The Role of the Microbiome inLeah T. Stiemsma,the PhD,Developmental Karin B. Michels, ScD, PhD Origins of Health and Disease abstract Although the prominent role of the microbiome in human health has been established, the early-life microbiome is now being recognized as a major influence on long-term human health and development. Variations in the composition and functional potential of the early-life microbiome are the result of lifestyle factors, such as mode of birth, breastfeeding, diet, and antibiotic usage. In addition, variations in the composition of the early-life NIH microbiome have been associated with specific disease outcomes, such as asthma, obesity, and neurodevelopmental disorders. This points toward Department of Epidemiology, Fielding School of Public this bacterial consortium as a mediator between early lifestyle factors and Health, University of California, Los Angeles, Los Angeles, California health and disease. In addition, variations in the microbial intrauterine environment may predispose neonates to specific health outcomes later in Dr Stiemsma conceptualized and outlined the review, conducted the literature search, drafted life. A role of the microbiome in the Developmental Origins of Health and the initial manuscript, and reviewed and revised Disease is supported in this collective research. Highlighting the early-life the manuscript; Dr Michels supervised the project critical window of susceptibility associated with microbiome development, and critically reviewed and edited the manuscript; and all authors approved the final manuscript as we discuss infant microbial colonization, beginning with the maternal- submitted and agreed to be accountable for all to-fetal exchange of microbes in utero and up through the influence of aspects of the work. breastfeeding in the first year of life. In addition, we review the available DOI: https://doi.org/10.1542/peds.2017-2437 disease-specific evidence pointing toward the microbiome as a mechanistic Accepted for publication Nov 29, 2017 mediator in the Developmental Origins of Health and Disease. Address correspondence to Karin B. Michels, ScD, PhD, Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, During the past decade, the research surrounding the maturation 650 Charles E. Young Dr S, Los Angeles, CA 90095. E-mail: [email protected] microbiome has emerged as a1 major of the early-life microbiome and how contributor to human health. It has transient variations in this bacterial PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, been suggested in current studies consortium can have long-term 1098-4275). that the early-life microbiome is a consequences for human health. Copyright © 2018 by the American Academy of Pediatrics crucial factor for proper immune 2,3 The DOHaD: Where Does the development and long-term health. Microbiome Fit? FINANCIAL DISCLOSURE: The authors have Transient microbial dysbiosis indicated they have no financial relationships during this time period has been relevant to this article to disclose. FUNDING: Dr Stiemsma is supported by T32 training associated with the development– of The developmental origins hypothesis immune-mediated, metabolic, and proposes variations in fetal and infant grant 5T32CA009142-37 from the National Cancer 4 7 Institute (NCI), National Institutes of Health (NIH). neurodevelopmental disorders. programming through environmental Funded by the National Institues of Health (NIH). In addition, increasing evidence has exposures during a critical window 9 POTENTIAL CONFLICT OF INTEREST: The authors been used to support a vital role of early life. Termed10,11 originally as the have indicated they have no potential conflicts of of the maternal and intrauterine Barker hypothesis, in which the interest to disclose. microbiomes 8in childhood health and association between fetal malnutrition development. Collectively, these and hypertension later in life was a To cite: Stiemsma LT and Michels KB. The Role findings have been used to support focus, this theory has since expanded of the Microbiome in the Developmental Origins the microbiome as a key participant to account for many types of early- of Health and Disease. Pediatrics. 2018;141(4): in the Developmental Origins of life exposures and birth outcomes e20172437 Health and Disease (DOHaD). In this associated with long-term health and review, we will discuss the current development. For example, high birth Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 141, number 4, April 2018:e20172437 State-of-the-Art Review Article weight is associated with an increase12,13 in breast and colon cancer risk, and the underlying mechanism of this association may be related to intrauterine exposure9 to high levels of growth hormones.
