An exposome perspective: Early-life events and immune development in a changing world
2017; Elsevier BV; Volume: 140; Issue: 1 Linguagem: Inglês
10.1016/j.jaci.2017.05.015
ISSN1097-6825
AutoresHarald Renz, Patrick G. Holt, Michael Inouye, Alan Logan, Susan L. Prescott, Peter D. Sly,
Tópico(s)Gut microbiota and health
ResumoAdvances in metagenomics, proteomics, metabolomics, and systems biology are providing a new emphasis in research; interdisciplinary work suggests that personalized medicine is on the horizon. These advances are illuminating sophisticated interactions between human-associated microbes and the immune system. The result is a transformed view of future prevention and treatment of chronic noncommunicable diseases, including allergy. Paradigm-shifting gains in scientific knowledge are occurring at a time of rapid global environmental change, urbanization, and biodiversity losses. Multifactorial and multigenerational implications of total environmental exposures, the exposome, require coordinated interdisciplinary efforts. It is clear that the genome alone cannot provide answers to urgent questions. Here we review the historical origins of exposome research and define a new concept, the metaexposome, which considers the bidirectional effect of the environment on human subjects and the human influence on all living systems and their genomes. The latter is essential for human health. We place the metaexposome in the context of early-life immune functioning and describe how various aspects of a changing environment, especially through microbiota exposures, can influence health and disease over the life course. Advances in metagenomics, proteomics, metabolomics, and systems biology are providing a new emphasis in research; interdisciplinary work suggests that personalized medicine is on the horizon. These advances are illuminating sophisticated interactions between human-associated microbes and the immune system. The result is a transformed view of future prevention and treatment of chronic noncommunicable diseases, including allergy. Paradigm-shifting gains in scientific knowledge are occurring at a time of rapid global environmental change, urbanization, and biodiversity losses. Multifactorial and multigenerational implications of total environmental exposures, the exposome, require coordinated interdisciplinary efforts. It is clear that the genome alone cannot provide answers to urgent questions. Here we review the historical origins of exposome research and define a new concept, the metaexposome, which considers the bidirectional effect of the environment on human subjects and the human influence on all living systems and their genomes. The latter is essential for human health. We place the metaexposome in the context of early-life immune functioning and describe how various aspects of a changing environment, especially through microbiota exposures, can influence health and disease over the life course. “Human biology should be primarily concerned with the responses that the body and the mind make to the surroundings and ways of life…little effort has been made to develop methods for investigating scientifically the interrelatedness of things. Epidemiological evidence leaves no doubt that many chronic and degenerative disorders which constitute the most difficult and costly medical problems of our societies have their origin in the surroundings and in the ways of life rather than in the genetic constitution of the patient. But little is known of these environmental determinants of disease.”— Rene J. Dubos, Keynote Lecture at the 25th Annual Meeting of the American Academy of Allergy, Asthma & Immunology, 19691Dubos R. The spaceship earth.J Allergy. 1969; 44: 1-9Abstract Full Text PDF PubMed Google Scholar Almost 50 years have passed since renowned microbiologist Rene Dubos (1901-1982) addressed his colleagues in allergy and immunology with the Robert A. Cooke keynote lecture entitled “Spaceship Earth.”1Dubos R. The spaceship earth.J Allergy. 1969; 44: 1-9Abstract Full Text PDF PubMed Google Scholar For the previous decade, Dubos had been performing studies with germ-free (GF) and specific pathogen-free mice to determine the effects of nutrition, stress, maternal care, housing conditions, social interactions, and sanitation on immune function and health over the life course. His research extended into the transgenerational health effects of these variables. Much of this groundbreaking work is captured in his classic reviews2Dubos R. Lasting biological effects of early influences.Perspect Biol Med. 1969; 12: 479-491Crossref PubMed Google Scholar, 3Dubos R. Savage D. Schaedler R. Biological Freudianism. Lasting effects of early environmental influences.Pediatrics. 1966; 38: 789-800PubMed Google Scholar and the book Man Adapting.4Dubos R. Man adapting. Yale University Press, New Haven (CT)1965Google Scholar The message was simple and applies equally today: rapid changes in the modern environment are intertwined with immune health through synergistic biological, psychological, social, and ecological factors. Multifactorial investigations with new conceptual and experimental methods characterizing health promotion and health risks throughout life would be required to solve complex problems. Thus modernity demands a new systems approach from scientists involved in allergy and immunology. Dubos referred to this novel approach as “environmental biology” in the context of human ecology, a new paradigm in which single-variable examinations will not suffice. Rather, this must encompass a simultaneous merger of bench, epidemiologic, and clinical investigations with an aim toward studying a subject from the perspective of synergy: examining interactions between exposures (some positive and some negative) across time. In his words, the way forward was to understand “the response of the total organism to the total environment.”5Dubos R. Environmental biology.Bioscience. 