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• W2048672502 abstract "The unparalleled burden of a diverse range of chronic noncommunicable diseases (NCDs) is a major global challenge in the 21st century. Chronic low-grade inflammation is a common feature of virtually all NCDs, indicating a central role of the immune system. Furthermore, as the most common and earliest-onset NCD, the epidemic of allergic diseases points to specific vulnerability of the developing immune system to modern environmental change. Indeed, many environmental risk factors implicated in the rise of other NCDs have been shown to mediate their effects through immune pathways. The innate immune system provides a clear example of this convergence, with evidence that physical activity, nutrition, pollutants, and the microbiome all influence systemic inflammation through Toll-like receptor pathways (notably Toll-like receptor 4), with downstream effects on the risk of insulin resistance, obesity, cardiovascular risk, immune diseases, and even mood and behavior. Common risk factors will likely mean common solutions, and interdisciplinary strategies to promote immune health should be an integral part of NCD prevention, with a greater focus early in the life course before disease processes are established. In this context allergic disease provides a very important early target to assess the effectiveness of environmental strategies to reduce immune dysregulation. The unparalleled burden of a diverse range of chronic noncommunicable diseases (NCDs) is a major global challenge in the 21st century. Chronic low-grade inflammation is a common feature of virtually all NCDs, indicating a central role of the immune system. Furthermore, as the most common and earliest-onset NCD, the epidemic of allergic diseases points to specific vulnerability of the developing immune system to modern environmental change. Indeed, many environmental risk factors implicated in the rise of other NCDs have been shown to mediate their effects through immune pathways. The innate immune system provides a clear example of this convergence, with evidence that physical activity, nutrition, pollutants, and the microbiome all influence systemic inflammation through Toll-like receptor pathways (notably Toll-like receptor 4), with downstream effects on the risk of insulin resistance, obesity, cardiovascular risk, immune diseases, and even mood and behavior. Common risk factors will likely mean common solutions, and interdisciplinary strategies to promote immune health should be an integral part of NCD prevention, with a greater focus early in the life course before disease processes are established. In this context allergic disease provides a very important early target to assess the effectiveness of environmental strategies to reduce immune dysregulation. Discuss this article on the JACI Journal Club blog: www.jaci-online.blogspot.com.Over millennia, our external environment has shaped the myriad elaborate interwoven pathways that maintain constant defense against a diverse range of potential threats. In equal measure our survival has been dependent on evolutionary pressure to limit and regulate immune responses that could be otherwise detrimental to the host. Our complex relationship with the environment is fundamental to understanding the very existence and evolution of the immune system, as well as the reasons for the unprecedented surge in noncommunicable inflammatory diseases in modern times.A global health challenge of pandemic proportionsDramatic environmental and lifestyle changes of the modern age pose a significant threat to human health. An unparalleled increase in a diverse range of chronic noncommunicable diseases (NCDs) is one of the major global challenges of the 21st century. This growing burden of NCDs currently poses the greatest threat to health in both developed and developing regions and is a major barrier to human development. The dominant focus of the NCDs agenda is usually on “the big four”: cardiovascular disease, metabolic disease (obesity and type 2 diabetes), cancer, and chronic lung disease. Although both asthma and smoking-related diseases are considered in the context of chronic lung disease, allergic diseases per se are typically overlooked in this agenda, despite now being