The existence of a neonatal window was first highlighted by epidemiological studies that revealed the particular importance of this early time in life for the susceptibility lớn immune-mediated diseases in humans. Recently, the first animal studies emerged that present examples of early-life exposure–triggered persisting immune events, allowing a detailed analysis of the factors that define this particular time period. The enteric microbiota & the innate và adaptive immune system represent prime candidates that impact on the pathogenesis of immune-mediated diseases và are known to lớn reach a lasting homeostatic equilibrium following a dynamic priming period after birth. In this nhận xét, we outline the postnatal establishment of the microbiota and maturation of the innate và adaptive sầu immune system và discuss examples of early-life exposure–triggered immune-mediated diseases that start to shed light on the critical importance of the early postnatal period for life-long immune homeostasis.
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Immune-mediated diseases, such as allergies và inflammatory bowel disease (IBD), are highly prevalent in western countries và are associated with significant morbidity. Despite decades of intensive retìm kiếm on the associated functional & structural alterations, the disease etiology &, thus, the decisive sầu molecular mechanisms underlying disease initiation have not been resolved. For example, the tìm kiếm for unknown pathogenic microorganisms revealed some interesting candidates but no uniform causative agent. Also, genome-wide association studies identified a large number of susceptibility loci, but many individuals that carry these mutations never experience clinical symptoms. Therefore, the identified factors might enhance disease susceptibility and/or promote the progression & severity of clinical symptoms rather than play a decisive role during the initiation of the disease. However, only the identification of the first step in disease pathogenesis will allow us khổng lồ develop effective strategies for future disease prevention.
Approximately three decades ago, researchers noticed dramatic changes in the interaction of the human host with pathogenic microorganisms in industrialized countries. The number of infections decreased very significantly during the second half of the twentieth century as a consequence of improved medical healthcare, including effective vaccine strategies & antibiotics, as well as better hygiene và living standards (1, 2). The concomitant increase in immune-mediated diseases, such as Crohn’s disease & asthma, as well as diabetes & multiple sclerosis, led to lớn the hygiene hypothesis that proposed a causative sầu relationship between the decrease in infectious diseases và the increasing burden of immune-mediated & allergic diseases. Consistent with this idea, a steady increase in IBD và asthma was subsequently observed in other geographical areas with previous very low incidence following the implementation of effective sầu healthcare systems and infection-control measures (3, 4). Even more strikingly, nematode infection, a highly endemic type of infection in geographic areas with low IBD incidence, resulted in a significant clinical improvement in IBD patients (5). Later, epidemiological studies extended this view khổng lồ include exposure to lớn environmental microbial constituents, as well as commensal bacteria (6, 7). This was first noted when farm children were compared with their urban counterparts (8). Raw milk consumption và exposure to lớn the livestock-produced feces within the stable environment with a high microbial load và potent immunomodulatory activity were identified as critical factors (9). High endotoxin concentrations in animal feces và the farm environment were identified as functional triggers of regulatory mechanisms và immune homeostasis, yet other less-well detectable microbial stimuli or even viable bacteria might contribute to lớn this effect (10, 11). Indeed, the reduction in the prevalence of certain infectious diseases was paralleled by major alterations in the enteric microbiota composition (12, 13). Loss of individual bacterial members of a healthy microbiota and a general reduction in bacterial diversity were noted và may contribute to lớn enhanced disease susceptibility (13). Consistently, individual members of the microbiota were assigned a specific preventive or disease-promoting function in immune modulation. For example, the segmented filamentous bacterium Faecalibacterium prausnitzii và the mucin-degrading bacterium Akkermansia muciniphilia were shown lớn promote mucosal immune cell maturation, immune homeostasis, or a beneficial host metabolism in mice và men (14–16). Yet, fecal transplantation, despite impressive clinical benefits in certain patient cohorts, such as patients with recurrent Clostridium difficile infection (17), has failed to lớn provide a unisize and lasting clinical response.
Soon, epidemiological studies identified the particular influence of age. For example, farm exposure during fetal & early postnatal life exerted the strongest protective sầu effect (8, 18). Also, antibiotic use during pregnancy và early childhood was reported lớn represent a risk factor for allergic disease development (19). These findings introduced yet another Mã Sản Phẩm in which exogenous factors present during early development could also directly or indirectly influence immune homeostasis and disease susceptibility during later life. Indeed, the immune system at birth differs significantly from that of adult individuals, & the postnatal period contributes significantly to immune development và maturation. Also, microbial colonization starts at birth and eventually generates a life-long, relatively stable ecosystem. This early priming was later described as the neonatal window khổng lồ highlight the exclusive sầu và nonredundant function of the early postnatal & infant period for life-long immune homeostasis (Fig. 1). A number of well-controlled animal studies has begun lớn unravel the mechanisms that underlie the observations from epidemiological studies (Table I) (20–23). In this article, we discuss human & mouse studies that reveal the critical and nonredundant role of the neonatal window for immune homeostasis & its implication for future retìm kiếm.