1964; 14: 11-14Crossref Google Scholar At the 1969 American Academy of Allergy, Asthma & Immunology meeting, Dubos made 3 additional forward-thinking arguments to his audience. First, he opined that the manifestations of allergy in the broadest sense of the term (ie, altered reactivity to the changing westernized environment) would not be fully realized for decades. In other words, he was positing that an impending epidemic of noncommunicable diseases (NCDs), including mental disorders, was not unrelated to allergy in both its narrow clinical definitions (ie, comorbidity with allergic diseases and asthma) and its etymological root (ie, “altered reactivity” based on an evolutionary mismatch with the total modern environment means virtually all NCDs are indeed in the realm of allergy). Second, he underscored that changes to the health of the external environment (eg, biodiversity losses and environmental degradation) were matters of importance to allergy and immunology. Third, although he conceded that much of the technology to objectively measure multiple factors, especially clinically relevant molecular biology, at community and population scales were not available (then) or cumbersome to implement (an argument that still exists), the future burden of NCDs should be enough to galvanize a different approach to population health. Four months before the lunar landing, Dubos called for a “massive effort similar to the one initiated by NASA” to help allergists and immunologists understand health from the perspective of the total environment. The idea was to study genes–total environment interactions over time with exposures that also include social policies and practices. He sought not simply to understand the single or even synergistic ways in which several objectionable pollutants damage health, act as allergens, and cause altered reactivity but also to learn the elements of an environment that actually promote human health over the life course.5Dubos R. Environmental biology.Bioscience. 1964; 14: 11-14Crossref Google Scholar, 6Dubos R. Human ecology.WHO Chron. 1969; 23: 499-504PubMed Google Scholar He pleaded for knowledge of the total environment that equates to health wherein it is defined not simply as being free of atopic dermatitis but a state conducive to reaching human potential. Half a century later, the total environment perspective is of massive importance not only to personal and public health but also to planetary health. The very limited causative role played by pure genetic factors in patients with chronic disease,7Rappaport S.M. Genetic factors are not the major causes of chronic diseases.PLoS One. 2016; 11: e0154387Crossref PubMed Scopus (0) Google Scholar as witnessed by the tremendous global increases in NCDs, especially allergic diseases,8von Hertzen L. Beutler B. Bienenstock J. Blaser M. Cani P.D. Eriksson J. et al.Helsinki alert of biodiversity and health.Ann Med. 2015; 47: 218-225Crossref PubMed Scopus (18) Google Scholar underscores the urgency of the total environment perspective. Thus despite elegant mechanistic insights provided by genome-wide association studies (GWASs), we are learning the hard way that environmental exposures, both detrimental and nourishing, manifest in personal and population health outcomes. Moreover, GWASs demonstrate that genes alone cannot explain major health disparities, nor can they explain why NCDs do not occur randomly in westernized populations. Instead, NCDs operate in a slanted direction, where the burden points to the socioeconomically disadvantaged. The multifactorial study of health as mediated by total environmental exposures over the life course, as originally proposed, has taken various names, including the developmental origins of health and disease concept,9Wadhwa P.D. Buss C. Entringer S. Swanson J.M. Developmental origins of health and disease: brief history of the approach and current focus on epigenetic mechanisms.Semin Reprod Med. 2009; 27: 358-368Crossref PubMed Scopus (208) Google Scholar the envirome,10Neiderhiser J.M. Understanding the roles of genome and envirome: methods in genetic epidemiology.Br J Psychiatry Suppl. 2001; 40: S12-S17Crossref PubMed Google Scholar environomics,11Anthony J.C. The promise of psychiatric enviromics.Br J Psychiatry Suppl. 2001; 40: S8-S11Crossref PubMed Google Scholar and, more recently, the exposome.12Wild C.P. Complementing the genome with an “exposome”: the outstanding challenge of environmental exposure measurement in molecular epidemiology.Cancer Epidemiol Biomarkers Prev. 2005; 14: 1847-1850Crossref PubMed Scopus (441) Google Scholar In each case the nomenclature is unified by understanding that although genetic factors matter, total health is not a genetic trait. It is also understood that the environment is not a static variable. and certain windows of vulnerability (for disease risk) and opportunity (for health promotion) can present themselves in interactions between genes, environment, and time (Fig 1). Remarkable advances in objectively measured end points allow for assessments of biological tissue, immune programming, and related physiology, such as oxidative stress, hormonal activity, and neuropeptides. Moreover, the increase in high-throughput molecular -omics techniques can produce large data sets from analysis of functional proteins (proteomics), metabolites (metabolomics), gene expression (epigenomics and transcriptomics), and genetic influences on drug/isolated nutrient metabolism (pharmacogenomics).13Manzoni C. Kia D.A. Vandrovcova J. Hardy J. Wood N.W. Lewis P.A. et al.Genome, transcriptome and proteome: the rise of omics data and their integration in biomedical sciences.Brief Bioinform. 