Early-life infections and microbial exposures were not originally associated with DOHaD but were proposed as significant environmental influences on infant immune development in the hygiene14 hypothesis of allergic disease. With the advancement of human FIGURE 1 microbiome research, a modern The infant microbiome is most vulnerable to environmental influences in early life. Maternal to fetal microbial transfer, mode of birth, antibiotics, and diet can alter the colonization and maturation of extension of the hygiene hypothesis the early-life microbiome. These lifestyle-induced variations in microbiome composition and function has since been proposed, known15 as can have prolonged influences on human health and may lead to the development of disease later the microflora hypothesis. In the in life. microflora hypothesis, it is suggested that early-life environmental exposures alter the development15 of the human microbiome. the developmental origins field molecular techniques in the amniotic Shifts in the composition of the (Fig 1). fluid and19, placentas20 of healthy microbiome are thought to bias Early-Life Development of the infants, suggesting a maternal- maturation of the immune system Microbiome to-fetal exchange of microbes. In addition, through comparisons toward a hypersensitive and/or15 hyperinflammatory state. For of the amniotic, placental, and example, the innate and adaptive The human microbiota is a composite meconium21 microbiotas, Collado et al report that the meconium branches of the immune system are organism, composed of 10 trillion to ∼ both highly involved in promoting 100 trillion microbial cells (bacteria, microbiota of infants delivered via an inflammatory response. However, archaea, and microbial eukaryotes) cesarean delivery shares 55% of – 16,17 exposure to microbes typically and viruses. To highlight the its bacterial taxa with the placenta evokes a T-helper 1 mediated impressive functional potential and amniotic fluid microbiotas. The of the microbiota, the genomic prenatal maternal microbiome may response, which suppresses ∼ the T-helper 2 activity often catalog of this super organism, the also modulate the Escherichiainfant immune coli microbiome, is composed of 3.3 system. For example, gestation-only associated with immune-mediated3 “ 16 ” million nonredundant genes. colonization with and hypersensitivity reactions. “ ” Discussion of the mechanisms Although the terms microbiota HA107 was reported to modify the regulating the interface between the and microbiome are descriptive intestinal mucosal innate immune immune system and the microbiota of the microbial composition and system and22 transcriptome of the genomic catalog, respectively, they offspring. is beyond the scope of this3 review; please see Tamburini et al for a are used interchangeably within this recent in-depth discussion on this research field. The following sections In humans, variations in the placental topic. are devoted to delineating the initial microbiome composition have colonization and establishment of been associated with maternal Analogous to DOHaD, an early-life the human bacterial microbiota in pregnancy-related (stress and critical window of development infancy, from conception through the gestational diabetes)– and neonatal firstMaternal-to-Fetal year of life. Microbial Transfer has also been proposed for the health outcomes7,23 (birth25 weight, microbiome. Transient microbial preterm birth). The placental dysbiosis (unhealthy microbial state) microbiome of infants born preterm during this time frame has been Until recently, the intrauterine was also reported to differ in associated with long-term immune2 environment18 was perceived as composition26 according to gestational and metabolic health issues, sterile. However, nonpathogenic weight gain, suggesting that this meriting its exploration within bacteria have since been detected by bacterial consortium may mediate Downloaded from www.aappublications.org/news by guest on September 28, 2021 2 Stiemsma and Michels fetal development depending on the meconium, etc) of cesarean delivered the first study aimed at recolonizing ’ health status of the mother. infants areStaphylococcus initially populated with infants delivered via cesarean bacteria residing on the mother s delivery with vaginal bacteria. After Isolation of bacteria from the skin (eg, spp.), swabbing neonates with maternal placenta is often associated with whereas vaginally delivered infants vaginal fluids within 2 minutes of a pathophysiological state, which Prevotella Atopobium are populated with typical vaginal birth, the authors report partial threatens the health of the mother bacteria (eg, , restoration of the microbiota of and child. Because of the lack 30 31 spp.). In a recent study, Chu et al infants delivered via cesarean of culture-based analyses of the suggest this finding may be specific delivery to that of vaginally delivered placental microbiome, there is 34 to the neonatal gut microbiome. In infants. However, the long-term some controversy surrounding its 27 their study of 81 mother and infant health effects and composition of validity. In addition, inclusion of dyads, the microbiomes of other the infant microbiome are not yet appropriate controls to address 34 body sites (nares, skin, etc) from known. Future analysis of these background contamination is infants delivered vaginally revealed cesarean delivered infants exposed also lacking in many molecular- ’ a bimodal pattern of maternal origin, to the vaginal microbiome will be based studies characterizing the 28 populated by both the mothers extremely valuable in determining intrauterine microbiome. vaginal and skin bacteria31 rather the benefits of vaginally derived It is also possible that the placenta than by one or the other. However, bacteria in long-term human health. does not harbor any viable it is suggested in both studies In addition, the establishment of bacteria but rather is composed of that the