earliest studies were published well over a century ago.For example,in 1902,Larrabee2provided evidence that changes in white blood cell differential counts in Boston marathon runners paralleled those seen in certain diseased conditions.Healso observed that“theexertion had gone far beyond physiological limits and our results certainly show that where this is the case we may get a considerable leukocytosisof the inf lammatory type.”2

The immune system is very responsive to exercise,with the extent and duration ref lecting the degree of physiological stress imposed by the workload.This review paper summarizes the research discoveries within 4 areas of exercise immunology that have received the most consideration:acute and chronic effectsof exercise on theimmunesystem,clinical benef its of this exercise-immune relationship,nutritional inf luences on the immune response to exercise,and the exercise effect on immunosenescence(Fig.1).3-7

These scientif ic discoveries can be organized into distinctive time periods(Fig.2).The earliest exercise immunology studies(1900-1979)focused on exercise-induced changes in basic immune cell counts and function.5The human immunodef iciency virus was identif ied as the cause of the AIDS in 1984.One of the markers for AIDS diagnosis was the CD4 antigen on helper T cells that required a f low cytometer for detection.Many medical universitiesacquired f low cytometers in the 1980s,and these instruments became available to exercise investigators,initiating the modern era of exercise immunology research.Another impetus was the publication of a brief review in a special issue of the Journal of the American Medical Association for the 1984 Olympic Games in Los Angeles.8This review concluded there was“no clear experimental or clinical evidence that exercise will alter the frequency or severity of human infections...Further studies will be needed before it can be concluded that exercise affects the host response to infection in any clinically meaningful way.”8This conclusion was consistent with the existing evidence at that timeand at thesametimeprovided aframework for future investigations.During the same time period(1980-1989),seminal papers were published with evidence that heavy exertion was associated with transient immune dysfunction,elevated inf lammatory biomarkers,and an increased risk of upper respiratory tract infections(URTIs).9-18For example,acute boutsof intenseand prolonged exercisewerelinked by several early exercise immunology pioneer investigatorsto suppressed salivary immunoglobulin A(IgA)output,decreased natural killer cell(NK)lytic activity,reduced T-and B-cell function,and a 2-to 6-fold increased URTI risk during the 1-2 week postrace time period.9-18In 1989,the International Society of Exercise Immunology was founded,leading to biannual conferences and the highly successful Exercise Immunology Review journal(www.isei.dk).5

Fig.1.Key research areasand basic f indingsin exerciseimmunology.

Fig.2.Exerciseimmunology researchcanbeorganized into4 distinctiveperiods.

During the time period from 1990 to 2009,additional focus areas were added to the f ield of exercise immunology,including theinteractiveeffectof nutrition,7,19,20effectson theagingimmune system,21-23and inf luenceson inf lammatory cytokines.24-27With advances in mass spectrometry and genetic testing technology since 2010,increasing attention isbeing focused on metabolomics,proteomics,lipidomics,gut microbiome characterization,and genomic approaches to exercise immunology,and how this information can be used to provide personalized exercise and nutrition guidelines.28-33Additionally,acute and chronic exercise-induced immunechangesarenow being described asimportantmechanistic pathways for elucidating reduced cancer and heart disease risk amongthephysically active.34-36

2.Acuteand chronic effectsof exerciseon theimmune system

The acute immune response to exercise depends on the intensity and duration of effort.For thepurposesof thisreview,moderate and vigorous exercises are differentiated using an intensity threshold of 60%of the oxygen update and heart ratereserve,and aduration threshold of 60 min.Exerciseimmunology investigators had an early focus on the large perturbations of basic leukocyte subsetsassociated with thephysiological stressof athletic endeavor.2,9-14,27Increasing attention is being directed to the enhanced immunosurveillance of distinct immune cell subtypes during exercise bouts of less than 60 min that have potential prevention and therapeutic value.37-48

Fig.3.Acute exercise stimulates the interchange of innate immune system cells and components between lymphoid tissues and the blood compartment.Although transient,a summation effect occurs over time,with improved immunosurveillance against pathogens and cancer cells and decreased systemic inf lammation.