2016; ([Epub ahead of print])PubMed Google Scholar The potential application of -omics in conjunction with bioinformatics and biostatistics represents an important step toward narrowing the gap between GWASs and the obvious need for environment-wide association studies of individual subjects and communities in their total dynamic environment. Despite their many differences, NCDs are most often united by the common threads of immune dysfunction and chronic low-grade inflammation. More recently, we are learning that alterations of the human microbiome, microorganisms, and their collective genome residing in an anatomic niche are deeply connected to most NCDs, including mental disorders.14Logan A.C. Jacka F.N. Craig J.M. Prescott S.L. The microbiome and mental health: looking back, moving forward with lessons from allergic diseases.Clin Psychopharmacol Neurosci. 2016; 14: 131-147Crossref PubMed Scopus (0) Google Scholar In part, this might explain the high levels of overlap between NCDs, such as allergic diseases and mental disorders.14Logan A.C. Jacka F.N. Craig J.M. Prescott S.L. The microbiome and mental health: looking back, moving forward with lessons from allergic diseases.Clin Psychopharmacol Neurosci. 2016; 14: 131-147Crossref PubMed Scopus (0) Google Scholar, 15Goodwin R.D. Robinson M. Sly P.D. Holt P.G. Childhood atopy and mental health: a prospective, longitudinal investigation.Psychol Med. 2017; 47: 317-325Crossref PubMed Scopus (0) Google Scholar The emerging science of the microbiome and its influence on early-life immune priming to be discussed below has forced a total environment perspective. Although the term dysbiosis is often confined to its definition as perturbations of gut microbiota, it formally translates as “difficult living” or “life in distress.” Climate change, biodiversity losses, pollution, environmental degradation, rapid urbanization, and a general disconnection from nature are causing distress at the global scale. Planetary distress in the Anthropocene is pressing on the discipline of allergy and immunology and the patients encountered.16Logan A.C. Jacka F.N. Prescott S.L. Immune-microbiota interactions: dysbiosis as a global health issue.Curr Allergy Asthma Rep. 2016; 16: 13Crossref PubMed Scopus (13) Google Scholar Today, we are past time for a NASA-like effort. Carefully designed, -omics–inspired megacohort studies with expert input from transdisciplinary teams will help provide a blueprint for the total environment that promotes health. Specifically, the exposome is not merely pollutants; diet, tobacco, and other lifestyle factors meet the internal/skin microbiome, and stress and immune function meet social capital, socioeconomic status, and/or the presence or absence of green space and other potentially beneficial aspects of natural environments. The term total environment can often become constricted. We define the exposome as the aforementioned, plus the policies and practices that drive global NCDs.17Moodie R. Stuckler D. Monteiro C. Sheron N. Neal B. 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Thus the exposome cannot be separated from scientific explorations of the ways in which policy influences gene-environment interactions over time.19Prescott S.L. Logan A.C. Transforming life: a broad view of the developmental origins of health and disease concept from an ecological justice perspective.Int J Environ Res Public Health. 2016; : 13Google Scholar Finally, in the midst of exposure science and the exposome, there is an almost exclusive focus on psychological stress. However, negative and positive emotions are not the opposite and are indeed only modestly correlated.19Prescott S.L. Logan A.C. Transforming life: a broad view of the developmental origins of health and disease concept from an ecological justice perspective.Int J Environ Res Public Health. 2016; : 13Google Scholar We include distinct psychological assets in our view of exposure science. For example, maternal optimism is a psychological asset associated with mental health in offspring,20McDonald S.W. Kehler H.L. 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Transforming life: a broad view of the developmental origins of health and disease concept from an ecological justice perspective.Int J Environ Res Public Health. 2016; : 13Google Scholar The exposome can be viewed through the prism of the holobiont (ie, human subjects and symbiotic functional microbes as a multispecies entity).22Bordenstein S.R. Theis K.R. Host biology in light of the microbiome: ten principles of holobionts and hologenomes.PLoS Biol. 2015; 13: e1002226Crossref PubMed Scopus (0) Google Scholar However, we underscore that the holobiont itself resides within a dynamic ecological theatre, one in which policy and positive psychology matter. Maturation of the human fetal innate immune system is initiated early during the first trimester of pregnancy, with pluripotent granuloma-macrophage progenitors appearing in the fetal circulation by week 5 and relevant precursor populations becoming detectable in the thymus and bone marrow between gestational weeks 8 to 12. 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The current genomic revolution provides the necessary tools with precision that will increase exponentially over time. As discussed in the final section of this review, the data mountain being generated by these technologies has created a new set of problems, notably the need for data integration on a scale previously unknown in biology, and this is driving the rapid development of the specialty of computational biology, which is now a crucial element of research in this and related biomedical areas (see further discussion below). As a result of recent studies, the evolving paradigm is now that colonization of the infant GIT with an “appropriate” microbiota within crucial developmental time windows is required to optimally drive immune function maturation,39Gensollen T. Iyer S.S. Kasper D.L. Blumberg R.S. 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