microbiotas of infants are prospective human studies and phagocytosed microbial 8,by-products22, 29 homogeneously distributed across animal models attempting similar or cell wall components. The body sites (eg, meconium, skin,30 nares, colonization with vaginal bacteria lack of viable bacteria does not etc) immediately after birth. among offspring delivered via negate the capacity of the placental cesarean delivery will be crucial Profiling of the neonatal intestinal microbiome to modulate fetal in elucidating the role of vaginal microbiome immediately after birth development because interactions microbes in the development of and up to age 2 years suggests that with pathogen-associated molecular Bdiseasereastfeeding. Furthers Microbiota birth mode can result in prolonged32 patterns may still regulate cell 8,22, 29 Maturation in Early Life differentiation and proliferation. infant gut microbial dysbiosis. In addition, upon implementation In a study of 43 mother and infant of stringent validation strategies for dyads, infants delivered via cesarean As the neonate grows, the placental metagenomic analyses, delivery exhibited increased homogeneous microbiome the placental microbiome might phylogenetic32 diversity immediately populating his or her body diverges be referenced as a biomarker for after birth. However, after 1 month 18,31 into microbe-specific body niches. maternal and fetal health and disease. of age, the phylogenetic diversity The maturation of the total infant Few studies have been conducted to of infants delivered via cesarean microbiome has been studied for explore the function of the placental delivery declined below that32 of 23,25 the first year of life, but beyond this microbiome, emphasizing an vaginally31 delivered infants. Chu time point, most researchers focus opportunity for future research et al challenge this finding slightly. specifically on the gut microbiome. in this area. Analysis of microbial In their recent study, birth mode Driven in large part by breastfeeding metabolites and the application of was associated with variations in and infant diet, the human gut metatranscriptomic approaches to the microbiomes of the nares, skin, microbiome continues to mature characterize the functional capacity and oral cavity immediately after until the child reaches 2 to 3 years of the placental microbiome will be birth but not with variations in of age, after which its composition keyVaginal in defining Birth: The its roleFirst in S DOHaDtep in . the infant meconium microbiome. 35 Postnatal Microbial Colonization Researchers of both studies do stabilizes. support the influence of birth mode Breastfeeding seeds the infant gut on neonatal colonization in general; microbiome through contact with however, more research is needed Postnatal bacterial colonization of maternal areolar and breast milk to determine the influence of this the infant begins during birth, at microbes and provides key energy early-life factor on the microbiomes – which time neonates are exposed sources for many bacteria (human of specific body sites. 36 39 to the maternal30 fecal and vaginal milk oligosaccharides). In a microbiotas. Within 24 hours of Because of the health benefits33 study of 107 mother and infant delivery, the microbiotas across associated with vaginal34 birth, dyads, infants who were breastfed various body sites (oral, skin, Dominguez-bello et al conducted during the first 30 to 40 days of life Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 141, number 4, April 2018 3 ∼ ∼ received a mean of 28% of their pregnancy and breastfeeding was was also reported to alter the infant52 bacteria from breast milk and38 10% reported to induce dysbiosis in the streptococcaceaeoral microbiome compositiongemellaceae. from maternal areolar skin. The offspring microbiome of Japanese Specifically, the bacterial families – 44 authors also report a dose-dependent macaques. These maternal and association between the infant gut diet induced microbial variations44 and the order lactobacillales were microbiome composition and the 38 persisted in juvenile macaques. decreased, whereas bacterial proportion of daily breastfeeding. In addition, a postweaning, low- families in the proteobacteria fat control diet was unable to phylum were enriched among There is a clear compositional – correct this maternal high-fat44 infants whose mothers received52 distinction between breastfed and diet induced dysbiosis. In a intrapartum antibiotics. In addition, formula-fed infants,Bifidobacteria with breastfed prospective cohort of 26 mother and among infants whose mothers infantsLactobacillus being populated with higher infant dyads, a high-fat maternal received antibiotics, the infant oral proportions of and gestational diet was associated microbiome composition was further spp. and formula- with distinct variations in the differentiated depending on whether fed infants being populated with a neonatal gut microbial composition the mother received a cocktail of greater prevalence of32, 40clostridiales (meconium), which45 persisted to antibiotics compared with52 if she and proteobacteria. In addition, 4 to 6 weeks of age. In a mouse received only 1 antibiotic. formula-fed infants exhibit decreased model, a maternal high-fiber diet diversity and bacterial richness – was associated with increased short- Postnatal antibiotic courses given even after the first year of life 32 chain fatty acid (SCFA) production to the infant in the first 3 to 9 (12 24 months of age). In a study 46 in the offspring. Emphasizing the months of life were reported to alter of 30 preterm infants, the effect – Ruminococcus immune-modulatory capacity of the abundances of specific gut bacterial of breastfeeding (versus formula maternal diet driven microbiome taxa (namely, and feeding) was also reported to mask 32 during pregnancy, higher frequencies clostridiales). In addition, antibiotic the influence of birth weight on the of thymic T-regulatory cells were