2.1.Enhanced immunosurveillancewith acuteexercisebouts of lessthan 60 min

During moderate-and vigorous-intensity aerobic exercise boutsof lessthan 60 min duration,theantipathogen activity of tissue macrophages occurs in parallel with an enhanced recirculation of immunoglobulins,anti-inf lammatory cytokines,neutrophils,NK cells,cytotoxic T cells,and immature B cells,all of which play critical roles in immune defense activity and metabolic health(Fig.3).37-40,44-47Acuteexerciseboutspreferentially mobilize NK cells and CD8+T lymphocytes that exhibit high cytotoxicity and tissue migrating potential.38,46,48Stress hormones,which can suppress immune cell function,and proinf lammatory cytokines,indicative of intense metabolic activity,do not reach high levels during short duration,moderate exercise bouts.40Over time,these transient,exercise-induced increases in selective lymphocyte subsets enhance immunosurveillance and lower inf lammation,and may be of particular clinical value for obese and diseased individuals.41-43

In general,acute exercise is now viewed as an important immunesystem adjuvant to stimulate theongoing exchangeof leukocytes between the circulation and tissues.37An ancillary benef it isthat acute exercise may serve as a simple strategy to enrich the blood compartment of highly cytotoxic T-cell and NK cell subsets that can be harvested for clinical use.38,44-46Metabolically,moderate exercise induces small,acute elevations in IL-6 that exert direct anti-inf lammatory effects,improving glucose and lipid metabolism over time.49,50Another benef it may include an enhanced antibody-specif ic response when vaccinations are preceded by an acute exercise bout,but more research is needed with better study designs to control for potential confounding inf luences.51

2.2.Transient immunedysfunction after heavy exertion

The measurement of immune responses to prolonged and intensive exercise by athletes continues to receive high attention.Taken together,the best evidence supports that high exercise training workloads,competition events,and the associated physiological,metabolic,and psychological stress are linked to immune dysfunction,inf lammation,oxidative stress,and muscle damage.9-14,24,27,52-54NK cell and neutrophil function,various measures of T-and B-cell function,salivary IgA output,skin delayed-typehypersensitivity response,major histocompatibility complex IIexpression in macrophages,and other biomarkers of immune function are altered for several hours to days during recovery from prolonged and intensive endurance exercise.52-58The contrast in the magnitude of immune responses between a 30-to 45-min walking bout and 42.2-km marathon race is summarized in Fig.4.3,4,27,40,52-57These immune changes occur in several compartments of the immune system and body including the skin,upper respiratory tract mucosal tissue,lung,blood,muscle,and peritoneal cavity.Although some investigators have challenged the clinical signif icance and linkage between heavy exertion and transient immune dysfunction,58the majority of investigators in the f ield of exercise immunology have supported the viewpoint that the immune system ref lects the magnitude of physiological stressexperienced by the exerciser.3-5,27,54,56,57

Fig.4.Thecontrast in acuteimmuneresponsesto heavy exertion(e.g.,amarathon race)and a 30-to 45-min walking bout.DTH=delayed-type hypersensitivity;IgA=immunoglobulin A;Ne/Ly=neutrophil/lymphocyte ratio;NK=natural killer;OB=oxidativeburst.

Recent improvementsin massspectrometry technology and bioinformatics support have improved the capacity to use a systems biology approach when measuring the complex interactions between exercise stress and immune function within the human athlete.29-33,59-63Metabolomics,proteomics,and lipidomics have revealed that metabolism and immunity are inextricably interwoven and has led to a new area of research endeavor termed immunometabolism.33,64In a typical study with human athletes exercising intensely for more than 2 h,signif icant increases in at least 300 identif ied metabolites can be measured as body glycogen stores are depleted and an extensive increase occurs in numerous and varied lipid superpathway metabolites,including oxidized derivatives called oxylipins.32,60-62Exercise-induced muscle tissue injury and inf lammation elicit a strong innate immune response involving granulocytes,monocytes,and macrophages.Immune-specif ic proteins are produced to regulate the innate immune response,with oxylipins involved in initiating,mediating,and resolving this process.29,30,60,63Most of the expressed immune-related proteins including lysozyme C,neutrophil elastase and defensin 1,proteins S100-A8/A12,cathelicidin antimicrobial peptide,α-actinin-1,and prof ilin-1 are involved with pathogen defense and immune cell chemotaxis and locomotion.Other proteinsincluding serum amyloid A-4,myeloperoxidase,complements C4B and C7,plasma protease C1 inhibitor,α-2-HSglycoprotein,andα-1-acid glycoprotein 2 increase chronically during recovery and are involved in the inf lammatory acute phase response.30

This profound,exercise-induced perturbation in metabolites,lipid mediators,and proteinsmorethan likely hasadirect inf luence on immune function,decreasing the capacity of immune cells to increase oxygen consumption rates after activation.31In response to an acute immunologic challenge such as exercise stress,cells of the immune system must be able to engage in growth and proliferation to generate effector cells that produce specif ic moleculessuch as cytokines and the proteins listed in the previous paragraph.64Immune activation is associated with oxygen and biosynthetic demands,and immune cells must engage in metabolic reprogramming to generate suff icient energy to fuel these demands.Although moreresearch isneeded,preliminary datasupport that immune cell metabolic capacity is decreased during recovery from physiologically demanding bouts of intensive exercise,resulting in transient immune dysfunction.31,33Immunonutrition support,especially increased intake of carbohydrate and polyphenols,has been shown to counter these exercise-induced decrementsin immune cell metabolic capacity.31,33

