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Air Pollution, Early Life Microbiome, and Development

Air Pollution, Early Life Microbiome, and Development Purpose of Review We review how an altered microbiome in early life impacts on immune, metabolic, and neurological development, focusing on some of the most widespread diseases related to each of these processes, namely atopic disease, obesity, and autism. Recent Findings The early development of the microbial communities that inhabit the human body is currently challenged by factors that range from reduced exposure to microbes, antibiotic use, and poor dietary choices to widespread environmental pollution. Recent work has highlighted some of the long-term consequences that early alterations in the establishment of these microbiotas can have for different aspects of human development and health. Summary The long-term consequences of early microbiome alterations for human development and health are only beginning to be understood and will require in-depth investigation in the years to come. A solid understanding of how present day environ- mental conditions alter microbiome development, and of how an altered microbiome in early life impacts on life-long health, should inform both public health policies and the development of dietary and medical strategies to counteract early microbiota imbalances. . . . . . Keywords Gut microbiome Infant development Early programming Immune disease Obesity Autism spectrum disorder Introduction industrial revolution, the discovery of antibiotics, the creation of agri-business, and recently the elaboration and massive dis- Human evolution has been punctuated by precise moments tribution of processed foods [1]. These changes appear to have throughout history associated to key changes in lifestyle: the had a profound effect on the evolution of human health and appearance of Homo sapiens sapiens, the shift from nomadic to disease. In the last century, such effects have likely included sedentary lifestyles with the introduction of agriculture, the the emergence and increased prevalence of allergies, asthma, and autoimmune diseases, with a concomitant decrease in the incidence of infectious diseases [2]. In fact, Strachan in 1989 proposed the “hygiene hypothesis”, which stated that lack of exposure to microbes during early infancy was at the source of This article is part of the Topical Collection on Early Life Environmental the observed increased prevalence of allergy and asthma in Health westernized populations [3, 4]. Later on, the “Barker Hypothesis” (also called “Developmental Origins of Health * M. Pilar Francino and Disease (DOHaD)”) postulated that exposure to environ- francino_pil@gva.es mental factors during both fetus development and immediately Department of Biological and Chemical Sciences, The University of after birth or nutritional deficiencies of the mother during ges- the West Indies, Cave Hill campus, Cave Hill, Barbados tation would result in an early programming for developing Unitat Mixta d’Investigació en Genòmica i Salut, Fundació per al cardiovascular, neurodevelopmental, and metabolic disorders Foment de la Investigació Sanitària i Biomèdica de la Comunitat [5–8]. The latter hypotheses emphasize the notion that infancy Valenciana (FISABIO-Salut Pública)/Institut de Biologia Integrativa is likely to be a critical stage in human development in which de Sistemes (Universitat de València), Avda. Catalunya 21, 46020 València, Spain interventions could potentially prevent or decrease risk factors of latent disorders. Interestingly, there is growing evidence that CIBER en Epidemiología y Salud Pública (CIBERESP), Madrid, Spain early microbiome-host interactions during fetus development Curr Envir Health Rpt (2018) 5:512–521 513 and early infancy are critical factors that will determine life- early onset of type 2 diabetes [33], and, in the latter case, the long health or disease states [9–11]. However, although it is dendritic cells of the immune system have been implicated in clear that the first months of life represent a crucial time win- mediating the increased translocation level. The proposition dow in the establishment of microbiome-host interactions, the that maternal bacteria reach the fetal gut is ground breaking, as precise boundaries of this window and the impact of microbial these organisms could start marking the trajectories of im- changes during later periods of infancy and childhood on life- mune, metabolic, and somatic development in utero, with long disease risks remain to be determined. enormous implications for the health of the individual [29]. Complex endeavors such as those undertaken by the Here, we review several aspects of human development and Human Microbiome Project and the MetaHit Consortium health that are known to be affected by the gut microbiome in have been key in highlighting the significance and complexity early life, as well as the emergent evidence for air pollution as a of the microbiota inhabiting the niches provided by the human hitherto rarely considered environmental factor that likely contrib- body. It is now well accepted that the human’s gastrointestinal utes to altering the establishment of the gut microbiome (Fig. 1). tract (GIT) gathers the most diverse and dense microbiota of the human body, which in turn plays fundamental roles in gut homeostasis [12, 13]. Supporting the hygiene and Barker hy- Air Pollution: an Environmental Factor potheses, there is now a great body of knowledge establishing Recently Associated to Microbiome Dysbiosis that GIT microbiota composition during infancy and child- hood are associated to an incredible array of human diseases, Air pollution is the presence of harmful substances in the air from GIT-related diseases (i.e., metabolic disorders such as that can result from natural causes (i.e., volcano eruptions, diabetes and obesity, inflammatory bowel disease), to immune wind dust) and human activities (i.e., combustion of fuels, diseases and neurological disorders [14–22]. industry, traffic, cooking, smoking). The presence in polluted The advent of sequencing technologies that enable the deep air of larger proportions of CO ,SO , other toxic gases, chem- 2 2 characterization of microbial communities without the need ical compounds, and different sizes of particulate matter (PM) for isolation and culturing of their individual members has constitutes a universal hazard to those organisms exposed to it. revealed the great complexity of the human microbiome, as In fact, correlations of long-term exposures to air pollution well as the presence of rare or unculturable organisms that had and mortality have been addressed in several cohort-based previously escaped detection. Interestingly, these advances studies in different parts of the world [34, 35]. They have have not only led to the discovery of the importance and demonstrated the existence of an association between long- involvement in health and disease of the human microbiome, term exposure to fine PM and an increased risk of cardiovas- but also to surprising breakthroughs challenging long- cular and lung disease, as well as increased risk of lung cancer standing dogmas. In particular, until recently, it was believed [36]. It has also been suggested that air pollution is associated that in health, the placenta was an impenetrable barrier to to gastrointestinal disorders by being potentially involved in bacteria maintaining an in utero sterile environment in which the pathophysiology of inflammatory bowel disease [37]. the fetus developed. However, numerous recent analyses Air pollutants are inhaled into the lungs. The smaller parti- based on the amplification and high-throughput