the most common and earliest-onset NCDs in most regions. Already, approximately 30% to 40% of the world's population is affected by 1 or more allergic conditions, with vast personal, social, and economic costs.1Pawankar R. Canonica G.W. Holgate S.T. Lockey R.F. World Allergy Organization (WAO) white book on allergy. World Allergy Organization, Milwaukee (WI)2011Google Scholar This needs to be recognized as a major element in the wider public health agenda, with strong efforts toward promoting immune health as an integral part of NCD prevention.Inflammation as a common feature of many NCDs: A central role of the immune systemChronic low-grade inflammation is a common feature of virtually all NCDs, highlighting the central multisystem interactions of the immune system.2Renz H. von Mutius E. Brandtzaeg P. Cookson W.O. Autenrieth I.B. Haller D. Gene-environment interactions in chronic inflammatory disease.Nat Immunol. 2011; 12: 273-277Crossref PubMed Scopus (129) Google Scholar The specific vulnerability of the immune system to recent environmental changes is also reflected in the dramatic increase in virtually all inflammatory disorders and, in particular, immune diseases, such as allergy and autoimmunity. Furthermore, clinical expression of allergy within the first months of life and detectable immune dysregulation at birth3Prescott S.L. Saffery R. The role of epigenetic dysregulation in the epidemic of allergic disease.Clin Epigenet. 2011; 2: 223-232Crossref PubMed Google Scholar provide clear evidence of very early environmental effects. The risk factors that are specifically associated with early immune dysfunction include modern dietary patterns, environmental pollutants, microbial patterns, and stress.4Prescott S.L. Clifton V.L. Asthma and pregnancy: emerging evidence of epigenetic interactions in utero.Curr Opin Allergy Clin Immunol. 2009; 9: 417-426Crossref PubMed Scopus (132) Google Scholar, 5Prescott S. Nowak-Wegrzyn A. Strategies to prevent or reduce allergic disease.Ann Nutr Metab. 2011; 59: 28-42Crossref PubMed Scopus (52) Google Scholar These all appear to promote inflammation and are common risks for many NCDs (Fig 1).2Renz H. von Mutius E. Brandtzaeg P. Cookson W.O. Autenrieth I.B. Haller D. Gene-environment interactions in chronic inflammatory disease.Nat Immunol. 2011; 12: 273-277Crossref PubMed Scopus (129) Google Scholar Reducing the risk of inflammatory responses through lifestyle and environmental interventions is likely to have benefits for the risk and progression of many other NCDs.Importantly, overcoming the adverse consequences of lifestyle changes will logically require somewhat more holistic approaches than the more focused pharmaceutical approach of immune therapies. Although there remains a clear role for developing better pharmaceutical interventions, holistic approaches are more likely to simultaneously modify a variety of innate immune responses—analogous to the multiple environmental changes currently acting simultaneously on many organ systems to exert chronic inflammatory changes.As practicing allergists, we must embrace the challenge of more fully understanding the interaction between the environment and immunity. We have the opportunity to be the specialty that leads the way in advising families about the significance of the immune system for many aspects of health, including the limitations of our current understanding. Clinicians often ignore this, and people then seek less rigorous sources for advice. Even if the answers are not clear, we need to be educated so we can put this in context for patients.Early life: A critical time of risk and opportunityPrevention is the ultimate approach to reducing the burden of NCDs, and the greatest potential for this lies in early life. There is already substantive evidence that initiatives to promote a healthy start to life can reduce the risk of both early and later NCDs, with wide social and economic benefits.6Hanson M. Gluckman P. Developmental origins of noncommunicable disease: population and public health implications.Am J Clin Nutr. 2011; 94: 1754S-1758SCrossref PubMed Scopus (201) Google Scholar, 7Hanson M. Gluckman P. Nutbeam D. Hearn J. Priority actions for the non-communicable disease crisis.Lancet. 