2.3.Illness risk and high exercise workloads

The potential linkage between prolonged,intensive exercise and increased risk for illness has been an active area of research sincethe 1980s.3,65-69Early epidemiologic studiesindicated that athletes engaging in marathon and ultramarathon race events and/or very heavy training were at increased risk of URTI.17,67(Table 1).For example,in a large group of 2311 endurance runners,nearly 13.0%reported illness during the week after the Los Angeles Marathon race compared with 2.2%of control runners(odds ratio(OR)=5.9;95%conf idence interval(CI):1.9-18.8).17Forty percent of the runners reported at least 1 illness episode during the 2-month winter period before the marathon race,and those running morethan 96 km/week vs.less than 32 km/week doubled their odds for illness.A 1-year retrospective study of 852 German athletes showed that URTI risk was highest in endurance athletes who also reported signif icant stress and sleep deprivation.70These seminal studies indicated that illness risk may be increased when an athlete participates in competitive events,goes through repeated cycles of unusually heavy exertion,or experiencesother stressorsto the immunesystem including lack of sleep and mental stress.Thedirect connection between exercise-induced immune changes and infection risk hasnot yet been established,and will requirelong-term studies with large cohorts.More research is needed to more clearly demonstrate the linkage between heavy exertion,illness symptoms,and pathogen-based illnesses,and the relative importance of associated factorssuch astravel,pathogen exposure,exerciseinduced immune perturbations,sleep disruption,mental stress,and nutrition support.3,4

As illness data from additional studies mounted,71-77several athletic organizations including the International Olympic Committee(IOC)and the International Association of Athletics Federation(IAAF)initiated acute illness surveillance systems to delineate the extent of the problem and underlying risk factors.65,78-89The stated goal was to improve illness prevention and treatment procedures.65,80The IOC has also focused on the inappropriate management of both internal(e.g.,psychological responses)and external loads(e.g.,trainingand competition workloads).Load management isa key strategy,according to the IOC,to decrease illnessincidence and associated downturnsin exercise performance,interruptionsin training,missed competitive events,and risk of seriousmedical complications.Thewealth of acuteillnessepidemiologic datacollected duringinternational competition eventshasrevealed that 2%-18%of eliteathletesexperienceillness episodes,with higher proportions for females and those engaging in endurance events(Table 1).78-89At least one-half of the acute illness bouts involve the respiratory tract,with other affected systemsincluding thedigestivetract,skin tissues,and the genitourinary tract.65Signif icantillnessrisk factorsincludefemale gender,high levels of depression or anxiety,engaging in unusually intensivetraining periodswith largef luctuations,international travel across several time zones,participation in competitive events especially during the winter,lack of sleep,and low diet energy intake.65,68-92The decrease in exercise performance after an URTI can last 2-4 days,and runners who unwisely start an enduranceracewith systemic URTIsymptomsare2-3 timesless likely to completetherace.65,92,93Paralympic athleteshaveunique preexisting medical conditions that predispose them to an increased risk of illness,and theincidencerateof illnessishigh in the Summer(10.0-13.2episodesper 1000athlete-days)and Winter(18.7 episodesper 1000 athlete-days)Paralympic Games.94

Athletes must train hard for competition and are interested in strategies to keep their immune systems robust and illness rates low despitethephysiologic stressexperienced.Theultimateobjectiveistoachieveperformancegoalswithlittleinterruptionfromillness and fatigue from training-induced subclinical immune dysfunction.Several training,hygienic,nutritional,and psychological strategies are recommended,and these require the coordinated involvement of themedical staff,coaches,and athletes.4,6,65,95The medical staff should develop and implement an illnessprevention program,with a focus on full preventative precautions for highrisk individuals such asfemale endurance athletes.Adjustments to

theguidelinescan beapplied based on how each individual athlete responds.Hereisasummary of themostimportant guidelinesprovided from consensusstatements:4,6,65,95

Table1.Research on therelationship between vigorousexerciseand illness.

2.3.1.Training and competition load management

a.Develop a detailed,individualized training and competition plan that also provides for suff icient recovery using sleep,nutrition,hydration,and psychological strategies.

b.Use small increments when changing the training load(typically lessthan 10%weekly).

c.Develop a competition event calendar that is based on the health of theathlete.

d.Monitor for early signs and symptoms of over-reaching,overtraining,and illness.

e.Avoid intensive training when ill or experiencing the early signs and symptoms of illness(which can make the illness moresevereand prolonged).

f.Participatein ongoing illnesssurveillancesystemsby sport agencies.