use in the first 6 to 12 months of life infant microbiome, highlighting 46 also found in these pups. Finally, has been associated with decreased breastfeeding as being potentially 32 demonstrating the effect of maternal maturation of the infant microbiota. protective (at least with regard to diet on the functional capacity of the This suggests antibiotics may stunt the infant microbiome) against a 41 infant microbiome, piglets born of the development of the microbiota if traditional DOHaD risk factor. sows that were fed a western diet administered during this time period, Epidemiologic evidence provides (high-energy, high-fat, fructose-based which could potentially predispose further support for the beneficial diet) during pregnancy displayed infants to microbiome-associated roles of breastfeeding in promoting 47 32 decreased SCFA production. In diseases later in life. infant health. Formula feeding has these studies, the importance of the been associated with an increased microbiome as a mediator linking In epidemiologic studies, it has risk of various hyperinflammatory 42,43 gestation-associated maternal been suggested that antibiotic- and immune-mediated diseases. diet to infant health is supported, induced dysbiosis in infancy In addition, researchers of a recent substantiating the role of the promotes the development of epidemiologic study reported that microbiome in DOHaD. Future many noncommunicable diseases breastfeeding protects against studies may shed more light on the in later childhood and adulthood wheezing during the first year of life – prolonged health and developmental (ie, obesity, asthma, inflammatory among infants born to mothers with 53 56 43 effects of gestation-associated bowel disease [IBD]). However, asthma. With the work discussed maternalAntibiotics diet Alter. Infant Colonization these epidemiologic analyses do in this section, we suggest that the and Decrease Microbiota Maturation not address whether these diseases microbiome may be a mediator are causally related to early-life between these associations. Gestation-Associated Maternal antibiotic use or whether they are Diet Shapes the Developing Infant Perhaps unsurprisingly, pre- and indicative of early-life immune Microbiome postnatal antibiotic exposure is deficiencies or propensity for a major early-life environmental infection. Nevertheless, there are stressor on the infant microbiome. some promising animal models Recent evidence has been used Prenatal maternal antibiotic – and prospective human cohort to support a significant role of exposure has been reported to alter48 50 studies that attempt to address this gestation-associated maternal diet in the diversity of51 both the neonatal quandary and provide additional shaping the microbiome of infancy. and maternal microbiotas. support for the microbiome as a key A maternal high-fat diet during Intrapartum antibiotic exposure developmental mediator in DOHaD. Downloaded from www.aappublications.org/news by guest on September 28, 2021 4 Stiemsma and Michels Dysbiosis-Associated Noncommunicable Diseases 58 Provide Additional Support for low birth weight neonates. The suggest its development is strongly the Microbiome in DOHaD increase in proteobacteria along influenced by commensal bacteria. with increased enterocyte Toll- The Critical Window in Early Life In a recent assessment of the like receptor 4 activity in these microbiome in asthma development, neonates with NEC suggest a a more substantial role of the hyperinflammatory response59 to a maternal microbiota in fetal As mentioned at the beginning of dysbiotic microbiome. However, development is supported than this review, DOHaD emphasizes a a recent study wasE coli conducted what was previously thought. In critical window of susceptibility in which researchers identified a mouse model of allergic airway from conception to early life in uropathogenic colonization59 as inflammation, high-fiber (which which environmental stressors most a significant risk marker for NEC. has been reported to stimulate profoundly affect long-term human This suggests an invasive microbial production of SCFAs by the health. A similar critical window 111 species may be synergistic in driving microbiome ) or acetate (a SCFA) has emerged for the development this dysbiosis-associated disorder. – feeding of pregnant mice modulated of the microbiome. Scientists have In addition, infants treated with E the maternal microbiota and narrowed the microbiome early-life antibioticscoli for 7 14 days (regardless protected the subsequent offspring critical window to the time period of NEC status) were enriched for – from developing allergic airway between conception and the first year 73 1 relative to infants treated59 with disease. The authors of this study of life (Fig 1). Though more research ’ antibiotics for 0 6 days. This also provided preliminary evidence is needed to confirm this theory, supports a role of neonatal antibiotic- of this association in humans; the microbiome s vulnerability to induced dysbiosis in NEC, which high acetate levels in the serum of environmental influences appears may enhance the vulnerability of the pregnant individuals correlated with to be time varying, more substantial neonatal gut microbiome to pathogen reduced general practitioner visits earlier in life and lessening as it invasion. Because of the apparent for coughing and wheezing in the matures toward that of an adult (Fig 1). link between microbial dysbiosis offspring during the first 12 months In the following sections, we will 73 and NEC, probiotic supplementation of life. discuss disease-specific research of preterm neonates is becoming a (specifically, necrotizing enterocolitis Postnatal early-life dysbiosis2,4, 5, 70 in prominent research area for109, NEC110 [NEC], asthma and atopic disease, prevention and treatment. both the78 human gut and obesity, and neurodevelopmental In a systematic review and meta- airway microbiomes is also disorders) that