sequencing cles can reach the alveolar space where they can be phagocy- of bacterial 16S-rRNA genes have demonstrated the presence tosed by alveolar macrophages and consequently transported to of bacteria in the placenta [23–25], umbilical cord [26], am- the oropharynx and into the GIT [38]. In addition, air pollutants niotic fluid [24], and meconium [27–29]. Moreover, experi- can also enter the body through the oral cavity being directly mental work has confirmed an efflux of bacteria from the ingested with food and liquids in significant amounts. Mutlu mother’s gut to that of the fetus, as genetically labeled bacteria et al. (2011) demonstrated that exposure to PM increased the orally inoculated to pregnant mice are recovered from the production of mitochondrial reactive oxygen species (ROS) meconium of offspring obtained by C-section [27]. and the release of inflammatory cytokines among other effects, Following the latter, several hypotheses have been proposed increasing overall gut permeability [39]. Thelatterinturncan as to how bacteria can reach in health the in utero environ- potentially affect the dynamics of the gut microbiota, possibly ment, including entry into the mother’s bloodstream via trans- resulting in imbalances of this community. A recent study in location events from the mother’s GIT and the oral cavity [23, which mice were exposed to ambient PM (PM with a diam- 2.5 24, 30]. The important physiological changes occurring in the eter of 2.5 μm or less), during 8 h a day, showed that there were GIT during pregnancy and in particular during the third tri- significant changes in the mice GIT microbial diversity and mester entail an inflammatory state of the intestinal epitheli- composition. Interestingly, there was a significant increase of um, similar to that present in obesity and diabetes [31], which the family S24_7 (order Bacteroidales), whose members have could enhance translocation events of bacteria. In fact, in high host glycan degradation potential, likely being involved in mice, enhanced bacterial translocation from the gut has been the degradation of the mucus layer and therefore increasing GIT shown to take place both during late pregnancy [32] and at the permeability [39]. Also, the proportions of Firmicutes were 514 Curr Envir Health Rpt (2018) 5:512–521 Fig. 1 Air pollution, among many other factors, may alter the balance of the gut microbiota and contribute to altered immune, metabolic, and neurological development significantly depleted, which could be accounted for, among Although human studies are still lacking, the results obtain- other reasons, by the observed disappearance of the genus ed in animal models, together with the widespread occurrence Lactobacillus, traditionally considered as a beneficial commen- of air pollution in present day cities, raise the possibility that sal promoting GIT homeostasis [39]. This depletion of this environmental factor is contributing significantly to Firmicutes has been correlated in other studies to an inflamma- microbiome-related health issues. Beyond metals and partic- tory state of the GIT. ular matter, numerous toxic gases and other chemical com- In 2013,Kishetal. showed that mice exposedbyoralin- pounds that can be present in polluted air could also have gestion to PM from Ottawa’s urban environment, during a important effects on the gut microbiota, but, to date, their period of 7–14 days, presented an altered gut microbiota com- potential roles in contributing to gut dysbioses associated with position and function and exhibited an acute and chronic in- modern urban life have yet to be studied. The fact that air flammatory response in the intestine [40]. Exposure of mice to pollution is associated to increased permeability and inflam- heavy metals administered through drinking water, such as lead mation of the GIT [38] likely has an important impact on (10ppm for13weeks [41� ]or 100–500 ppm for 8 weeks [42]), pregnant women exposed to it, as it could exacerbate undesir- arsenic (10 or 250 ppm for periods of 2, 5, and 10 weeks [43]or able bacterial translocation events through the gut barrier, set- −1 −1 3mg L for 90 days [44]), and iron (5 mg L for 90 days ting the stage for an imbalance in the types of bacteria that [44]), whether independently or in a combination of arsenic and may reach the fetal gut and seed the infant’smicrobiota. iron [44], resulted in changes of the relative abundances of taxa when comparing controls to exposed groups, as well as changes in metabolic functions. For example, in those mice exposed to Immune Health: Atopic Disease arsenic and/or iron, an increased prevalence of antibiotic resis- tance genes was observed, implying a fitness advantage for those The microbiota of the gut develops in close interaction with bacteria that possess them and increasing the potential for path- immune development in a process that can shape the main de- ogens to acquire them as well through horizontal gene transfer. terminants of life-long propensity to immune disease. Innate Curr Envir Health Rpt (2018) 5:512–521 515 immunity is most developed in the intestinal tract, where both products, such as short-chain fatty acids, have also been asso- immune and epithelial cells encode a variety of receptors for ciated with food allergies [76, 77], confirming that the metabol- ligands of microbial origin [45, 46]. Engagement of these recep- ic output of the microbiota is relevant for atopy development. tors results in the production of cytokines that will direct the differentiation of the naïve T cells of the adaptive immune sys- tem. These cells can differentiate into regulatory cells (Tregs) or into helper cells, such as Th1, Th2, and Th17 [46, 47]. The Metabolic Disorders: Obesity activity of Tregs results in a variety of anti-inflammatory roles and suppresses the activation and development of other naïve T Obesity, or excessive body fat accumulation, is a complex cells towards Th types [47–49]. The different Th cells play spe- disease characterized by a low-grade systemic inflammatory cific roles in shaping the immune response [47, 50, 51]and tone that is influenced by genetic, environmental, and lifestyle produce cytokines that suppress other Th types [52, 53]. Thus, factors. Obesity has become in the past few decades one of the an aberrant microbial colonization can produce an imbalance major public health concerns worldwide, as its prevalence has among the different types of T cells, and the consequent immune increased at an alarming rate in adults and what is more deregulation can generate a variety of pathological outcomes, disturbing, in children, particularly in urban settings of low- ranging from atopy to autoimmune disease [9–11, 54–58]. and middle-income countries [78]. In fact, the World Health In support of this notion, it has long been known that a Organization (WHO) reported that the number of overweight reduced exposure to microbes increases the likelihood of dis- children under the age of 5 was estimated in 2013 to be over eases related to immune imbalances [11]. For instance, infants 42 million worldwide [78]. These facts are unsettling as that have higher numbers of siblings, that co-inhabit with overweight/obese children are likely to remain overweight/ household pets, that attend group day care at an earlier age, or obese when adults and are more prone to develop non- that live in farms have a much lower incidence of atopic dis- communicable diseases like diabetes and cardiovascular dis- ease, presumably mediated by their higher exposure to mi- orders at a younger age [78, 79]. crobes [4, 59–61]. Nowadays, a large number of studies have One of the main functions of the GIT microbiota is the been able to