Prematurity and Perinatal Antibiotics: A Tale of Two Factors Influencing Development of the Neonatal Gut Microbiota

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espite robust global research efforts, preterm birth recommunity composition between term and preterm infants mains a relatively intractable and pervasive problem. were evident at the 3 latter time points: preterm infants Indeed, preterm birth continues to impact >10% of harbored significantly lower proportions of Bacteroidetes at live births in the US, and is the leading cause of neonatal 10, 30, and 90 days, and higher proportions of Proteobacteria morbidity and mortality worldwide.1 Compared with fulland lower proportions of Actinobacteria at 10 and 30 days. term births, preterm deliveries are typified These overall differences in taxonomic See related article, p  by more frequent use of perinatal antibicomposition, which appear to have been otics, that is, antibiotics administered either intra-partum driven largely by a handful of bacterial families (especially to the mother, or post-partum to the newborn. The decision Bacteroidaceae and Enterobacteriaceae), are broadly consisto treat with perinatal antibiotics is a clinical judgment based tent with prior reports. Beyond this finding, a particular on perceived risks and benefits to both mother and baby. strength of the report by Arboleya et al is that the distribution However, it is undoubtedly the rare clinician who takes in their study of mothers and newborns who received antibiinto consideration the potential effects of antibiotics on the otics enabled an analysis of the potential impact of perinatal infant’s future gut microbiota. This might be particularly antimicrobial use on the developing gut microbiota of pretrue when perinatal antibiotics consist of a single dose of term infants. Among the 27 preterm deliveries, 14 mothers intra-partum antibiotics prescribed to the mother, as and 17 neonates received antibiotics, including 9 instances opposed to a multi-dose post-partum regimen given directly where antibiotics were given to both members of the to the newborn. Such a scenario whereby the potential mother-preterm infant pairs. Using hierarchical clustering impact of maternal antibiotics on the infant’s microbiota reanalysis, Arboleya et al found that at days 10, 30, and 90, ceives little consideration is not surprising—at least for now. the mother-preterm infant pairs in which any antibiotic After all, our current understanding of the effects of antibiwas administered perinatally—whether to mother, preterm otics on microbial communities in the neonatal gut is itself infant, or both—appeared to demonstrate an effect on gut in its infancy and far from complete. To enable such decisions microbiota composition. The effect following a single dose to be evidence-based requires a vastly improved understandof intra-partum antibiotics administered solely to the mother ing of the establishment of a healthy gut microbiota, appeared to be at least equal to the effect following multiple including initial community assembly, subsequent succesdoses of antibiotics given directly to the neonate after birth. sion events, and transient as well as durable responses to This apparent effect of intra-partum antibiotics was most various disturbances such as antibiotic exposure. evident at the 30-day sampling time point and was associated The human body plays host to a rich assembly of diverse with changes in community composition that in part were microbes—primarily bacteria—residing on mucosal and qualitatively similar to the differences observed between the skin surfaces and in the intestinal lumen. These commensal preterm and term groups. Indeed, a higher proportion of microbes, which outnumber human cells by at least an order taxa from the phylum Proteobacteria, driven primarily by of magnitude, plus their combined genomes, constitute the an increase in Enterobacteriaceae, were found in preterm inhuman microbiome. The microbiome performs a wide array fants delivered in the setting of intra-partum antibiotic use. of diverse functions beneficial to its human host, including At 90 days, differences in taxonomic composition between nutrient acquisition, immune programming, and protection the treatment groups were less pronounced but still detectfrom pathogen invasion, among others.2 Evidence indicates able. Analysis by real-time quantitative polymerase chain reaction targeting specific microbial groups revealed a that the amniotic cavity is sterile during healthy pregnancy3 decreased abundance at 90 days of the genus Bifidobacterium and that colonization of the newborn gut begins at delivin the group of preterm infants with any antibiotic treatment ery.4,5 Microbial community composition appears to be exposure (ie, either intra-partum to the mother, or postbroadly shaped initially by early environmental factors such partum to the infant), compared with the group that received as delivery mode (ie, vaginal vs cesarean delivery5) and no antibiotic exposure. soon thereafter by incidental exposures to the ambient enviThe findings by Arboleya et al,8 although limited and still ronment as well as diet.4,6,7 requiring the type of robust corroboration that comes only It is against this backdrop that Arboleya et al in this issue of The Journal report their findings from a longitudinal study of the gut microbiota at 4 sampling time points (2, 10, 30, and 90 days) over the first 3 months of life in 13 term and 27 The author declares no conflicts of interest. preterm infants.8 The authors found that even at the coarse 0022-3476//$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved. taxonomic scale of bacterial phyla, distinct differences in http://dx.doi.org/10.1016/j.jpeds.2014.11.048