2.3.2.Hygienic,lifestyle,nutritional,and behavioral stra tegies

a.Minimize pathogen exposure by avoiding close contact with infected individuals in crowded,enclosed spaces,and not sharing drinking or eating implements.Avoid exercise sessions in poorly ventilated clubs and gymnasium facilities.Themedical staff should isolateinfected athletes.

b.Limit hand-to-face contact(i.e.,self-inoculation)and wash hands regularly and effectively.The medical staff should educate the athletesto minimize pathogen spread to others(e.g.,sneezing and coughing into thecrook of theelbow).

c.Follow other hygienic practices to limit all types of infections including safe sex and the use of condoms,wearing open footwear when using public facilities to limit skin infections,using insect repellents,and covering the arms and legswith clothing at dawn or dusk.

d.Maintain vaccines needed for home and foreign travel,with a focuson annual inf luenza vaccination.

e.Follow strategiesthat facilitateregular,high-quality sleep.

f.Avoid excessive alcohol intake.

g.Consume a well-balanced diet with suff icient energy to maintain a healthy weight,with a focus on grains,fruits,and vegetables to provide suff icient carbohydrate and polyphenols that reduce exercise-induced inf lammation and improveviral protection.

2.3.3.Psychological load management

a.Follow stress management techniques that decrease the extraneousload of lifehasslesand stresses.

b.Develop coping strategies that minimize the internalized impact of negativelifeeventsand emotions.

c.Periodically monitor psychological stresses using available instruments.

3.Clinical inf luencesof immuneresponsesto chronic exercise

Each bout of moderatephysical activity promotesimproved but transient immunosurveillanceand,when repeated on aregular basis,confersmultiplehealth benef itsincluding decreased illnessincidenceand dampened systemic inf lammation.95

3.1.J-curve relationship between exercise and URTIs

Table 2 summarizes published evidence from randomized clinical trials and epidemiologic studies on the inverse relationship between moderate exercise training and URTI incidence.The randomized clinical trials(8 weeks to 1 year in length)are consistent in demonstrating that study participants assigned to moderate exercise programs experience reduced URTI incidence and duration.21,96-100The magnitude of reduction in URTI symptom days with near-daily moderate exercise in these randomized clinical trials (typically 40%-50%)exceeds levels reported for most medications and supplements,and bolsters public health guidelines urging individuals to be physically active on a regular basis.The protective effect of moderate activity on illness incidence contrasts with theincreased illnessrisk linked with prolonged and intensive exercise,as summarized in the J-curve model(Fig.5).95The IOC consensus group provided support for the J-curve model,but cautioned that the right side of the model may not apply to elite athleteson thehighest level,wherehigh training loads are not consistently associated with an increased risk of illness.65

Retrospective and prospective epidemiologic studies have measured illness incidence in large groups of individuals engaging in self-selected and varied physical activity workloads(Table2).101-104Collectively,the epidemiologic studies summarized in Table 2 consistently show reduced URTIrates(weighted mean,28%)in high vs.low physical activity and f itness groups.Fig.6 summarizes the results from a group of 1002 adults(aged 18-85 years;60%female and 40%male)studied for 12 weeks(one-half during thewinter,one-half during the fall),with monitoring of URTIsymptoms and severity using the validated Wisconsin Upper Respiratory Symptom Survey.103,105The number of days with URTIwas 43%lower in subjects engaging in an average of 5 or more days per week of aerobic exercise(20 min bouts or longer)compared with those who were largely sedentary(≤1 day/week),and 46%lower when comparing subjectsin thehighest vs.lowest tertile for perceived physical f itness.This relationship persisted,even after adjustment for confounders such as age,education level,marital status,gender,body mass index(BMI),and perceived mental stress.

Physical activity may lower ratesof infection for other types of viral and bacterial diseases,but more data are needed.Several epidemiologic studies suggest that regular physical activity is associated with decreased mortality and incidence rates for inf luenza and pneumonia.106-109These f indings are in accordance with rodent-based studies demonstrating a positive link between chronic exercise and improved host responses to inf luenza and pneumonia infection.110-113These data must be carefully balanced with published reports of increased infectious disease severity when vigorous exercise was engaged in during active inf luenza or other viral infections.114-116There is also increasing support for improved antibody responses to inf luenza immunization in elderly adults who engage in regular exercisetraining regimens.117-119

Fig.5.J-curvemodel of the relationship between theexerciseworkload continuum and risk for upper respiratory tract infection(URTI).Other factors such as travel,pathogen exposure,sleep disruption,mental stress,and dietary patterns may inf luencethisrelationship.Thisf igurewasadapted from Nieman.95