points toward this analysis of 26 probiotic intervention associated with asthma and atopic early-life critical window and further studies for NEC, it is suggested that disease development in children. supports the role of the microbiome This dysbiosis is characterized by probiotic60 intervention does prevent inNEC DOHaD (summarized in Table 1). NEC. However, the particular shifts in the4,5 prevalence of specific70 strains to be used and the effects on bacterial and fungal taxa, which high-risk populations (extremely are transient and most prominent between birth and 3 months of In addition to the health risks low birth weight60 infants) requires associated with preterm birth, further study. Nonetheless, it may life. The majority of human studies preterm infants display marked be possible in the near future to in this research area reveal only neonatal microbial dysbiosis. optimize the neonatal microbiome correlative evidence to link the early- This dysbiosis enhances their to combat development of this life dysbiosis4 with asthma. However, susceptibility to disease, particularly disease and prevent associated infant Arrieta et al provide preliminary NEC, which may be modified by mortality. evidence of causality related to Asthma and Atopic Disease early-life transient dysbiosis and exposure to antibiotics57 during this critical time period. Through immune development in the context analysis of existing 16S ribosomal of asthma. In this study, inoculation RNA gene sequence data, the NEC studies highlight the dynamic of previously germ-free (GF) mice authors identified differential relation between the gut microbiome with 4 bacterial species, which were abundances of proteobacteria, and the developing immune system. reduced in infants at high risk of asthma, ameliorated allergic4 airway firmicutes, and bacteroidetes, 57 However, although the neonatal which preceded the onset of NEC. immune system is on high alert for inflammation in these mice. Gut dysbiosis characterized by pathogenic invaders, researchers There is also evidence to support a similar variations in bacterial who have conducted studies of role of the early-life microbiome74 in taxa was also reported to precede asthma and atopic diseases (food food allergies. Azad et al report a NEC in a study of 122 extremely allergies, atopic dermatitis, etc) decrease in microbial diversity at Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 141, number 4, April 2018 5 57 58 59 60 61 62 Ref. No. Summary of Findings tality in infants firmicutes and bacteroidetes preceded NEC onset. Antibiotics, diet, and mode of delivery do contribute to microbial dysbiosis associated with NEC. However, causality related to these factors cannot be determined decreases in negativicutes and clostridia - negativicutes classes over time preceded NEC development at 17 – 22 before NEC development. However, d postpartum, infants with high antibiotic treatment were enriched for E coli . The group later identified uropathogenic E coli as a major risk factor for NEC and associated death significantly reduced the incidence of NEC and mor per subject and the temporal changes in microbiome composition were assessed. Throughout early life, before the development of NEC, different microbial populations dominate the gut and are associated with NEC development. In addition, the microbiome compositional progression appears to be associated with the timing of NEC onset associated with NEC development. Microbiomes of subjects tended to cluster according to NEC status. These microbial variations were associated with shifts in urine metabolites, namely alanine and histidine Increased proteobacteria and decreased Increases in gammaproteobacteria and Variations in the microbiome were detected Enteral probiotic supplementation An average of 7 samples were collected Lower α diversity 4 – 9 d postbirth was ∼ 30 wk Health Outcome and Timing of Assessment infancy postconception infants NEC at Stage II and stage III NEC in NEC in infancy NEC in very low birth wt NEC in infancy NEC in infancy Timing of Microbiome microbiome before NEC development supplementation before NEC development microbiome before NEC development microbiome before NEC development microbiome before NEC development microbiome before NEC development Analysis or Intervention Variations in the Enteral probiotic Variations in the Variations in the Variations in the Variations in the Timing of Exposure Early-Life Factors and None None None None None None t t t n = 35) Animal Model Study Population or and meta-analysis of 14 human fecal microbiome studies of NEC meta-analysis of 24 randomized or quasi- randomized controlled trials in humans design ( analysis (primary cohort, n = 122; secondary cohorts, n = 44) analysis ( n = 166) analysis ( n = 38) Systematic review Prospective human cohor Prospective human cohor Systematic review and Prospective human cohor Nested case-control Studies in Which Researchers Relate the Early-Life Microbiome With Health Outcomes Later Childhood and Adulthood
1 dysbiosis before NEC in a systematic review and meta-analysis gut bacterial taxa differ between cases of NEC and controls resolution of NEC- associated pathogens by using deep shotgun metagenomics sequencing and safety of enteral probiotic administration in preventing NEC microbiota composition before NEC development in infants who developed NEC and controls metabolic biomarkers of NEC E L To assess microbial To determine if 1 or more To enhance strain-level To compare the efficacy To assess the intestinal To identify microbial and AB Research Objective
NEC T