demonstrate associations between gut microbiota extraction of energy from otherwise indigestible dietary composition during infancy and early childhood and a variety polysaccharides, which can be used or stored in adipocytes of atopic diseases [9, 10, 45, 58, 62–68, 69]. In particular, a [80, 81]. In fact, Bäckhed et al. in 2004 were able to show deficiency in bifidobacteria has often been linked to increased that germ-free (GF) mice accumulated less fat than wild-type risks of atopy, although two large prospective studies could not mice and that introducing gut microbiota into the GF mice confirm such an association [68, 70]. Discrepancies may arise resulted in an increase of body fat accumulation despite a from the fact that different human populations will have distinct low-calorie intake diet [82]. genetic backgrounds and may carry different bacterial species The GIT’s microbiome in healthy individuals is character- and strains of Bifidobacterium. More recently, a large analysis ized by a highly diverse taxonomic composition where most of of the gut microbiota of children enrolled in the Canadian the organisms pertain to five major phyla: Firmicutes, Healthy Infant Longitudinal Development (CHILD) Study Bacteroidetes, Actinobacteria, Proteobacteria, and has shown that infants at risk of asthma had a lower abundance Fusobacteria [83]. While obesity has been linked in multiple of the Firmicutes genera Lachnospira, Veillonella, studies comparing lean and obese individuals with changes in Faecalibacterium,and Rothia, accompanied by decreased the abundance ratio between Firmicutes and Bacteroidetes, con- levels of fecal acetate and dysregulation of enterohepatic me- flicting results have been reported as well [80, 81, 84–86]. What tabolites. Importantly, the inoculation of germ-free mice with is well established is that obesity is related to a decrease in these four bacteria ameliorated airway inflammation, demon- microbial diversity in general and that this phenotype predis- strating their causal role in preventing asthma [69]. On the poses the individuals to further inflammation [87]. other hand, increased abundances of Clostridium and of the The prevalence of obesity among women in age of repro- enteric bacteria have also been associated with atopic disease duction worldwide has considerably increased in the past few [58, 62, 64–67, 71–75], as well as an overall decrease in the decades and with it the predisposition of their infants to also diversity of the infants’ GIT microbiota [62, 67]. Moreover, a develop obesity during childhood [88, 89]. The latter can be study of meconium samples from the INMA cohort has shown due to inheritance of obesity susceptibility genes and/or expo- that the association of low diversity and high levels of enteric sure to high-calorie diets but also, as noted above, to the pres- bacteria with atopic disease may be initiated by maternal factors ence of an aberrant GIT microbiota. Since initial colonization in utero [28]. In this work, these compositional patterns were of the infant’s GIT starts in utero and may involve bacteria already detected in the meconium of children who developed deriving from the mother’s GIT, we expect that the infant’s eczema by 4 years of age or whose mothers had a history of GIT will be influenced by the mother’s condition, presenting from birth an anomalous microbial community. eczema. Finally, the fecal levels of bacterial fermentation �� �� 516 Curr Envir Health Rpt (2018) 5:512–521 Multiple studies have addressed this question. Among them, continues after birth, being continuously influenced by cue Collado et al. (2010) looked at the GIT’s microbiota composi- signals from the environment. The latter can have, later on, a tion in infants at 1 and 6 months of age, finding that at 6 months, profound impact on brain and behavior development during there was a correlation between microbiota composition and the early childhood, in line with the “Barker’shypothesis” [6]. It obesity status of the mother [90]. In contrast, Laursen and col- is well accepted that normal development of the fetus brain leagues (2016) found no association between the mother’sbody while in utero requires a specific balance of cytokines in both mass index (BMI) and the infant’s gut microbiota [91]. the maternal and fetal environments [102]. Stanislawski et al. (2017) explored whether pre-pregnancy Remarkably, an association has been found between ASD overweight/obesity and gestational weight gain were associated and the prevalence of gastrointestinal disorders [103]. In ad- to different gut microbial communities at the time of delivery as dition, recent work has demonstrated that the composition and well as with the infants’ gut microbiotas. They found that al- diversity of the gut microbiome, which, as discussed above, though the maternal gut microbiota composition was associated plays a key role in the modulation of immune system re- to their overweight/obese and gestational weight gain status, sponses (i.e., cytokine and neurotransmitter secretion), are there was only a weak association to their infants’ gut microbi- significantly associated with cognition and neurological dis- ota composition [92]. Yet, Cerdó et al. (2018) found that the orders such as ASD in human infants and children [20, mother’s pre-pregnancy BMI status was actually associated to 104–106]. In fact, epidemiological studies and experimental the functional profile of the infant’s microbial community, sug- work with mice have revealed a direct link between microbial gesting a possible role of maternal imprinting in the selection of pathogen infections during the prenatal phase and post-natal gut microbial communities with specific functional potentials development of autism and behavioral abnormalities, respec- [16]. In spite of the inconclusive results observed in the latter tively [7, 107]. Moreover, Diaz Heijtz et al. (2011) found that studies, it is important to remember that the initial stages of an GF mice displayed higher motor activity and less anxiety infant’s gut microbiota establishment are hectic and dramatic when compared to mice with a normal gut microbiota (SPF) changes can occur in short lapses of time, thus complicating the and showed that GF mice inoculated early on with SPF mi- possibility of finding reliable associations [93]. Moreover, crobiota displayed motor abilities and anxiety levels similar to many additional variables can confound association analyses normal SPF mice. Although only males were used in this due to their effects on the infant’s microbiota composition, such study, the integration of measurements of motor activity, as the mode of birth, milk supply (breastfeeding versus formu- anxiety-like behavior, neurochemical analysis, and gene ex- la), solid food introduction, exposure to antibiotics (strength, pression, among others, strengthens the results observed, duration, and number of doses), and exposure to the surround- linking the GIT microbiota to the gut-brain axis [107]. ing environment [15, 93–95, 96� , 97, 98]. Furthermore, based on the fact that epidemiological studies have demonstrated the association between maternal infection On the other hand, the relevance of early life gut microbiota for the development of obesity has been clearly demonstrated. and increased autism risk in the offspring, Hsiao et al. (2013) Several analyses have shown that infants with a higher abun- showed that injecting pregnant mice of the Maternal Immune dance of Bifidobacterium during the first year of life have lower Activation (MIA) model with the viral mimic polyinosinic/ adiposity levels, BMI, and obesity risk at later ages, ranging polycytidylic acid (poly(I/C)), a synthetic