3.2.Reduced systemic inf lammation in physically activeand lean individuals

Each exercise bout causes transient increases in total white blood cells,granulocyte-related proteins,and a variety of plasma cytokines including interleukin-6(IL-6),IL-8,IL-10,IL-18,IL-1 receptor antagonist(IL-1ra),granulocyte colony stimulating factor,and monocyte chemoattractant protein 1.30,40,52Themagnitudeof changein theseinf lammation-related biomarkers depends on the overall exercise workload.Acute phase proteins including C-reactive protein(CRP)are also increased after heavy exertion,but increases are delayed in comparison with most cytokines.30,52Despite regular increases in these inf lammation biomarkers during each intense exercisebout,physically f it individualshavelower resting levelsin contrast with those who are overweight and unf it.Fig.7 compares serum CRP(4.4-fold difference)and plasma IL-6(1.3-fold)in large groups of obese individuals(n=950;mean BMI=31.7 kg/m2)and endurance athletes(n=383;mean BMI=23.0 kg/m2)studied over the course of the past 2 decadesin the author's laboratory.There is increasing evidence that regular exercise training has an overall anti-inf lammatory inf luence mediated through multiple pathways including improved control of inf lammatory signaling pathways,release of muscle myokines that stimulate production of IL-1ra and IL-10(perhaps by blood mononuclear immune cells),a decrease in dysfunctional adipose tissue and improved oxygenation,enhanced innate immune function,and an improved balance of oxylipins.7,33,50,55,120

Table2.Research on therelationship between moderateexerciseand illness.

Fig.6.The upper tertiles of f itnessand exercise frequency areassociated with reduced numbers of days with upper respiratory tract infections(URTI).Data from Nieman et al.103

Fig.7.C-reactive protein(CRP)and interleukin-6(IL-6)valuesfor obese and athletic groups(data expressed as mean±SD).Data arefrom ongoing studies in thef irst author'slab during thepast 2 decades.BMI=body massindex.

The persistent increase in inf lammation biomarkers is def ined as chronic or systemic inf lammation,and is linked with multiple disorders and diseases including obesity,arthritis,atherosclerosis and cardiovascular disease,chronic kidney disease,liver disease,metabolic syndrome,insulin resistance and type2 diabetesmellitus,sarcopenia,arthritis,boneresorption and osteoporosis,chronic obstructive pulmonary disease,dementia,depression,and various types of cancers.121-127Obesity induces a constant state of low-grade inf lammation characterized by activation and inf iltration of proinf lammatory immune cells such as macrophages and granulocytes,and a dysregulated production of acute-phase proteins,reactive oxygen species,metalloproteinases,oxylipins,adipokines,and proinf lammatory cytokines.124,128Many of the inf lammation biomarkers increased transiently after intense and prolonged exercise bouts are chronically expressed at lower levels in obeseindividuals(resting state).

Epidemiologic studiesconsistently show reduced white blood cell count,CRP,IL-6,IL-18,tumor necrosis factor alpha,and other inf lammatory biomarkers in adults with higher levels of physical activity and f itness,even after adjustment for potential confounders such as BMI.129-131For example,in a study of 1002 community-dwelling adults(aged 18-85 years),a general linear model analysis showed that BMI had the strongest effect on CRP followed by gender(greater in females),exercise frequency,age,and smoking status.129Another study of 1293 middle-aged Danes showed that cardiorespiratory f itness was inversely associated with CRP,IL-6,and IL-18,and was only partly explained by lower levelsof abdominal obesity.130

Most randomized,controlled trials,however,have failed to demonstrate that inf lammation isdecreased by a clinically signif icant level with exercise training in the absence of weight loss.132-136There are several potential explanations for these null f indings when compared with epidemiologic studies,including the small reported changes in aerobic f itness and activity levels,the short duration of the intervention trials,and issues with compliance.In general,moderate exercise training is unlikely to lower chronic inf lammation at the individual level unless the exercise workload is increased to more than 300 min per week and signif icant weight lossisexperienced.