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from additional investigations, are nonetheless intriguing. In particular, the possibility that indirect exposure to an antibiotic administered as a single dose to the mother during the delivery process might alter the composition of the infant’s gut microbiota at 1 to 3 months of age, and possibly beyond, is significant and merits additional investigative efforts. It has been hypothesized for some time that antibiotic administration in the perinatal period (to either the mother or the neonate) might lead to delayed health consequences for the baby as a result of alterations in the developing gut microbiota,9 but direct evidence has been sparse. The report by Arboleya et al lends support to this hypothesis and argues for additional studies on the establishment and succession of the infant gut microbiota, including in the presence of various disturbances such as antibiotic exposure. The precise process of community assembly of the initial gut microbiota in the neonate remains as yet unclear; however, various general models of microbial community assembly have been proposed. A detailed discussion of these models is beyond the scope of this editorial. The interested reader is referred elsewhere,7,10,11,12 however, salient features of some overarching models merit brief discussion. One model, termed ‘neutral assembly’, generally proposes that microbial groups gain a foothold in a particular niche primarily as a result of stochastic exposures. This model assumes that functional equivalency exists among trophically similar taxa, thereby effectively neutralizing potential influences exerted by local environmental conditions within a particular niche. A second model proposes that community assembly is a deterministic process that follows ‘assembly rules’. Examples of assembly rules include species assortment (eg, competitive exclusion between microbial species fighting for the same limited resource) and habitat filtering (eg, varying affinities of microbial species for different niches owing to divergent environmental conditions present within those niches).12 These two broad approaches are not mutually exclusive. Indeed, they may contribute in varying degrees to the assembly of a given community, and their relative contributions may vary over time, with the relevant time scale being either developmental or chronological. In fact, the assembly of the gut microbiota has been characterized as having an early ‘unstable’ phase likely resulting from incidental exposures to microbial communities during and soon after delivery,4,6,7 followed by a succession of facultative anaerobes and subsequently strict anaerobes7,13 that have co-evolved to be adapted to their human host and appear in discrete steps of bacterial succession with abrupt shifts punctuated by life events.6 The early stage of assembly therefore appears to follow, at least in part, a ‘neutral assembly’ model. By contrast, recent studies based on metabolic modeling suggest that an ‘assembly rules’ process and, specifically, habitat filtering, is the dominant structural force in the latter stages of succession.12 A deeper understanding of the assembly process of neonatal gut bacterial communities, including the metabolic interactions of successive communities, is not merely an academic exercise and is potentially of great practical importance. Among the beneficial services that the gut 2