double-stranded im- from 18 months to 7 years [96� , 99, 100]. These studies dem- mune-stimulant, resulted in offspring exhibiting characteristic onstrate that dysbiosis of the GIT’s microbiota does precede the symptoms of ASD (i.e., communicative and social onset of obesity. Interestingly, one of these studies revealed that impairments) and defects of intestinal barrier integrity [108]. the influence exerted by the abundance of Bifidobacterium and In addition, MIA offspring presented a similar microbial other taxa on BMI appeared to be especially strong among composition to that observed in humans affected by ASD children with a history of antibiotic use [99]. which was significantly different from offspring controls, with differences driven mostly by changes in the diversity of members of the Clostridia and Bacteroidia classes. More Neurological Disorders: Autism importantly, treatment of the MIA offspring with inoculations of Bacteroides fragilis corrected intestinal barrier integrity and Autism spectrum disorders (ASD) are an array of attenuated the abnormal communicative and social behaviors neurodevelopmental disorders characterized mainly by defi- observed [108]. These findings and the fact that ASD shares ciencies in social behavior and communication skills, the many symptoms with many other neuropathophysiological prevalence of which has dramatically risen in the past few disorders are encouraging as they show the potential of decades [101]. Initially believed to be a consequence only of developing therapies by modulation of the gut microbiome as a environmental exposures, there is now enough evidence that a safe and effective way of treatment. strong neurodevelopmental component is also at play [101]. More recently, Kang et al. (2017) demonstrated that microbi- ota transfer therapy (MTT) with a standardized human gut Brain development in mammals starts early in utero and Curr Envir Health Rpt (2018) 5:512–521 517 microbiota, after 14 days of vancomycin treatment followed by adolescence, and the subsequent health effects, have received to 12–24-h fasting with bowel cleansing, was able to alter the gut date little attention. On the other hand, microbiotas other than microbiome and virome of children with ASD and to improve the one present in the gut have been comparatively neglected in GIT and behavioral symptoms, whether administered orally or terms of understanding their development and the potential ef- rectally [109 ]. More importantly, the improvements lasted for fects of early life alterations on later health and should be further 8 weeks after the end of treatment, suggesting a long-term im- investigated in this respect. Ideally, the establishment of lasting pact, and indicating that MTT could be a promising approach to longitudinal birth cohorts should be promoted, so that the eval- treat ASD. Despite these promising results, it is important to take uation of microbiome-related outcomes can be extended into into account that the number of participants included in the study adulthood. Such long-term projects should aim at gathering a was low and that patients were not necessarily homogeneous in wide scope of medical and environmental metadata, as well as the GI symptoms that they presented. In addition, the use of samples enabling the study of bacterial communities in a variety placebo controls would have strengthened the results obtained. of body sites, including, beyond the GIT, the oral cavity, respi- Environmental factors like air pollution might trigger or ratory system, skin, and urogenital tract. In particular, it is clear exacerbate ASD by impacting the gut microbiota, which in that environmental factors such as air pollution and exposure to dysbiosis potentially leads to an increased gut barrier perme- chemical contaminants present in food and water have received ability, increasing in turn bacterial translocation events and little attention in spite of their strong potential to impinge on potential leakage of other pathogens and compounds (antigens microbiome development and associated health outcomes. and bacterial metabolites) that can induce inflammatory re- On the positive side, the same malleability that renders early sponses and indirectly impinge on brain functions. microbiome development susceptible to negative alterations should make it responsive to strategic interventions aimed at modulating the microbiome to promote health. Research on early Conclusions microbiome development and on the effects of present day life conditions on this critical process will enable novel approaches in In the upcoming years, further efforts should focus on delineating public health, nutrition, and medicine that ensure the establish- the variety of long-term health outcomes that can result from or ment of a health-promoting microbiota. Such approaches will be aggravated by an unbalanced microbiota development. likely include the development of preventive or therapeutic treat- Because we now know that there are fetal microbial GIT com- ments based on the early administration of beneficial bacteria and munities, further research should better define how and when of nutritional supplements capable of promoting their growth. such communities are formed and to which extent they are capa- ble of influencing human development and disease risk during Compliance with Ethical Standards gestation. In this respect, it is also crucial to invest research efforts Conflict of Interest The authors declare that they have no conflicts of in understanding the health and environmental factors that shape interest. the maternal microbiome during pregnancy and how these affect the types of bacteria that reach the fetus. Regarding timing and Human and Animal Rights and Informed Consent This is a review mode of birth, although it is well established that these factors article and does not report any unpublished work with human or animal have a strong effect on early microbiome development, much subjects performed by any of the authors. research remains to be done in order to elucidate the specific Open Access This article is distributed under the terms of the Creative mechanisms through which these early events impinge on the Commons Attribution 4.0 International License (http:// establishment of microbiome-host interactions, at the immune, creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appro- metabolic, and neurodevelopmental level. Further, it will also be priate credit to the original author(s) and the source, provide a link to the necessary to delineate the post-natal time window during which Creative Commons license, and indicate if changes were made. the main traits of such microbiome-host interactions are defined, as this will be the critical period in which any preventative or therapeutic interventions aimed at modulating the microbiome References should be most effective. In addition, it will be important to investigate whether this time window is altered by the many Papers of particular interest, published recently, have been variables that affect the course and pace of microbiome develop- highlighted as: ment during the first months of life, such as type of milk feeding, � Of importance solid food introduction, exposure to antibiotics, and the many �� Of major importance environmental and lifestyle factors that shape infant exposure to microbes [15, 93–98]. 1. Eaton SB, Konner M. Paleolithic nutrition. 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Infant gut microbiome associated with cognitive http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Current Environmental Health Reports Springer Journals

Air Pollution, Early Life Microbiome, and Development

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Springer Journals