2011; 378: 566-567Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar The early environment in both pregnancy and early childhood can determine physiologic, structural, immune, metabolic, and behavioral development and modify response patterns that influence future disease susceptibility.6Hanson M. Gluckman P. Developmental origins of noncommunicable disease: population and public health implications.Am J Clin Nutr. 2011; 94: 1754S-1758SCrossref PubMed Scopus (201) Google Scholar, 7Hanson M. Gluckman P. Nutbeam D. Hearn J. Priority actions for the non-communicable disease crisis.Lancet. 2011; 378: 566-567Abstract Full Text Full Text PDF PubMed Scopus (22) Google ScholarAlthough many NCDs might not become apparent until later in life, allergic diseases frequently manifest within the first months of life.8Prescott S.L. Allen K.A. Food allergy: riding the second wave of the allergy epidemic.Paediatr Allergy Immunol. 2011; 22: 155-160Crossref PubMed Scopus (359) Google Scholar This is the clearest indication that the developing immune system is exquisitely sensitive to modern environmental pressures, together with mounting evidence that these effects must begin in utero.3Prescott S.L. Saffery R. The role of epigenetic dysregulation in the epidemic of allergic disease.Clin Epigenet. 2011; 2: 223-232Crossref PubMed Google Scholar Furthermore, the longer-term implications for this new generation need to be considered. Allergy is a systemic disease associated with systemic release of cytokines and chemokines and with distal recruitment of inflammatory progenitors into the circulation from the bone marrow.9Holt P.G. Sly P.D. Interaction between adaptive and innate immune pathways in the pathogenesis of atopic asthma: operation of a lung/bone marrow axis.Chest. 2011; 139: 1165-1171Crossref PubMed Scopus (71) Google Scholar Low-grade systemic inflammation has now been clearly linked with the risk for metabolic dysregulation and vascular disease.10Hotamisligil G.S. Erbay E. Nutrient sensing and inflammation in metabolic diseases.Nat Rev Immunol. 2008; 8: 923-934Crossref PubMed Scopus (767) Google Scholar Although there are some associations between cardiovascular disease and allergic disease in later life,11Knoflach M. Kiechl S. Mayr A. Willeit J. Poewe W. Wick G. Allergic rhinitis, asthma, and atherosclerosis in the Bruneck and ARMY studies.Arch Intern Med. 2005; 165: 2521-2526Crossref PubMed Scopus (81) Google Scholar, 12Matheson E.M. Player M.S. Mainous 3rd, A.G. King D.E. Everett C.J. The association between hay fever and stroke in a cohort of middle aged and elderly adults.J Am Board Fam Med. 2008; 21: 179-183Crossref PubMed Scopus (23) Google Scholar the long-term multisystem implications of allergic inflammation in earlier life have not yet been determined, particularly in the current high-prevalence generation yet to reach maturity.The mandate of the interdisciplinary Developmental Origins of Health and Disease (DOHaD) movement is to promote a life-course approach to disease prevention, beginning with maternal health before conception. It is important to encourage a specific focus on achieving optimal immune development as a core part of the DOHaD agenda because this is likely to be central in reducing the wider burden of NCDs and inflammatory pathology in the future. Studying the early effects of lifestyle interventions on early immune function and allergic disease will provide a useful early barometer in evaluating effectiveness.Common risk factors mean common solutions: The need for interdisciplinary collaborationAlthough genetic factors can determine individual susceptibility and patterns of disease, only environmental change can account for the rapid increase in NCDs. This also suggests common risk factors and the need for common solutions. Moving forward, there is a clear imperative for coordinated interdisciplinary strategies, particularly those focused on early life. There are a number of good examples of immunomodulatory interventions explored for allergy prevention that might have additional multisystem benefits. Anticipating a new collaborative era of preventive medicine, these are considered here in a more interdisciplinary context.Multisystem benefits of anti-inflammatory ω-3 polyunsaturated fatty acidWith well-recognized anti-inflammatory properties, ω-3 polyunsaturated fatty acid (PUFA)–rich fish oils have been logical interventions for the prevention and treatment of a number of inflammatory conditions. In one of the earliest intervention studies for allergy prevention, we supplemented allergic women with fish oil from 20 weeks' gestation, with immunomodulatory effects in their neonates13Dunstan J. Mori T.A. Barden A. Beilin L.J. Taylor A. Holt P.G. et al.Fish oil supplementation in pregnancy modifies neonatal allergen-specific immune responses and clinical outcomes in infants at high risk of atopy: a randomised controlled trial.J Allergy Clin Immunol. 