Downloaded from www.aappublications.org/news by guest on September 28, 2021 6 Stiemsma and Michels 63 64 65 66 67 68 Ref. No. Summary of Findings associated with NEC severity. There were also no differences in the microbiome post- NEC compared with controls 6 – 8-wk-old mice to mouse pups conditioned for NEC reduced incidence and severity compared with controls. This was dependent on Grx1 . The mechanism of action is potentially through TLR-mediated inflammation and gut permeability dorei were increased in the meconium of infants who developed NEC. C perfringens abundance persisted in neonatal stool samples. The amount of breast milk before NEC and earlier enteral feeding was negatively associated with NEC and associated with increased lactate- producing bacilli whereas lesions in piglets that were treated with parenteral antibiotics were increased. Enteral antibiotics decreased bacterial load and abundances of Gram-positive bacteria in the intestine. It is suggested that delayed colonization (particularly with Gram-positive bacteria) although may prevent NEC. However, microbiome variations correlate with NEC, they do not necessarily precede NEC and the abundance of Clostridium species. Density of C perfringens was associated with NEC severity. Microbiome variations correlate with NEC but do not necessarily precede NEC associated with NEC development ( C perfringens type A dominant and Klebsiella dominant) Variations in the microbiome were not Clostridium perfringens and Bacteroides Identification of 2 fecal microbiota profiles Health Outcome and Timing of Assessment NEC in preterm piglets Enteral feeding increased microbial diversity NEC in infancy NEC 5 d postbirth Fecal microbiota transplant from healthy NEC in infancy NEC in preterm piglets Enteral antibiotics prevented NEC lesions, NEC in infancy th) Timing of Microbiome antibiotic treatment (for 5 d post bir microbiome after feeding methods microbiome before NEC development from 1 to 4 d postbirth microbiome and neonatal microbiome before NEC microbiome before NEC diagnosis Analysis or Intervention Variations in the Variations in the Fecal microbiota transplant Variations in meconium Variations in the Timing of Exposure Early-Life Factors and nutrition breast milk None None Early enteral feeding and None t t t Grx1 − / Animal Model Study Population or analysis ( n = 30) mouse models of NEC analysis ( n = 33) analysis ( n = 369) Prospective human cohor Wild-type and Prospective human cohor Piglet model of NEC Antibiotic-induced Enteral and parenteral Piglet model of NEC Enteral and total parenteral Prospective human cohor t of Continued
1 microbiome composition can be used to predict NEC severity fecal microbiota transplantation is an effective treatment of NEC at risk for NEC can be identified by their meconium and early postnatal microbiota parenteral antibiotics in preventing formula- induced NEC lesions in pigs parenteral nutrition, before the star enteral feeding, can prevent NEC-associated gut dysfunction and inflammation before NEC diagnosis E L To determine if gut To assess whether To determine if patients To compare enteral versus To determine if total To identify microbial profiles AB Research Objective
T
Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 141, number 4, April 2018 7 5 4 70 71 72 73 69 Ref. No. Summary of Findings Lachnospira / Clostridium neonatale postbirth associated with highest relative risk of asthma. Sterile fecal water from the highest-risk group induces CD4+ T-cell dysfunction expansion of firmicutes and exacerbates airway inflammation in mice of bacteroidetes and results in exaggerated hypersensitivity pneumonitis in pregnancy prevents robust AAD adult offspring. Maternal serum levels of acetate were inversely associated with general practitioner visits for coughing and wheezing in the first 12 mo of life ratio at 3 mo of age was associated with asthma by 4 y of age treatment alters DNA methylation of tight junction and TLR genes associated inflammatory pathways in fetuses and guts of 2-wk-old offspring. Both prenatal exposures also altered the offspring microbiome. Azacytidine treatment induces global demethylation, suggesting that the pre- and neonatal epigenome influences neonatal microbial colonization Lachnospira , Veillonella and Rothia ) were decreased among infants with atopy and wheezing at 1 y of age. Supplementation asthma-induced mice with these 4 bacteria ameliorated airway inflammation Perinatal vancomycin exposure promotes Perinatal streptomycin promotes expansion High-fiber diet or acetate feeding of dams Prenatal dexamethasone and azacytidine Four bacterial taxa ( Faecalibacterium , Health Outcome and Timing of Assessment in life pneumonitis in adulthood coughing and wheeze by 1 y of age signaling pathways in offspring y of age Asthma at 4 y of age Variations in bacterial and fungal taxa at 35 d Asthma induced later Hypersensitivity AAD induced in adulthood; Asthma by 4 y of age Decreased TLR and tight junction- Atopy and wheezing at 1 Timing of Microbiome microbiome 35 d postbirth through weaning) exposure exposure; prenatal acetate exposure gut microbiome crosstalk in perinatal life gut microbiome Analysis or Intervention Variations in gut Prenatal antibiotic Variations in the 3-mo-old Microbiome to epigenome Variations in the 3-mo-old Timing of Exposure Early-Life Factors and fiber diet; maternal serum levels of acetate 5-azacytidine treatment None Antibiotic-induced Perinatal (in utero and Antibiotic-induced Perinatal antibiotic Maternal acetate or high- None Prenatal dexamethasone or None t − / , and n = 319) n = 319) and Animal Model Study Population or analysis ( n = 168) mouse model HDAC9 − / house dust mite mouse models of AAD; nested case- control design ( n = 40) model design ( enterocytes) and mouse models (dexamethasone or 5-azacytidine to induce epigenetic changes) design ( Ovalbumin-challenged mouse models of asthma Ovalbumin-challenged Prospective human cohor Th1/Th17-mediated mouse Wild-type, Gpr43 Nested case-control Tissue-based (immature Nested case-control gic Continued