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Copyright © 2018 by The Author(s)
Subject
Biomedicine; Pharmacology/Toxicology; Medicine/Public Health, general; Environmental Health
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2196-5412
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10.1007/s40572-018-0215-y
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Abstract

Purpose of Review We review how an altered microbiome in early life impacts on immune, metabolic, and neurological development, focusing on some of the most widespread diseases related to each of these processes, namely atopic disease, obesity, and autism. Recent Findings The early development of the microbial communities that inhabit the human body is currently challenged by factors that range from reduced exposure to microbes, antibiotic use, and poor dietary choices to widespread environmental pollution. Recent work has highlighted some of the long-term consequences that early alterations in the establishment of these microbiotas can have for different aspects of human development and health. Summary The long-term consequences of early microbiome alterations for human development and health are only beginning to be understood and will require in-depth investigation in the years to come. A solid understanding of how present day environ- mental conditions alter microbiome development, and of how an altered microbiome in early life impacts on life-long health, should inform both public health policies and the development of dietary and medical strategies to counteract early microbiota imbalances. . . . . . Keywords Gut microbiome Infant development Early programming Immune disease Obesity Autism spectrum disorder Introduction industrial revolution, the discovery of antibiotics, the creation of agri-business, and recently the elaboration and massive dis- Human evolution has been punctuated by precise moments tribution of processed foods [1]. These changes appear to have throughout history associated to key changes in lifestyle: the had a profound effect on the evolution of human health and appearance of Homo sapiens sapiens, the shift from nomadic to disease. In the last century, such effects have likely included sedentary lifestyles with the introduction of agriculture, the the emergence and increased prevalence of allergies, asthma, and autoimmune diseases, with a concomitant decrease in the incidence of infectious diseases [2]. In fact, Strachan in 1989 proposed the “hygiene hypothesis”, which stated that lack of exposure to microbes during early infancy was at the source of This article is part of the Topical Collection on Early Life Environmental the observed increased prevalence of allergy and asthma in Health westernized populations [3, 4]. Later on, the “Barker Hypothesis” (also called “Developmental Origins of Health * M. Pilar Francino and Disease (DOHaD)”) postulated that exposure to environ- francino_pil@gva.es mental factors during both fetus development and immediately Department of Biological and Chemical Sciences, The University of after birth or nutritional deficiencies of the mother during ges- the West Indies, Cave Hill campus, Cave Hill, Barbados tation would result in an early programming for developing Unitat Mixta d’Investigació en Genòmica i Salut, Fundació per al cardiovascular, neurodevelopmental, and metabolic disorders Foment de la Investigació Sanitària i Biomèdica de la Comunitat [5–8]. The latter hypotheses emphasize the notion that infancy Valenciana (FISABIO-Salut Pública)/Institut de Biologia Integrativa is likely to be a critical stage in human development in which de Sistemes (Universitat de València), Avda. Catalunya 21, 46020 València, Spain interventions could potentially prevent or decrease risk factors of latent disorders. Interestingly, there is growing evidence that CIBER en Epidemiología y Salud Pública (CIBERESP), Madrid, Spain early microbiome-host interactions during fetus development Curr Envir Health Rpt (2018) 5:512–521 513 and early infancy are critical factors that will determine life- early onset of type 2 diabetes [33], and, in the latter case, the long health or disease states [9–11]. However, although it is dendritic cells of the immune system have been implicated in clear that the first months of life represent a crucial time win- mediating the increased translocation level. The proposition dow in the establishment of microbiome-host interactions, the that maternal bacteria reach the fetal gut is ground breaking, as precise boundaries of this window and the impact of microbial these organisms could start marking the trajectories of im- changes during later periods of infancy and childhood on life- mune, metabolic, and somatic development in utero, with long disease risks remain to be determined. enormous implications for the health of the individual [29]. Complex endeavors such as those undertaken by the Here, we review several aspects of human development and Human Microbiome Project and the MetaHit Consortium health that are known to be affected by the gut microbiome in have been key in highlighting the significance and complexity early life, as well as the emergent evidence for air pollution as a of the microbiota inhabiting the niches provided by the human hitherto rarely considered environmental factor that likely contrib- body. It is now well accepted that the human’s gastrointestinal utes to altering the establishment of the gut microbiome (Fig. 1). tract (GIT) gathers the most diverse and dense microbiota of the human body, which in turn plays fundamental roles in gut homeostasis [12, 13]. Supporting the hygiene and Barker hy- Air Pollution: an Environmental Factor potheses, there is now a great body of knowledge establishing Recently Associated to Microbiome Dysbiosis that GIT microbiota composition during infancy and child- hood are associated to an incredible array of human diseases, Air pollution is the presence of harmful substances in the air from GIT-related diseases (i.e., metabolic disorders such as that can result from natural causes (i.e., volcano eruptions, diabetes and obesity, inflammatory bowel disease), to immune wind dust) and human activities (i.e., combustion of fuels, diseases and neurological disorders [14–22]. industry, traffic, cooking, smoking). The presence in polluted The advent of sequencing technologies that enable the deep air of larger proportions of CO ,SO , other toxic gases, chem- 2 2 characterization of microbial communities without the need ical compounds, and different sizes of particulate matter (PM) for isolation and culturing of their individual members has constitutes a universal hazard to those organisms exposed to it. revealed the great complexity of the human microbiome, as In fact, correlations of long-term exposures to air pollution well as the presence of rare or unculturable organisms that had and mortality have been addressed in several cohort-based previously escaped detection. Interestingly, these advances studies in different parts of the world [34, 35]. They have have not only led to the discovery of the importance and demonstrated the existence of an association between long- involvement in health and disease of the human microbiome, term exposure to fine PM and an increased risk of cardiovas- but also to surprising breakthroughs challenging long- cular and lung disease, as well as increased risk of lung cancer standing dogmas. In particular, until recently, it was believed [36]. It has also been suggested that air pollution is associated that in health, the placenta was an impenetrable barrier to to gastrointestinal disorders by being potentially involved in bacteria maintaining