2003; 112: 1178-1184Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar, 14Barden A. Mori T.A. Dunstan J.A. Taylor A.L. Thornton C.A. Croft K.D. et al.Fish oil supplementation in pregnancy lowers F2 Isoprostanes in neonates at high risk of atopy.Free Radic Res. 2004; 38: 233-239Crossref PubMed Scopus (84) Google Scholar, 15Prescott S.L. Barden A.E. Mori T.A. Dunstan J.A. Maternal fish oil supplementation in pregnancy modifies neonatal leukotriene production by cord-blood-derived neutrophils.Clin Sci (Lond). 2007; 113: 409-416Crossref PubMed Scopus (57) Google Scholar and reduced risk of subsequent allergen (egg) sensitization and eczema severity.13Dunstan J. Mori T.A. Barden A. Beilin L.J. Taylor A. Holt P.G. et al.Fish oil supplementation in pregnancy modifies neonatal allergen-specific immune responses and clinical outcomes in infants at high risk of atopy: a randomised controlled trial.J Allergy Clin Immunol. 2003; 112: 1178-1184Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar More recently, in a much larger, more definitive randomized controlled trial of 706 pregnant women, we observed that fish oil supplementation also achieved a reduction in egg sensitization by 12 months of age in high-risk infants.16Palmer D.J. Sullivan T. Gold M.S. Prescott S.L. Heddle R. Gibson R.A. et al.Effect of n-3 long chain polyunsaturated fatty acid supplementation in pregnancy on infants' allergies in first year of life: randomised controlled trial.BMJ. 2012; 344: e184Crossref PubMed Scopus (162) Google Scholar Rates of atopic eczema (eczema with associated sensitization) were also less in the fish oil group. We also examined the effects of early postnatal fish oil supplementation in high-risk infants (n = 420) from birth to 6 months.17Meldrum S.J. D’Vaz N. Dunstan J.A. Mori T. Prescott S.L. The Infant Fish Oil Supplementation Study (IFOS): design and research protocol of a double-blind, randomized controlled n-3 LCPUFA intervention trial in term infants.Contemp Clin Trials. 2011; 32: 771-778Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar The intervention increased infant ω-3 PUFA levels and was associated with decreased allergen-specific TH2 responses and increased polyclonal TH1 responses.18D'Vaz N. Meldrum S.J. Dunstan J.A. Lee-Pullen T.F. Metcalfe J. Holt B.J. et al.Fish oil supplementation in early infancy modulates developing infant immune responses.Clin Exp Allergy. 2012; 42: 1206-1216Crossref PubMed Scopus (77) Google Scholar Although ω-3 PUFA levels at 6 months were associated with lower risk of eczema and recurrent wheeze, there was no effect of the intervention per se on the primary study outcomes (intention to treat analysis).19D’Vaz N. Meldrum S.J. Dunstan J.A. Martino D. McCarthy S. Metcalfe J. et al.Postnatal fish oil supplementation in high risk infants to prevent allergy: a randomized controlled trial.Pediatrics. 2012; 130: 674-682Crossref PubMed Scopus (106) Google Scholar However, in a per-protocol analysis, infants who received more than 75% of the intended supplementation (the highest adherence quartile) had a significantly lower prevalence of eczema at 12 months in the fish oil group.19D’Vaz N. Meldrum S.J. Dunstan J.A. Martino D. McCarthy S. Metcalfe J. et al.Postnatal fish oil supplementation in high risk infants to prevent allergy: a randomized controlled trial.Pediatrics. 