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microbiota provides are critical developmental functions that confer potentially long-reaching effects on the host, such as immune system programming and promotion of host tissue differentiation.2,7,13 Whether specific time windows exist in the lifespan of humans during which particular bacterial consortia must be present in the gut for these functions to be optimally performed is unknown. If such time windows indeed exist, some roles of the host microbiota might be viewed as analogous to developmental programming, whereby events occurring during a critical period of fetal or neonatal life can affect the organism at much later life stages. The classic developmental programming model is based largely on animal studies and proposes that maternal stressors occurring during fetal life cause epigenetic changes that influence physiological function and risk of disease in adult life.14 Such a paradigm would suggest that ‘missing’ a window, for example by virtue of a perturbed or otherwise ‘unhealthy’ gut microbiota during a critical time period, might have detrimental effects on the health of the host, possibly at a much later point in life. Studies like the one by Arboleya et al,8 which provide longitudinal analyses of the human microbiota during critical life stages and incorporate clinical metadata such as medication exposures and clinical outcomes, are essential for furthering our understanding of the relationship between the microbiome and human health. In addition to conducting such studies at high spatiotemporal resolution and for long sampling durations, investigations that incorporate either natural or controlled community disturbances of interest, such as antibiotic exposure,15 are apt to be particularly enlightening. The types of investigative and analytic approaches brought to bear should include multi-‘omics’ methods to interrogate genomic, transcriptomic, proteomic, and metabolomic features and interactions. New insights from these types of investigations hold promise for informing clinical treatment decisions as well as rationally designing potential new interventions for modulating the host microbiota in specific ways to promote better health at various life stages. n Daniel B. DiGiulio, MD Division of Infectious Diseases Department of Medicine Stanford University School of Medicine Veterans Affairs Palo Alto Health Care System Palo Alto, California Reprint requests: Daniel B. DiGiulio, MD, Division of Infectious Diseases, Department of Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Mail Code 5107, Stanford, CA 94305-5107. E-mail: [email protected]

References 1. Lawn JE, Cousens S, Zupan J, Lancet Neonatal Survival Steering Team. 4 million neonatal deaths: When? Where? Why? Lancet 2005;365:891900. 2. Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. The human microbiome project. Nature 2007;449:804-10. 3. DiGiulio DB. Diversity of microbes in amniotic fluid. Semin Fetal Neonatal Med 2012;17:2-11.

- 2015 4. Palmer C, Bik EM, DiGiulio DB, Relman DA, Brown PO. Development of the human infant intestinal microbiota. PLoS Biol 2007;5:e177. 5. Dominguez-Bello MG, Costello EK, Contreras M, Magris M, Hidalgo G, Fierer N, et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A 2010;107:11971-5. 6. Koenig JE, Spor A, Scalfone N, Fricker AD, Stombaugh J, Knight R, et al. Succession of microbial consortia in the developing infant gut microbiome. Proc Natl Acad Sci U S A 2011;108(Suppl 1):4578-85. 7. Costello EK, Stagaman K, Dethlefsen L, Bohannan BJ, Relman DA. The application of ecological theory toward an understanding of the human microbiome. Science 2012;336:1255-62. 8. Arboleya et al. (this journal issue). 9. Bedford Russell AR, Murch SH. Could peripartum antibiotics have delayed health consequences for the infant? BJOG 2006;113:758-65.

EDITORIAL 10. Hubbell SP. The Unified Neutral Theory of Biodiversity and Biogeography. Princeton, NJ: Princeton University Press; 2001. 11. Lindstr€ om ES, Langenheder S. Local and regional factors influencing bacterial community assembly. Environ Microbiol Rep 2012;4:1-9. 12. Levy R, Borenstein E. Metabolic modeling of species interaction in the human microbiome elucidates community-level assembly rules. Proc Natl Acad Sci U S A 2013;110:12804-9. 13. Sommer F, B€ackhed F. The gut microbiota—masters of host development and physiology. Nat Rev Microbiol 2013;11:227-38. 14. Langley-Evans SC. Developmental programming of health and disease. Proc Nutr Soc 2006;65:97-105. 15. Dethlefsen L, Relman DA. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci U S A 2011;108(Suppl 1): 4554-61.

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Prematurity and perinatal antibiotics: a tale of two factors influencing development of the neonatal gut microbiota.

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