3.3.Exercise-immunelinkagesto reduced chronic disease

Do exercise-induced perturbations in immunity help to explain altered risks of cancer,heart disease,type 2 diabetes,arthritis,nonalcoholic fatty liver disease,and other chronic conditions?Research in this area is still emergent,but there is increasing evidence that the circulation surge in cells of the innate immune system with each exercise bout and the antiinf lammatory and antioxidant effect of exercise training have a summation effect over time in modulating tumorigenesis,atherosclerosis,and other disease processes.36,137-139Obesity,the metabolic syndrome,and most common chronic diseases such asatherosclerosis,specif ic types of cancer,and type 2 diabetes are characterized in part by high inf lammation,oxidative stress,and immune dysfunction.137Exercise training counters these elements of the disease process,stimulating many cellular and molecular changes throughout body tissues that promote anti-inf lammatory and antioxidant responses,and augment immunosurveillance.For example,IL-1βis a proinf lammatory cytokine that is involved in disease pathogenesis,and the release of IL-6 from the exercising muscle induces high levelsof plasma IL-1ra during recovery that competitively inhibits IL-1βsignaling.137Exercise training also downregulates Toll-like receptor 4 expression,a key transmembrane receptor that is activated by numerous ligands including oxidized low-density lipoproteins and involved in obesity-induced insulin resistance and type 2 diabetes,and atherosclerosis.137

Inf lammation involves several types of immune cells,including macrophages and neutrophils,and is an important mediator of oxidative stress.Reactive oxygen species(ROS)or reactive nitrogen species(RNS),are double-edged molecules.ROS/RNS can function as important inf lammatory effectorsin supporting immunesystem clearance of pathogens and repair of damaged muscle tissue,or they can amplify chronic inf lammation(e.g.,during obesity)and induce tissue damage.Oxinf lammation is a term used to describe the complex interactions between oxidative stress and inf lammation.138Exercise training decreases oxidative stress by augmenting antioxidant defenses consisting of enzymes such as catalase,superoxide dismutase,and glutathione peroxidase,and nonenzymatic antioxidantsincluding glutathione.137,138

Exercise training has immunomodulating effects that may alter the cross-talk between the immune system and tumorigenesis.For example,exercise may increase intra-tumoral cytotoxic T-cell inf iltration and reduce regulatory T-cell inf iltration,enhance the recirculation and function of tumorspecif ic NK cells,and decrease inf lammatory inf luences that support cancer cell growth.139

In general,exercisepromotestherecirculation of key immune cells and mediates an anti-inf lammatory and antioxidant state through multiple mechanisms.Although many information gaps exist,these exercise-induced effects may help to counter the development of chronic metabolic diseasesand are likely multiplied when body fat massisreduced.

3.4.Exercise,gut immunefunction,and the microbiome

The gastrointestinal tract is colonized by trillions of microorganisms that include a gene set 150 timeslarger than that of the human genome.140The most abundant bacterial phyla are the Firmicutes(～60%)and Bacteriodetes(～20%),with low proportions of Actinobacteria,Proteobacteria,and Verrucomicrobia.One-third of the adult gut microbiota is similar between most individuals,but diversity is associated with a healthier status.The gut bacteria composition and diversity is inf luenced by a variety of factors,including dietary and exercise habits,age,gender,genetics,ethnicity,antibiotics,health,and disease.

The gut microbiota inf luences human health and immune function,in part through the fermentation of indigestible food components in the large intestine.The microbiome and derived metabolites including short chain fatty acids and biotransformed bile acids have been shown to inf luence immune function both within the gut and systematically.141Although research in this area is emerging,recent studies indicate that exercise and physical f itness diversif ies the gut microbiota,enhancing thenumber of benign microbial communities.142,143The underlying mechanisms are still being explored,with no clear consensus,in part owing to confounding from diet,exercise workload and intensity,and body composition.More human research is needed to establish whether the positive linkage between long-term exercise training and a diverse microbiome translates to improved immune function in physically f it individualsand athletes.144,145

4.Nutritional interactionson exercise-induced immune changes

Several comprehensive reviews have been published on the value of nutritional support as countermeasures to exerciseinduced immune dysfunction,inf lammation,and oxidative stress.4,6,7,33The most effective nutritional strategies for athletes,especially when evaluated from amultiomicsperspective,includeincreased intakeof carbohydratesand polyphenols.

4.1.Carbohydratesattenuate postexercise inf lammation

During the 1990s,several studies reported that carbohydrate ingestion(30-60 g/h)during prolonged endurance exercise(90 min and longer)was linked with lower postexercise plasma stress hormone levels and inf lammation.20,146-150Theseresultshavebeen conf irmed by many subsequent studies(Table 3).31,151-165A consistent f inding is that carbohydrate intake during prolonged and intense exercise,whether from 6%-8%beveragesor sugar-densefruitssuch asbananas(with water),is associated with higher plasma glucose and insulin levels;lower plasma stress hormones(epinephrine and cortisol),adrenocorticotropic hormone,and growth hormone;diminished fatty acid mobilization and oxidation;and reduced inf lammation as measured by a variety of biomarkers including skeletal muscle IL-6 and IL-8 messenger ribonucleic acid(mRNA),blood neutrophil and monocyte cell counts,cytokines such as IL-6,IL-1ra,and IL-10,and granulocyte phagocytosis(Table 3 and Fig.8).The effect of carbohydrate ingestion in attenuating postexercise inf lammation is strong(about 30%-40%),especially when contrasted with wateronly intake in overnight fasted athletes.7,27,31-33,164,166