2012; 130: 674-682Crossref PubMed Scopus (106) Google Scholar These findings suggest that achieving higher ω-3 PUFA levels in infancy gives some protection against allergic outcomes but that postnatal supplementation is not an effective strategy. Even before these more recent large studies, the collective literature appeared to be gathering strength to support an allergy-protective effect of fish oil in pregnancy rather than the postnatal period, as suggested by a 2011 systematic review.20Klemens C.M. Berman D.R. Mozurkewich E.L. The effect of perinatal omega-3 fatty acid supplementation on inflammatory markers and allergic diseases: a systematic review.BJOG. 2011; 118: 916-925Crossref PubMed Scopus (7) Google Scholar The inclusion of additional data from the new studies (above)16Palmer D.J. Sullivan T. Gold M.S. Prescott S.L. Heddle R. Gibson R.A. et al.Effect of n-3 long chain polyunsaturated fatty acid supplementation in pregnancy on infants' allergies in first year of life: randomised controlled trial.BMJ. 2012; 344: e184Crossref PubMed Scopus (162) Google Scholar, 19D’Vaz N. Meldrum S.J. Dunstan J.A. Martino D. McCarthy S. Metcalfe J. et al.Postnatal fish oil supplementation in high risk infants to prevent allergy: a randomized controlled trial.Pediatrics. 2012; 130: 674-682Crossref PubMed Scopus (106) Google Scholar in repeated meta-analyses is expected to provide stronger data that will be better positioned to inform clinical practice recommendations in the very near future.Notably, these early interventions with fish oil aimed at allergy prevention in early childhood18D'Vaz N. Meldrum S.J. Dunstan J.A. Lee-Pullen T.F. Metcalfe J. Holt B.J. et al.Fish oil supplementation in early infancy modulates developing infant immune responses.Clin Exp Allergy. 2012; 42: 1206-1216Crossref PubMed Scopus (77) Google Scholar, 19D’Vaz N. Meldrum S.J. Dunstan J.A. Martino D. McCarthy S. Metcalfe J. et al.Postnatal fish oil supplementation in high risk infants to prevent allergy: a randomized controlled trial.Pediatrics. 2012; 130: 674-682Crossref PubMed Scopus (106) Google Scholar, 21Mihrshahi S. Peat J.K. Marks G.B. Mellis C.M. Tovey E.R. Webb K. et al.Eighteen-month outcomes of house dust mite avoidance and dietary fatty acid modification in the Childhood Asthma Prevention Study (CAPS).J Allergy Clin Immunol. 2003; 111: 162-168Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar also have benefits for metabolic programming22Innis S.M. Metabolic programming of long-term outcomes due to fatty acid nutrition in early life.Matern Child Nutr. 2011; 7: 112-123Crossref PubMed Scopus (119) Google Scholar and reducing cardiovascular risk.23Skilton M.R. Ayer J.G. Harmer J.A. Webb K. Leeder S.R. Marks G.B. et al.Impaired fetal growth and arterial wall thickening: a randomized trial of omega-3 supplementation.Pediatrics. 2012; 129: e698-e703Crossref PubMed Scopus (48) Google Scholar, 24Forsyth J.S. Willatts P. Agostoni C. Bissenden J. Casaer P. Boehm G. Long chain polyunsaturated fatty acid supplementation in infant formula and blood pressure in later childhood: follow up of a randomised controlled trial.BMJ. 2003; 326: 953-958Crossref PubMed Google Scholar A recent follow-up of one of these allergy prevention studies at 8 years of age (n = 363) showed that dietary fish oil supplementation over the first 5 years of life reduced the carotid intima-media thickening (as a noninvasive measure of subclinical atherosclerosis) that had been associated with reduced fetal growth.23Skilton M.R. Ayer J.G. Harmer J.A. Webb K. Leeder S.R. Marks G.B. et al.Impaired fetal growth and arterial wall thickening: a randomized trial of omega-3 supplementation.Pediatrics. 2012; 129: e698-e703Crossref PubMed Scopus (48) Google Scholar This might be mediated, at least in part, by a reduction in the low-grade systemic inflammation that has been linked directly with the risk for cardiometabolic disease.25Huang R.C. Mori T.A. Burke V. Newnham J. Stanley F.J. Landau L.I. et al.Synergy between adiposity, insulin resistance, metabolic risk factors, and inflammation in adolescents.Diabetes Care. 2009; 32: 695-701Crossref PubMed Scopus (74) Google Scholar In keeping with this, we have previously shown that fish oil supplementation in pregnancy decreased neonatal oxidative stress14Barden A. Mori T.A. Dunstan J.A. Taylor A.L. Thornton C.A. Croft K.D. et al.Fish oil supplementation in pregnancy lowers F2 Isoprostanes in neonates at high risk of atopy.Free Radic Res. 2004; 38: 233-239Crossref PubMed Scopus (84) Google Scholar and neutrophil production of leukotriene B4, which correlated with reduced Toll-like receptor (TLR) 4–mediated inflammatory responses.15Prescott S.L. Barden A.E. Mori T.A. Dunstan J.A. Maternal fish oil supplementation in pregnancy modifies neonatal leukotriene production by cord-blood-derived neutrophils.Clin Sci (Lond). 