1 airways responses in mice and fungal microbiomes in neonates before asthma development at 4 y of age early-life critical window associated with exacerbated aller perinatal antibiotic treatment on development of hypersensitivity pneumonitis mechanisms associated with diet or microbiota- mediated immune regulation of infants before asthma development by 4 y of age to microbiome crosstalk at critical neonatal stages of development of infants before atopic disease development at 1 y of age E L To characterize the bacterial To characterize the To analyze the effects of To characterize the cellular To analyze the microbiota To characterize epigenome To analyze the microbiome
AB Research Objective
Asthma and atopic disease T
Downloaded from www.aappublications.org/news by guest on September 28, 2021 8 Stiemsma and Michels 77 78 79 80 74 75 76 Ref. No. Summary of Findings T-regulatory cells. This is mediated T-regulatory − by PD-L1. Blockage of PD-L1 in the first 2 wk airway of life results in enhanced allergic inflammation 5 – 7 y of age and were atopic by 2 twice as likely to have been colonized with asymptomatic Streptococcus age with Staphylococcus was associated with decreased incidence of atopic dermatitis at 1 y of age wk and 3 mo of age were associated with the risk of eczema at 1 y age. However, microbiome was not analyzed after 3 mo of age enterobacteriaceae/bacteroidaceae ratio associated with food sensitization to at (milk, egg, peanut, least 1 food allergen soy) at 1 y of age. in microbiomes of subjects whose milk resolved by 8 y of age. Bacteroidetes allergy and Enterobacter were enriched among did not resolve by those whose milk allergy 8 y of age microbiota (compared with GF conditions) increased iNKT in the lungs and protected asthma induced in against allergic adulthood. In addition, hypomethylation of CXCL16, driven by the microbiome, was associated with iNKT induction, implicating the microbiome in gene regulation gammaproteobacteria and firmicutes to bacteroidetes) associated with decreased responsiveness and increased aeroallergen Helios Children who developed chronic wheezing at Colonization of antecubital fossa at 2 mo Variations in Bifidobacterium species at 1 Decreased α diversity and increased Firmicutes and clostridia were enriched Neonatal exposure to a conventional Variations in the lung microbiome (shift from Health Outcome and Timing of Assessment y of age of age of age age 8 y of age in life in life Chronic wheezing at 5 – 10 Atopic dermatitis at 1 y Atopic dermatitis at 1 y Food sensitivity at 1 y of resolution by Milk allergy Asthma induced later Asthma induced later th Timing of Microbiome nasopharyngeal microbiome 7 – 9 wk postbirth (antecubital fossa) microbiome at 2 mo of age Bifidobacterium species at 1 wk and 3 mo of age microbiome at 3 mo of age microbiome at 3 – 6 mo of age microbiome at bir susceptibility (lung microbiome) Analysis or Intervention Variations in the Variations in the skin Variations in Variations in the gut Variations in the gut Exposure to maternal gut 2-wk window of Timing of Exposure Early-Life Factors and influenced by household pets, number of siblings, and maternal allergic status None None Colonization patterns None None None None t n = 20) n = 166) Animal Model Study Population or design ( study ( n = 234) design ( n = 117) design ( design ( n = 226 subjects with milk allergy) mouse model dust mite – induced airway inflammation Prospective human cohor Nested case-control Nested case-control Nested case-control Nested case-control Ovalbumin-challenged Mouse model of house ’ s species gen-induced airway Continued
1 nasopharyngeal microbiome in infancy in association with respiratory disease later in life in the skin microbiome early life are associated with atopic dermatitis between neonatal gut Bifidobacterium and eczema or atopy development in the first year of life milk allergy microbiota in association with food sensitization microbiota in association with resolution of cow microbial modulation of iNKTs in mouse models of IBD and asthma early-life lung microbiota in aller inflammation E L To analyze the To determine if variations To analyze associations To analyze the infant To analyze the early-life To investigate age-dependent To analyze the role of AB
Research Objective
T
Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 141, number 4, April 2018 9 81 82 83 84 44 Ref. No. , Summary of Findings (particularly asthma) displayed a lower proportion of IgA bound to fecal bacteria. IgA recognition patterns for the microbiota and varied between children with allergies healthy children at 1 wk of age microbial diversity than children without asthma more GI symptoms (38% compared reactions (43% with 22%) and allergic compared with 0%), which were associated with variations in the microbiome. This microbiome was characterized by less lactic acid bacteria and Akkermansia greater Escherichia , Enterobacter and Serratia abundance of streptococci was positively associated with BMI at 5 – 6 y of age, and relative abundance of bifidobacteria was negatively associated with BMI at 5 – 6 y of age. Among children with a history multiple antibiotic courses, the firmicutes phylum was significantly associated with microbiome composition was BMI. However, not measured at any other time point outcome was not established. However a maternal high-fat diet did alter the microbiome composition of offspring macaques, which persisted in juvenile macaques. Offspring displayed altered metabolic pathways on the basis of maternal diet. Additionally, these functional pathways (amino acid, carbohydrate, and lipid metabolism) correlated with abundances of specific gut bacteria At 12 mo of age, children with allergic disease At 12 mo of age, children with allergic Infants exposed to prenatal stress displayed In the 3-mo-old microbiome, relative In this study, a link to specific health Health Outcome and Timing of Assessment rhinoconjunctivitis, urticaria, and allergic eczema by 7 y of age response by 3 mo of age metabolic pathways Asthma, allergic Asthma, allergic Asthma at 7 y of age Children with asthma displayed lower overall GI symptoms and allergic BMI at 5 – 6 y Shifts in microbial Timing of Microbiome measured at 1 wk and y of age of age microbiome at postnatal days 7, 14, 28, 80, and 110 microbiome at 3 mo of age microbiome composition Analysis or Intervention IgA and total bacterial load Microbial diversity at 1 mo Variations in the Variations in the offspring Timing of Exposure Early-Life Factors and during pregnancy and breastfeeding None None Antibiotic treatment Variations in the gut Maternal high-fat diet Prenatal stress ts n = 56) Animal Model Study Population or design ( n = 48) design ( n = 47) design ( design from 2 cohor (Bibo cohort, n = 87; Flora cohort, n = 75) versus standard diet) Nested case-control Nested case-control Nested case-control Nested case-control Primate model (high-fat gies tions of Continued