4.2.Polyphenolscounter exercise-induced immunechanges

Fruitscontain a mixture of sugars and awide variety of biologically active polyphenols.Polyphenols,in particular f lavonoids,have attracted much attention owing to their bioactivity and related health benef its,and new evidence using metabolomics supportstheir valueaspotential countermeasures to exercise-induced immune changes.6,7,31,33

Table 3.Research showing the effect of carbohydrates on inflammation and immune biomarkers after ＞90 min of endurance exercise.

Table 3. (Continued)

Fig.8.Carbohydrateingestion beforeand during exerciseattenuatespostexerciseinf lammation.

Many of the earlier studies reported few discernable immune-related inf luences of increased polyphenol intake for athletes,but research design def iciencies portrayed a misunderstanding of polyphenol bioavailability and metabolism,and theappropriateoutcomemeasures.Polyphenol absorption,disposition,metabolism,and excretion is complex and requires both untargeted and targeted metabolomicsproceduresto measure small molecule shiftsin humansafter increased intake.167A high proportion of ingested polyphenolsfrom fruits,vegetables,and other plant foods pass through the small intestine unabsorbed and reach the colon,where bacterial degradation produces smaller phenolics that can reabsorbed into the circulation after undergoing phase 2 conjugation in the liver.33The biotransformed,gut-derived phenolicscirculatethroughout the body,exerting a variety of bioactive effects that are important to athletes including anti-inf lammatory,antiviral,antioxidative,and immune cell signaling effects.167-172

Several studiesusing metabolomicsand ex vivo cell cultures comparing ingestion of bananas with intake of water only or a 6%sugar beverageduring prolonged and intensivecycling have shown large-fold increasesin at least 18 banana-related metabolites.31,163,164Banana f lesh contains many unique molecules including serotonin,dopamine,phenolics,and xenobiotics.Soon after ingestion,plasma levelsof metabolitesderived from bananaf lesh moleculesincrease,and may confer anti-inf lammatory effects by countering cyclooxygenase-2(COX-2)mRNA expression the morning after heavy exertion.31

In general,evolving data support the intake of fruitssuch as dates,raisins,and bananas by athletes during training to provide the sugars and polyphenols that exert anti-inf lammatory inf luences that may enhance metabolic recovery.Future studies using system-wide approaches such as metabolomics,lipidomics,and proteomics will improve scientif ic understanding regarding the complex and multilevel interactions between exercise,nutrition,and theimmuneand metabolic systems.

5.Exerciseinf luencesimmunosenescence

Immunosenescence is def ined as immune dysregulation with aging and isrelated to an increased susceptibility to infections,autoimmune diseases,neoplasias,metabolic diseases,osteoporosis,and neurologic disorders.Recent evidence supportsthat immunity can beremodeled during theaging process as a result of interactions with the environment and lifestyle and is instrumental in shaping immune status in later life.173-175Immune system interactions with pathogens,the host microbiome,nutritional and exercise inf luences,mental stress,and many other extrinsic factors are considered as crucial modulatorsof theimmunosenescenceprocess. Early cross-sectional studies compared immune function in highly conditioned and sedentary elderly men and women.31,176One study contrasted immune function in 30 sedentary elderly women and 12 age-matched,highly conditioned elderly women who wereactivein stateand national senior gameand road race endurance events.31Thehighly conditioned elderly women had signif icantly higher levels of NK cells and T-lymphocyte function and reduced illness rates compared with the 30 sedentary elderly women.Another study compared immune function in 17 elderly runners who had trained for about 17 years and 19 elderly controls,and reported signif icantly higher Tlymphocyte function in theelderly runners.176

These studies stimulated many additional studies on the effects of exercise training on immunosenescence.Data support that habitual exerciseiscapableof regulating the immune system and delaying the onset of immunosenescence,and has been associated with thefollowing:31,175,177-179

·Enhanced vaccination responses,

·Lower numbersof exhausted/senescent Tcells,

·Increased T-cell proliferativecapacity,

·Lower circulatory levels of inf lammatory cytokines(i.e.,decreased“inf lamm-aging”),

·Increased neutrophil phagocytic activity,

·Lowered inf lammatory responseto bacterial challenge,

·Greater NK cell cytotoxic activity,and

·Longer leukocytetelomere lengths.