2007; 113: 409-416Crossref PubMed Scopus (57) Google Scholar Furthermore, in addition to immunomodulation13Dunstan J. Mori T.A. Barden A. Beilin L.J. Taylor A. Holt P.G. et al.Fish oil supplementation in pregnancy modifies neonatal allergen-specific immune responses and clinical outcomes in infants at high risk of atopy: a randomised controlled trial.J Allergy Clin Immunol. 2003; 112: 1178-1184Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar, 18D'Vaz N. Meldrum S.J. Dunstan J.A. Lee-Pullen T.F. Metcalfe J. Holt B.J. et al.Fish oil supplementation in early infancy modulates developing infant immune responses.Clin Exp Allergy. 2012; 42: 1206-1216Crossref PubMed Scopus (77) Google Scholar and allergy reduction,13Dunstan J. Mori T.A. Barden A. Beilin L.J. Taylor A. Holt P.G. et al.Fish oil supplementation in pregnancy modifies neonatal allergen-specific immune responses and clinical outcomes in infants at high risk of atopy: a randomised controlled trial.J Allergy Clin Immunol. 2003; 112: 1178-1184Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar, 16Palmer D.J. Sullivan T. Gold M.S. Prescott S.L. Heddle R. Gibson R.A. et al.Effect of n-3 long chain polyunsaturated fatty acid supplementation in pregnancy on infants' allergies in first year of life: randomised controlled trial.BMJ. 2012; 344: e184Crossref PubMed Scopus (162) Google Scholar we have also seen beneficial effects on aspects of neurodevelopment after both prenatal26Dunstan J.A. Simmer K. Dixon G. Prescott S.L. Cognitive assessment at 2.5 years following fish oil supplementation in pregnancy: a randomized controlled trial.Arch Dis Child Fetal Neonatal Ed. 2008; 93: F45-F50Crossref PubMed Scopus (261) Google Scholar and early postnatal27Meldrum S.J. D'Vaz N. Simmer K. Dunstan J.A. Hird K. Prescott S.L. Effects of high-dose fish oil supplementation during early infancy on neurodevelopment and language: a randomised controlled trial.Br J Nutr. 2012; 108: 1443-1454Crossref PubMed Scopus (56) Google Scholar fish oil supplementation. In summary, restoring the higher ω-3 PUFA levels seen in subjects with more traditional diets is a clear example of an early immunomodulatory intervention that has multisystem benefits.Effects of the gut microbiome, probiotics, and other microbial productsChanging microbial exposure and diversity remains one of the leading explanations for the increase in rates of many inflammatory diseases. Animal models provide clear evidence that the gut microbiota modulates immune programming and that manipulation of the microbiome can prevent not only allergic disease28Sudo N. Sawamura S. Tanaka K. Aiba Y. Kubo C. Koga Y. 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Jury J. et al.The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice.Gastroenterology. 2011; 141 (e1-3): 599-609Abstract Full Text Full Text PDF PubMed Scopus (1093) Google Scholar, 32Bercik P. Collins S.M. Verdu E.F. Microbes and the gut-brain axis.Neurogastroenterol Motil. 2012; 24: 405-413Crossref PubMed Scopus (235) Google ScholarFig 2A central role of the immune system in mediating the multisystem effects of diet, physical activity, and the microbiota.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Importantly, there is accumulating evidence that many of these multisystem effects are mediated through the immune system (Fig 2). Adverse changes in gut microbiome (induced by the high-fat, low-fiber Western diet) are associated with altered gut barrier function, increased systemic endotoxin levels,33Cani P.D. Amar J. Iglesias M.A. Poggi M. Knauf C. 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• W2048672502 created "2016-06-24" @default.
• W2048672502 creator A5077492180 @default.
• W2048672502 date "2013-01-01" @default.
• W2048672502 modified "2023-10-15" @default.
• W2048672502 title "Early-life environmental determinants of allergic diseases and the wider pandemic of inflammatory noncommunicable diseases" @default.
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• W2048672502 doi "https://doi.org/10.1016/j.jaci.2012.11.019" @default.
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