The Bacterial Microbiome and Virome Milestones of Infant Development
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Review The Bacterial Microbiome and Virome Milestones of Infant Development 1 1 2, Efrem S. Lim, David Wang, and Lori R. Holtz * The human gut harbors a complex community of bacteria, viruses, fungi, Trends protists, and other microorganisms (collectively termed the microbiome) that The gut bacterial microbiome and vir- impact health and disease. Emerging studies indicate that the gut bacterial ome affect healthy infant development. microbiome and virome play an important role in healthy infant development. In In contrast to the adult's gut bacterial turn, the composition of the microbiome during development can be influenced microbiome and virome, those in the by factors such as dietary, environmental, and maternal conditions. As such, the infant are dynamic. microbiome trajectory during early infancy could be predictors of healthy devel- Transkingdom interactions between opment. Conversely, adverse early events in life may have consequences later in viruses and bacteria influence the life. This review focuses on our understanding of the bacterial microbiome and health and disease of the host. virome during early development, conditions that might influence these pro- Infant gut bacterial colonization is cor- cesses, and their long-term implications for infant health. related with a contraction in the bacter- iophage community. Microbial Communities of the Infant Gut While microbes are historically viewed as potential pathogens, we now appreciate their beneficial role in health, immune function, and metabolism. The gut harbors the highest density microbial community within the human body. This gut microbiome (see Glossary) encompasses the diverse community of eukaryotic viruses and bacteriophages (virome), bacteria (bacterial microbiome), and other microorganisms. An emerging concept from recent studies is that these microbial communities are important for healthy infant develop- ment. The developmental trajectory includes milestones such as the choreographed coloni- zation of bacterial populations, dynamic alterations in the virome, and transkingdom interactions between members of the two communities. Alterations in the bacterial micro- biome and virome early in life are significant because they could set the stage for the infant's future health and disease risk. Thus, early infancy may present a unique opportunity to leverage the bacterial microbiome and virome to intervene and influence immune develop- ment and disease outcomes. 1 The aim of this review is to summarize current understanding of the early development of the Departments of Molecular human gut bacterial microbiome and virome in terms of the dynamic nature of this progression Microbiology and Pathology and Immunology, Washington University and the factors that influence its trajectory. We discuss the potential interactions between School of Medicine, St Louis, MO, members of these two kingdoms and how perturbations of the infant gut bacterial microbiome USA 2 and virome may set the stage for disease later in life. Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Washington University Development of the Gut Bacterial Microbiome School of Medicine, St Louis, MO, Multiple factors influence the composition of the bacterial microbiome (Figure 1, Key Figure). USA Many variables early in life, including mode of delivery, infant diet, use of antibiotics, the physical environment surrounding the infant, host genetics, and perhaps even the in utero environment, *Correspondence: fl in uence this complex process. [email protected] (L.R. Holtz). Trends in Microbiology, October 2016, Vol. 24, No. 10 http://dx.doi.org/10.1016/j.tim.2016.06.001 801 © 2016 Elsevier Ltd. All rights reserved. Womb Exposure Glossary Traditionally the womb has been considered a sterile sanctuary for the developing fetus. Bacterial microbiome: community However, recently this dogma has been questioned by numerous observations, raising the of bacteria that share an ecological space. possibility that the infant gut is colonized before birth. Specifically, bacteria have been detected in Microbiome: community of full-term placentas using culture-based methods [1] and they have been visualized in the microorganisms, including bacteria, placental basal plate from healthy pregnancies [2]. Bacterial sequences have been detected viruses, fungi, protists, and other in the placenta [3], amniotic fluid [4], cord blood [5], and meconium [6]. Aagaard et al. found that microorganisms, within an ecological space. the placental bacterial microbiome resembled the oral bacterial microbiome [3]. Interestingly, the Virome: community of eukaryotic connection between these two microbial communities has also been seen in murine