The Neonatal Window of Opportunity: Setting Rupted, Drives Far-Ranging Clinical Consequences
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e Journal of Immunology VOLUME 198, NUMBER 2 • JANUARY 15, 2017 • WWW.JIMMUNOL.ORG The Macro Influence of the Microbiome am pleased to draw your attention to this, the first ever topical issue of Brief Reviews in The Journal of Immunology. I Through seven Brief Reviews, this issue of The JI high- lights the pervasive impact of the gut microbiome on immune functions, both in the gut and at distal sites, and features a cover chosen from a themed competition for this issue. These compiled Brief Reviews underscore our recent appreci- ation that the far-reaching influence of commensal gut microbes on immune function reflects the coevolution of this symbiotic mi- crobial ecosystem and its mammalian hosts. Authors Torow and Hornef emphasize that the nature of this microbial community in Downloaded from human and mouse early neonates impacts immune homeostasis throughout life (1). Grigg and Sonnenberg explore the reciprocal influence of the identity and localization of the microbiome components on the balance between inflammation and immune homeostasis both within and outside the gut, and point to the therapeutic potential for diseases of chronic inflammation pro- http://www.jimmunol.org/ vided by manipulation of the microbiota-host interactions (2). Elinav and coauthors describe the microbially derived and mi- crobially modified small metabolites whose bioactivity mediates much of the influence on sterile host tissues described in the ac- companying reviews, in part by modulating nutrient content, digestion, inflammation, and epigenetic control of transcription (3). Recognizing the sweeping impact of lifestyle changes in the Western world, Plunkett and Nagler highlight the influence of the microbiota and environmental exposure to microbial products on by guest on January 26, 2017 the acquisition of food allergies (4), whereas the focus of the Brief Review by Paun, Yau, and Danska is the effect of the resident gut microbiota on the rapid rise in the incidence of type I diabetes Ag-specific CD8 T cells (red) and CXC3R11 APCs (green) in the small among genetically stable populations (5). Colpitts and Kasper intestine (visualized with a DNA stain in blue) 9 d after oral infection document the influence of the gut microbiome on autoimmunity with Ag-expressing Yersinia pseudotuberculosis. Image provided by in the CNS mediated by alterations in the balance of effector and Dr. T. Bergsbaken, University of Washington. suppressor cells along the bidirectional gut–brain axis (6). Landay and coauthors highlight the clinical consequences of microbiome in Washington, DC, May 12–16, 2017, for the focus of next dysbiosis through the documented cross-talk between the gut year’s topical issue of Brief Reviews. microbiome and the immune system during HIV infection, with an eye to some of the recent technical advances that have illu- Pamela J. Fink, Ph.D. minated this field (7). Taken together, these Brief Reviews provide Editor-in-Chief an impressive illustration of the ongoing dialogue between the gut microbiota and the immune system which, when balanced at the References ideal set point, maintains immune homeostasis, and when dis- 1. Torow, N., and M. W. Hornef. 2017. The neonatal window of opportunity: setting rupted, drives far-ranging clinical consequences. the stage for life-long host-microbial interaction and immune homeostasis. We are excited that this collection of topical Brief Reviews on J. Immunol. 557–563. 2. Grigg, J. B., and G. F. Sonnenberg. 2017. Host-microbiota interactions shape local “The Macro Influence of the Microbiome” inaugurates the 101st and systemic inflammatory diseases. J. Immunol. 564–571. year of continuous publication of The Journal of Immunology, 3. Blacher, E., M. Levy, E. Tatirovsky, and E. Elinav. 2017. Microbiome-modulated metabolites at the interface of host immunity. J. Immunol. 572–580. and underscores the breadth of the journal’s scope and the 4. Plunkett, C. H., and C. R. Nagler. 2017. The influence of the microbiome on eclectic research interests of its readership. We hope to make this allergic sensitization to food. J. Immunol. 581–589. topical issue an annual event. Look for an announcement at the 5. Paun, A., C. Yau, and J. S. Danska. 2017. The influence of the microbiome on type 1 diabetes. J. Immunol. 590–595. annual meeting of The American Association of Immunologists 6. Colpitts, S. L., and L. H. Kasper. 2017. Influence of the gut microbiome on au- toimmunity in the central nervous system. J. Immunol. 596–604. 7. Liu, J., B. Williams, D. Frank, S. M. Dillon, C. C. Wilson, and A. L. Landay. 2017. Inside out: HIV, the gut microbiome, and the mucosal immune system. Copyright Ó2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 J. Immunol. 