6.Conclusion

This review summarized research discoveries within 4 areas of exercise immunology:acute and chronic effects of exercise on the immune system,clinical benef its of the exercise-immunerelationship,nutritional inf luenceson theimmune response to exercise,and the exercise effect on immunosenescence.The immune system is very responsive to exercise,with theextent and duration ref lecting the degreeof physiological stress imposed by the workload.Key exercise immunology discoveriessince1980 includethefollowing.

·Acute exercise(moderate-to-vigorous intensity,less than 60 min)is now viewed as an important immune system adjuvant to stimulate the ongoing exchange of distinct and highly active immunecell subtypes between the circulation and tissues.In particular,each exercise bout improves the antipathogen activity of tissuemacrophagesin parallel with an enhanced recirculation of immunoglobulins,anti-inf lammatory cytokines,neutrophils,NK cells,cytotoxic T cells,and immature B cells.With near daily exercise,these acute changes operate through a summation effect to enhance immunedefense activity and metabolic health.

·In contrast,high exercise training workloads,competition events,and the associated physiological,metabolic,and psychological stress are linked with transient immune perturbations,inf lammation,oxidative stress,muscle damage,and increased illness risk.Metabolomics,proteomics,and lipidomics have revealed that metabolism and immunity are inextricably interwoven,providing new insights on how intense and prolonged exercise can cause transient immune dysfunction by decreasing immune cell metabolic capacity.

·Illness risk may be increased when an athlete competes,goes through repeated cycles of unusually heavy exertion,and experiences other stressors to the immune system.The wealth of acute illness epidemiologic data collected during international competition events has revealed that 2%-18%of elite athletes experience illness episodes,with higher proportionsfor femalesand thoseengaging in endurance events.Other illnessrisk factorsinclude high levelsof depression or anxiety,participation in unusually intensive training periods with large f luctuations,international travel across several time zones,participation in competitive events especially during the winter,lack of sleep,and low diet energy intake.

·The IOC has also focused on load management of both internal(e.g.,psychological responses)and external factors(e.g.,training and competition workloads),and lifestyle strategies(e.g.,hygiene,nutritional support,vaccination,regular sleep)to reduce illness incidence and associated downturns in exercise performance,interruptions in training,missed competitive events,and risk of serious medical complications.

·Randomized clinical trials and epidemiologic studies consistently support the inverse relationship between moderate exercise training and incidence of URTI.These data led to the development of the J-curve model that links URTI risk with the exercise workload continuum.Several epidemiologic studies also suggest that regular physical activity is associated with decreased mortality and incidence rates for inf luenzaand pneumonia.

·Regular exercise training has an overall anti-inf lammatory inf luence mediated through multiple pathways.Epidemiologic studies consistently show decreased levels of inf lammatory biomarkers in adults with higher levels of physical activity and f itness,even after adjustment for potential confounderssuch as BMI.

·There is increasing evidence that the circulation surge in cells of the innate immune system with each exercise bout and theanti-inf lammatory and antioxidant effect of exercise training have a summation effect over time in modulating tumorigenesis,atherosclerosis,and other diseaseprocesses.

·Recent studies indicate that exercise and physical f itness diversif ies the gut microbiota,but more human research is needed to determine potential linkages to immune function in physically f it individualsand athletes.

·Themosteffectivenutritional strategiesfor athletes,especially when evaluated from a multiomics perspective,include increased intake of carbohydrates and polyphenols.A consistent f inding is that carbohydrate intake during prolonged and intense exercise,whether from 6%-8%beverages or sugardense fruits such as bananas is associated with reduced stress hormones,diminished blood levels of neutrophils and monocytes,and dampened inf lammation.Gut-derived phenolicscirculate throughout the body after increased polyphenol intake,exerting avariety of bioactiveeffectsthatareimportantto athletes including anti-inf lammatory,antiviral,antioxidative,and immunecell signaling effects.

·Immunosenescence is def ined as immune dysregulation with aging.Emergent data support that habitual exercise is capable of improving regulation of the immune system and delaying theonset of immunosenescence.

The future of exercise immunology will take advantage of advances in mass spectrometry and genetic testing technology,with increased utilization of metabolomics,proteomics,lipidomics,microbiome characterization,and genomics.Use of these system-wide approacheswill provide new insightson the interactions between exercise,nutrition,and immune function,with application down to the personalized level.Additionally,these methodologies will improve mechanistic understanding of how exercise-induced immune changes reduce risk for common chronic diseases.

Authors'contributions

DCN and LMW conducted the literature review and wrote the manuscript.Both authors have read and approved the f inal version of the manuscript,and agree with the order of presentation of theauthors.

Competinginterests

Both authorsdeclarethat they have no competing interests.