systems. viruses and bacteriophages that Tail vein injection of Fusobacterium, an oral anaerobe, localizes to the placenta, but does not share an ecological space. colonize other organs [7]. It is unclear from where the bacteria that comprise the pIacental microbiome originate. One hypothesis suggests that the bacteria are spread hematogenously either from the oral cavity or the gut to the placenta. In support of this model, labeled Enterococcus fed to pregnant mice can be detected in the meconium of the pup [6]. It has been noted that bacterial translocation from the gut to the blood is higher in pregnant mice than in nonpregnant mice [8], which may permit seeding of the placenta. Alternatively, it has been suggested that the nonpregnant uterus is colonized with microbes in the endometrial epithelium as bacteria have been cultured from the endometrium and these could be the source of the placental bacterial microbiome [9]. Bacteria have been isolated from the amniotic fluid of mothers with chorioamnionitis. Commonly recovered bacteria include Ureaplasma, Mycoplasma, Fusobacterium, Streptococcus, Bacter- oides, and Prevotella. Broad-range PCR assays have demonstrated the presence of Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, and fusobacteria DNA in amniotic fluid [4]. The relative abundances of specific bacterial taxa in amniotic fluid differs between preterm labor with Key Figure Influences on the Gut Microbiome during Infant Development Influences on microbiome during infant development Mode of Gestaonal Diet Womb delivery age Genecs Environment Anbiocs Microbiome or Healthy Disease development Figure 1. The infant gut bacterial microbiome and virome can be influenced by various factors as shown. Notably, while most studies have demonstrated their effects on modulation of the bacterial microbiome, further research is needed to extend these findings to the virome (e.g., mode of delivery and gestational age). Collectively, alterations in the infant gut bacterial microbiome and virome can lead towards a healthy development or disease. 802 Trends in Microbiology, October 2016, Vol. 24, No. 10 intact membranes versus preterm labor with ruptured membranes [4]. The role of bacteria in the amniotic fluid from women with preterm delivery remains unknown. Jimenez et al. collected cord blood from 20 healthy infants born via Cesarean section (C-section) [5]. From 9 (45%) of these samples, they cultured and identified by 16S sequencing multiple taxa of Gram-positive bacteria, including Enterococcus, Streptococcus, Staphylococcus, and Propionibacterium. Studies have also suggested that meconium is not sterile as once previously thought, supporting the hypothesis that gut colonization occurs before birth. Jimenez et al. [5] showed, using culture, that Staphylococcus and Enterococcus were the predominant bacteria in meconium. Subse- quent 16S-based studies of meconium found that samples had low bacterial diversity and that the microbiome is dominated by a few genera in a given individual [10]. Additionally, Ardissone et al. [10] demonstrated that the bacterial microbiome in meconium most closely resembled that of amniotic fluid. Mode of Delivery The mode of delivery (vaginal versus C-section) has a strong correlation with the bacterial communities that first colonize the gut [11,12]. Infants born vaginally have gut bacterial micro- biomes that resemble their mother's vaginal bacterial microbiome, which is dominated by Lactobacillus [11]. By contrast, infants born by C-section have a gut microbiome most similar to their mother's skin bacterial microbiome. Interestingly, this altered colonization pattern seen in babies delivered via C-section persists to at least 1 year of age [12,13] and has been hypothe- sized to be responsible for the increased risk of obesity [14] and asthma [15] seen in children delivered by C-section. A pilot study to expose infants delivered by C-section to maternal vaginal fluids [16] demonstrated that vaginal microbes could be partially restored at birth in C-section- delivered babies. However, the long-term impact and possible benefits of this procedure as well as potential risks (e.g., exposure to bacteria that may be harmful to the infant) have yet to be defined [17]. Gestational Age The gut bacterial microbiome also differs with gestational age. A longitudinal study of preterm infants showed that the pace of the gut bacterial microbiome development was most strongly driven by postconceptional age [18,19]. The importance of gestational age in the development of the bacterial microbiome has also been seen in a longitudinal study of term and near-term infants in Singapore [20]. Furthermore, a study of meconium showed that gestational age had the greatest influence on the microbial community structure [10]. While factors such as delivery mode and diet