605–614. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1690022 Th eJournal of Brief Reviews Immunology The Neonatal Window of Opportunity: Setting the Stage for Life-Long Host-Microbial Interaction and Immune Homeostasis Natalia Torow and Mathias W. Hornef The existence of a neonatal window was first high- Approximately three decades ago, researchers noticed dra- lighted by epidemiological studies that revealed the par- matic changes in the interaction of the human host with ticular importance of this early time in life for the pathogenic microorganisms in industrialized countries. The susceptibility to immune-mediated diseases in humans. number of infections decreased very significantly during the Recently, the first animal studies emerged that present second half of the twentieth century as a consequence of examples of early-life exposure–triggered persisting im- improved medical healthcare, including effective vaccine mune events, allowing a detailed analysis of the factors strategies and antibiotics, as well as better hygiene and living Downloaded from that define this particular time period. The enteric standards (1, 2). The concomitant increase in immune- microbiota and the innate and adaptive immune sys- mediated diseases, such as Crohn’s disease and asthma, as well tem represent prime candidates that impact on the path- as diabetes and multiple sclerosis, led to the hygiene hy- ogenesis of immune-mediated diseases and are known pothesis that proposed a causative relationship between the decrease in infectious diseases and the increasing burden of to reach a lasting homeostatic equilibrium following a http://www.jimmunol.org/ dynamic priming period after birth. In this review, we immune-mediated and allergic diseases. Consistent with this idea, a steady increase in IBD and asthma was subsequently outline the postnatal establishment of the microbiota observed in other geographical areas with previous very low and maturation of the innate and adaptive immune sys- incidence following the implementation of effective health- tem and discuss examples of early-life exposure–triggered care systems and infection-control measures (3, 4). Even more immune-mediated diseases that start to shed light on strikingly, nematode infection, a highly endemic type of in- the critical importance of the early postnatal period fection in geographic areas with low IBD incidence, resulted for life-long immune homeostasis. The Journal of in a significant clinical improvement in IBD patients (5). Immunology, 2017, 198: 557–563. Later, epidemiological studies extended this view to include by guest on January 26, 2017 exposure to environmental microbial constituents, as well as mmune-mediated diseases, such as allergies and inflam- commensal bacteria (6, 7). This was first noted when farm matory bowel disease (IBD), are highly prevalent in western children were compared with their urban counterparts I countries and are associated with significant morbidity. (8). Raw milk consumption and exposure to the livestock- Despite decades of intensive research on the associated func- produced feces within the stable environment with a high tional and structural alterations, the disease etiology and, thus, microbial load and potent immunomodulatory activity were identified as critical factors (9). High endotoxin concentra- the decisive molecular mechanisms underlying disease initiation tions in animal feces and the farm environment were identi- have not been resolved. For example, the search for unknown fied as functional triggers of regulatory mechanisms and pathogenic microorganisms revealed some interesting candidates immune homeostasis, yet other less-well detectable microbial but no uniform causative agent. Also, genome-wide association stimuli or even viable bacteria might contribute to this effect studies identified a large number of susceptibility loci, but many (10, 11). Indeed, the reduction in the prevalence of certain individuals that carry these mutations never experience clinical infectious diseases was paralleled by major alterations in the symptoms. Therefore, the identified factors might enhance dis- enteric microbiota composition (12, 13). Loss of individual ease susceptibility and/or promote the progression and severity bacterial members of a healthy microbiota and a general re- of clinical symptoms rather than play a decisive role during the duction in bacterial diversity were noted and may contribute initiation of the disease. However, only the identification of the to enhanced disease susceptibility (13). Consistently, individual first step in disease pathogenesis will allow us to develop effective members of the microbiota were assigned a specific preventive strategies for future disease prevention. or disease-promoting function in immune modulation. For Institute of Medical Microbiology,