an in utero sterile environment in which the pathophysiology of inflammatory bowel disease [37]. the fetus developed. However, numerous recent analyses Air pollutants are inhaled into the lungs. The smaller parti- based on the amplification and high-throughput sequencing cles can reach the alveolar space where they can be phagocy- of bacterial 16S-rRNA genes have demonstrated the presence tosed by alveolar macrophages and consequently transported to of bacteria in the placenta [23–25], umbilical cord [26], am- the oropharynx and into the GIT [38]. In addition, air pollutants niotic fluid [24], and meconium [27–29]. Moreover, experi- can also enter the body through the oral cavity being directly mental work has confirmed an efflux of bacteria from the ingested with food and liquids in significant amounts. Mutlu mother’s gut to that of the fetus, as genetically labeled bacteria et al. (2011) demonstrated that exposure to PM increased the orally inoculated to pregnant mice are recovered from the production of mitochondrial reactive oxygen species (ROS) meconium of offspring obtained by C-section [27]. and the release of inflammatory cytokines among other effects, Following the latter, several hypotheses have been proposed increasing overall gut permeability [39]. Thelatterinturncan as to how bacteria can reach in health the in utero environ- potentially affect the dynamics of the gut microbiota, possibly ment, including entry into the mother’s bloodstream via trans- resulting in imbalances of this community. A recent study in location events from the mother’s GIT and the oral cavity [23, which mice were exposed to ambient PM (PM with a diam- 2.5 24, 30]. The important physiological changes occurring in the eter of 2.5 μm or less), during 8 h a day, showed that there were GIT during pregnancy and in particular during the third tri- significant changes in the mice GIT microbial diversity and mester entail an inflammatory state of the intestinal epitheli- composition. Interestingly, there was a significant increase of um, similar to that present in obesity and diabetes [31], which the family S24_7 (order Bacteroidales), whose members have could enhance translocation events of bacteria. In fact, in high host glycan degradation potential, likely being involved in mice, enhanced bacterial translocation from the gut has been the degradation of the mucus layer and therefore increasing GIT shown to take place both during late pregnancy [32] and at the permeability [39]. Also, the proportions of Firmicutes were 514 Curr Envir Health Rpt (2018) 5:512–521 Fig. 1 Air pollution, among many other factors, may alter the balance of the gut microbiota and contribute to altered immune, metabolic, and neurological development significantly depleted, which could be accounted for, among Although human studies are still lacking, the results obtain- other reasons, by the observed disappearance of the genus ed in animal models, together with the widespread occurrence Lactobacillus, traditionally considered as a beneficial commen- of air pollution in present day cities, raise the possibility that sal promoting GIT homeostasis [39]. This depletion of this environmental factor is contributing significantly to Firmicutes has been correlated in other studies to an inflamma- microbiome-related health issues. Beyond metals and partic- tory state of the GIT. ular matter, numerous toxic gases and other chemical com- In 2013,Kishetal. showed that mice exposedbyoralin- pounds that can be present in polluted air could also have gestion to PM from Ottawa’s urban environment, during a important effects on the gut microbiota, but, to date, their period of 7–14 days, presented an altered gut microbiota com- potential roles in contributing to gut dysbioses associated with position and function and exhibited an acute and chronic in- modern urban life have yet to be studied. The fact that air flammatory response in the intestine [40]. Exposure of mice to pollution is associated to increased permeability and inflam- heavy metals administered through drinking water, such as lead mation of the GIT [38] likely has an important impact on (10ppm for13weeks [41� ]or 100–500 ppm for 8 weeks [42]), pregnant women exposed to it, as it could exacerbate undesir- arsenic (10 or 250 ppm for periods of 2, 5, and 10 weeks [43]or able bacterial translocation events through the gut barrier, set- −1 −1 3mg L for 90 days [44]), and iron (5 mg L for 90 days ting the stage for an imbalance in the types of bacteria that [44]), whether independently or in a combination of arsenic and may reach the fetal gut and seed the infant’smicrobiota. iron [44], resulted in changes of the relative abundances of taxa when comparing controls to exposed groups, as well as changes in metabolic functions. For example, in those mice exposed to Immune Health: Atopic Disease arsenic and/or iron, an increased prevalence of antibiotic resis- tance genes was observed, implying a fitness advantage for those The microbiota of the gut develops in close interaction with bacteria that possess them and increasing the potential for path- immune development in a process that can shape the main de- ogens to acquire them as well through horizontal gene transfer. terminants of life-long propensity to immune disease. Innate Curr Envir Health Rpt (2018) 5:512–521 515 immunity is most developed in the intestinal tract, where both products, such as short-chain fatty acids, have also been asso- immune and epithelial cells encode a variety of receptors for ciated with food allergies [76, 77], confirming that the metabol- ligands of microbial origin [45, 46]. Engagement of these recep- ic output of the microbiota is relevant for atopy development. tors results in the production of cytokines that will direct the differentiation of the naïve T cells of the adaptive immune sys- tem. These cells can differentiate into regulatory cells (Tregs) or into helper cells, such as Th1, Th2, and Th17 [46, 47]. The Metabolic Disorders: Obesity activity of Tregs results in a variety of anti-inflammatory roles and suppresses the activation and development of other naïve T Obesity, or excessive body fat accumulation, is a complex cells towards Th types [47–49]. The different Th cells play spe- disease characterized by a low-grade systemic inflammatory cific roles in shaping the immune response [47, 50, 51]and tone that is influenced by genetic, environmental, and lifestyle produce cytokines that suppress other Th types [52, 53]. Thus, factors. Obesity has become in the past few decades one of the an aberrant microbial colonization can produce an imbalance major public health concerns worldwide, as its prevalence has among the different types of T cells, and the consequent immune increased at an alarming rate in adults and what is more deregulation can generate a variety of pathological outcomes, disturbing, in children, particularly in urban settings of low- ranging from atopy to autoimmune disease [9–11, 54–58]. and middle-income countries [78]. In fact, the World Health In support of this notion, it has long been known that a Organization (WHO) reported that the number of overweight reduced exposure to microbes increases the likelihood of dis- children under the age of 5 was estimated in 2013 to be over eases related to immune imbalances [11]. For instance, infants 42 million worldwide [78]. These facts are unsettling as that have higher numbers of siblings, that co-inhabit with overweight/obese children are likely to remain overweight/ household pets, that attend group day care at an earlier age, or obese when adults and are more prone to develop non- that live in farms have a much lower incidence of atopic dis- communicable diseases like diabetes and cardiovascular dis- ease, presumably mediated by their higher exposure to mi- orders at a younger age [78, 79]. crobes [4, 59–61]. Nowadays, a large number of studies have One of the main functions of the GIT microbiota is the been able to demonstrate associations between gut microbiota extraction of energy from otherwise indigestible dietary composition during infancy and early childhood and a variety polysaccharides, which can be used or stored in adipocytes of atopic diseases [9, 10, 45, 58, 62–68, 69]. In particular, a [80, 81]. In fact, Bäckhed et al. in 2004 were able to show deficiency in bifidobacteria has often been linked to increased that germ-free (GF) mice accumulated less fat than wild-type risks of atopy, although two large prospective studies could not mice and that introducing gut microbiota into the GF mice confirm such an association [68, 70]. Discrepancies may arise resulted in an increase of body fat accumulation despite a from the fact that different human populations will have distinct low-calorie intake diet [82]. genetic backgrounds and may carry different bacterial species The GIT’s microbiome in healthy individuals is character- and strains of Bifidobacterium. More recently, a large analysis ized by a highly diverse taxonomic composition where most of of the gut microbiota of children enrolled in the Canadian the organisms pertain to five major phyla: Firmicutes, Healthy Infant Longitudinal Development (CHILD) Study Bacteroidetes, Actinobacteria, Proteobacteria, and has shown that infants at risk of asthma had a lower abundance Fusobacteria [83]. While obesity has been linked in multiple of the Firmicutes genera Lachnospira, Veillonella, studies comparing lean and obese individuals with changes in Faecalibacterium,and Rothia, accompanied by decreased the abundance ratio between Firmicutes and Bacteroidetes, con- levels of fecal acetate and dysregulation of enterohepatic me- flicting results have been reported as well [80, 81, 84–86]. What tabolites. Importantly, the inoculation of germ-free mice with is well established is that obesity is related to a decrease in these four bacteria ameliorated airway inflammation, demon- microbial diversity in general and that this phenotype predis- strating their causal role in preventing asthma [69]. On the poses the individuals to further inflammation [87]. other hand, increased abundances of Clostridium and of the The prevalence of obesity among women in age of repro- enteric bacteria have also been associated with atopic disease duction worldwide has considerably increased in the past few [58, 62, 64–67, 71–75], as well as an overall decrease in the decades and with it the predisposition of their infants to also diversity of the infants’ GIT microbiota [62, 67]. Moreover, a develop obesity during childhood [88, 89]. The latter can be study of meconium samples from the INMA cohort has shown due to inheritance of obesity susceptibility genes and/or expo- that the association of low diversity and high levels of enteric sure to high-calorie diets but also, as noted above, to the pres- bacteria with atopic disease may be initiated by maternal factors ence of an aberrant GIT microbiota. Since initial colonization in utero [28]. In this work, these compositional patterns were of the infant’s GIT starts in utero and may involve bacteria already detected in the meconium of children who developed deriving from the mother’s GIT, we expect that the infant’s eczema by 4 years of age or whose mothers had a history of GIT will be influenced by the mother’s condition, presenting from birth an anomalous microbial community. eczema. Finally, the fecal levels of bacterial fermentation �� �� 516 Curr Envir Health Rpt (2018) 5:512–521 Multiple studies have addressed this question. Among them, continues after birth, being continuously influenced by cue Collado et al. (2010) looked at the GIT’s microbiota composi- signals from the environment. The latter can have, later on, a tion in infants at 1 and 6 months of age, finding that at 6 months, profound impact on brain and behavior development during there was a correlation between microbiota composition and the early childhood, in line with the “Barker’shypothesis” [6]. It obesity status of the mother [90]. In contrast, Laursen and col- is well accepted that normal development of the fetus brain leagues (2016) found no association between the mother’sbody while in utero requires a specific balance of cytokines in both mass index (BMI) and the infant’s gut microbiota [91]. the maternal and fetal environments [102]. Stanislawski et al. (2017) explored whether pre-pregnancy Remarkably, an association has been found between ASD overweight/obesity and gestational weight gain were associated and the prevalence of gastrointestinal disorders [103]. In ad- to different gut microbial communities at the time of delivery as dition, recent work has demonstrated that the composition and well as with the infants’ gut microbiotas. They found that al- diversity of the gut microbiome, which, as discussed above, though the maternal gut microbiota composition was associated plays a key role in the modulation of immune system re- to their overweight/obese and gestational weight gain status, sponses (i.e., cytokine and neurotransmitter secretion), are there was only a weak association to their infants’ gut microbi- significantly associated with cognition and neurological dis- ota composition [92]. Yet, Cerdó et al. (2018) found that the orders such as ASD in human infants and children [20, mother’s pre-pregnancy BMI status was actually associated to 104–106]. In fact, epidemiological studies and experimental the functional profile of the infant’s microbial community, sug- work with mice have revealed a direct link between microbial gesting a possible role of maternal imprinting in the selection of pathogen infections during the prenatal phase and post-natal gut microbial communities with specific functional potentials development of autism and behavioral abnormalities, respec- [16]. In spite of the inconclusive results observed in the latter tively [7, 107]. Moreover, Diaz Heijtz et al. (2011) found that studies, it is important to remember that the initial stages of an GF mice displayed higher motor activity and less anxiety infant’s gut microbiota establishment are hectic and dramatic when compared to mice with a normal gut microbiota (SPF) changes can occur in short lapses of time, thus complicating the and showed that GF mice inoculated early on with SPF mi- possibility of finding reliable associations [93]. Moreover, crobiota displayed motor abilities and anxiety levels similar to many additional variables can confound association analyses normal SPF mice. Although only males were used in this due to their effects on the infant’s microbiota composition, such study, the integration of measurements of motor activity, as the mode of birth, milk supply (breastfeeding versus formu- anxiety-like behavior, neurochemical analysis, and gene ex- la), solid food introduction, exposure to antibiotics (strength, pression, among others, strengthens the results observed, duration, and number of doses), and exposure to the surround- linking the GIT microbiota to the gut-brain axis [107]. ing environment [15, 93–95, 96� , 97, 98]. Furthermore, based on the fact that epidemiological studies have demonstrated the association between maternal infection On the other hand, the relevance of early life gut microbiota for the development of obesity has been clearly demonstrated. and increased autism risk in the offspring, Hsiao et al. (2013) Several analyses have shown that infants with a higher abun- showed that injecting pregnant mice of the Maternal Immune dance of Bifidobacterium during the first year of life have lower Activation (MIA) model with the viral mimic polyinosinic/ adiposity levels, BMI, and obesity risk at later ages, ranging polycytidylic acid (poly(I/C)), a synthetic double-stranded im- from 18 months to 7 years [96� , 99, 100]. These studies dem- mune-stimulant, resulted in offspring exhibiting characteristic onstrate that dysbiosis of the GIT’s microbiota does precede the symptoms of ASD (i.e., communicative and social onset of obesity. Interestingly, one of these studies revealed that impairments) and defects of intestinal barrier integrity [108]. the influence exerted by the abundance of Bifidobacterium and In addition, MIA offspring presented a similar microbial other taxa on BMI appeared to be especially strong among composition to that observed in humans affected by ASD children with a history of antibiotic use [99]. which was significantly different from offspring controls, with differences driven mostly by changes in the diversity of members of the Clostridia and Bacteroidia classes. More Neurological Disorders: Autism importantly, treatment of the MIA offspring with inoculations of Bacteroides fragilis corrected intestinal barrier integrity and Autism spectrum disorders (ASD) are an array of attenuated the abnormal communicative and social behaviors neurodevelopmental disorders characterized mainly by defi- observed [108]. These findings and the fact that ASD shares ciencies in social behavior and communication skills, the many symptoms with many other neuropathophysiological prevalence of which has dramatically risen in the past few disorders are encouraging as they show the potential of decades [101]. Initially believed to be a consequence only of developing therapies by modulation of the gut microbiome as a environmental exposures, there is now enough evidence that a safe and effective way of treatment. strong neurodevelopmental component is also at play [101]. More recently, Kang et al. (2017) demonstrated that microbi- ota transfer therapy (MTT) with a standardized human gut Brain development in mammals starts early in utero and Curr Envir Health Rpt (2018) 5:512–521 517 microbiota, after 14 days of vancomycin treatment followed by adolescence, and the subsequent health effects, have received to 12–24-h fasting with bowel cleansing, was able to alter the gut date little attention. On the other hand, microbiotas other than microbiome and virome of children with ASD and to improve the one present in the gut have been comparatively neglected in GIT and behavioral symptoms, whether administered orally or terms of understanding their development and the potential ef- rectally [109 ]. More importantly, the improvements lasted for fects of early life alterations on later health and should be further 8 weeks after the end of treatment, suggesting a long-term im- investigated in this respect. Ideally, the establishment of lasting pact, and indicating that MTT could be a promising approach to longitudinal birth cohorts should be promoted, so that the eval- treat ASD. Despite these promising results, it is important to take uation of microbiome-related outcomes can be extended into into account that the number of participants included in the study adulthood. Such long-term projects should aim at gathering a was low and that patients were not necessarily homogeneous in wide scope of medical and environmental metadata, as well as the GI symptoms that they presented. In addition, the use of samples enabling the study of bacterial communities in a variety placebo controls would have strengthened the results obtained. of body sites, including, beyond the GIT, the oral cavity, respi- Environmental factors like air pollution might trigger or ratory system, skin, and urogenital tract. In particular, it is clear exacerbate ASD by impacting the gut microbiota, which in that environmental factors such as air pollution and exposure to dysbiosis potentially leads to an increased gut barrier perme- chemical contaminants present in food and water have received ability, increasing in turn bacterial translocation events and little attention in spite of their strong potential to impinge on potential leakage of other pathogens and compounds (antigens microbiome development and associated health outcomes. and bacterial metabolites) that can induce inflammatory re- On the positive side, the same malleability that renders early sponses and indirectly impinge on brain functions. microbiome development susceptible to negative alterations should make it responsive to strategic interventions aimed at modulating the microbiome to promote health. Research on early Conclusions microbiome development and on the effects of present day life conditions on this critical process will enable novel approaches in In the upcoming years, further efforts should focus on delineating public health, nutrition, and medicine that ensure the establish- the variety of long-term health outcomes that can result from or ment of a health-promoting microbiota. Such approaches will be aggravated by an unbalanced microbiota development. likely include the development of preventive or therapeutic treat- Because we now know that there are fetal microbial GIT com- ments based on the early administration of beneficial bacteria and munities, further research should better define how and when of nutritional supplements capable of promoting their growth. such communities are formed and to which extent they are capa- ble of influencing human development and disease risk during Compliance with Ethical Standards gestation. In this respect, it is also crucial to invest research efforts Conflict of Interest The authors declare that they have no conflicts of in understanding the health and environmental factors that shape interest. the maternal microbiome during pregnancy and how these affect the types of bacteria that reach the fetus. Regarding timing and Human and Animal Rights and Informed Consent This is a review mode of birth, although it is well established that these factors article and does not report any unpublished work with human or animal have a strong effect on early microbiome development, much subjects performed by any of the authors. research remains to be done in order to elucidate the specific Open Access This article is distributed under the terms of the Creative mechanisms through which these early events impinge on the Commons Attribution 4.0 International License (http:// establishment of microbiome-host interactions, at the immune, creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appro- metabolic, and neurodevelopmental level. Further, it will also be priate credit to the original author(s) and the source, provide a link to the necessary to delineate the post-natal time window during which Creative Commons license, and indicate if changes were made. the main traits of such microbiome-host interactions are defined, as this will be the critical period in which any preventative or therapeutic interventions aimed at modulating the microbiome References should be most effective. In addition, it will be important to investigate whether this time window is altered by the many Papers of particular interest, published recently, have been variables that affect the course and pace of microbiome develop- highlighted as: ment during the first months of life, such as type of milk feeding, � Of importance solid food introduction, exposure to antibiotics, and the many �� Of major importance environmental and lifestyle factors that shape infant exposure to microbes [15, 93–98]. 1. Eaton SB, Konner M. Paleolithic nutrition. 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