1 later in life between propor IgA coating and bacteria bound to IgA in infancy development and allergy later in life diversity and bacterial abundances in the first year of life in association with asthma and aller intestinal microbiota composition in association with maternal prenatal stress and infant health microbiota composition is associated with childhood BMI and if antibiotic use modifies this association diet on the early-life microbiome in a primate model E L To analyze associations To analyze fecal microbial To investigate the infant To analyze if the early-life To analyze the impact of AB Research Objective
Obesity and metabolism T
Downloaded from www.aappublications.org/news by guest on September 28, 2021 10 Stiemsma and Michels 6 85 86 87 88 24 Ref. No. Summary of Findings born to mothers at a normal wt, whereas bacteroidetes were enriched in infants born to women who were obese. In this study, a link to an infant health outcome was not established, but differential microbiome metabolic functions that were based on whether infants were born to mothers at a normal wt or to women who were obese was identified resulted in increased fat accumulation in male offspring. Alterations microbiome composition occurred before measurements of body composition. In addition, through microbiota transfer experiments, the group reported that fat accumulation was driven by the cadmium- exposed microbiome in children who were obese infancy. Greater abundances of bifidobacteria in children at a normal wt in infancy accelerates total mass and bone growth. The authors also report that response to high-fat diet is altered depending on the particular antibiotic and number of courses used to perturb the microbiota microbiome richness and variations in the abundances of specific bacterial taxa compared with normal birth wt infants. Lactobacillus percentage was positively correlated with birth wt mice exposed to LDP for 4 or long-term LDP, 8 wk after birth displayed elevated caloric intake and faster total mass fat accumulation. The authors also report that the penicillin-selected microbiota can induce metabolic changes when transferred to GF mice Firmicutes were reported enriched in children Cadmium exposure in parental mice Early-life pulsed antibiotic treatment Low birth wt infants displayed lower gut Compared with controls and mice exposed to Health Outcome and Timing of Assessment mo of age measured in adulthood 3 – 6 wk adulthood Infant metabolism at 18 Body composition BMI measured at 7 y of age Greater abundance of Staphylococcus aureus Body composition from Birth wt Body composition in tly after ved at 8 wk and Timing of Microbiome completed shor microbiome composition and function microbiome composition obser adulthood (20 wk) microbiome composition between 6 and 12 mo of age weaning microbiome composition through weaning Analysis or Intervention Variations in infant Variations in the Variations in the Variations in the placental Timing of Exposure Early-Life Factors and obesity before parental mating Antibiotic-induced Pulsed antibiotic treatment Maternal prepregnancy None None Antibiotic-induced LDP exposure from birth n = 39) n = 49) Animal Model Study Population or versus standard diet) design ( design ( analysis ( n = 24) versus standard diet) Mouse model (high fat Nested case-control SPF mouse model Cadmium exposure 1 wk Nested case-control Prospective human cohort Mouse model (high-fat th wt Continued turbation with
1 early-life antibiotic use alters the gut microbiome composition and metabolic development maternal prepregnancy BMI on the infant gut microbiome composition and functional potential cadmium exposure on the early-life gut microbiota and metabolism in adulthood life gut microbiota composition is associated with wt development in early childhood microbiome varies in association with bir early-life microbial per antibiotic treatment on host metabolism and adiposity E L To better understand how To analyze the impact of To investigate the effect of To determine if the early- To determine if the placental To analyze the effect of AB Research Objective
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Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 141, number 4, April 2018 11 89 90 91 92 93 Ref. No. Summary of Findings Collinsella at a later age displayed lower adiposity at 18 mo of age. Infants who acquired these taxa at 6 mo showed the lowest adiposity at 18 mo. In addition, acquisition of these bacterial taxa was influenced by length of gestation and delivery mode adiposity by exposing mice in early life to antibiotics. Variations in microbial composition before adiposity measurement the antibiotics was not assessed. However, did alter the microbiome composition, SCFA metabolism, and hepatic metabolism of fatty acids and lipids wk of age is associated with BMI SD score between 1 and 3 y of age. Abundance Staphylococcus at 3 and 52 wk is inversely associated with BMI SD score between 1 and 3 y hypercorticosteronemia, enhanced intestinal permeability, decreased microbial diversity, and variations in specific microbial taxa compositional variations in the gut microbiome of offspring mice. Offspring mice of mothers on a high-fat diet cohoused with mice born of mothers raised on a regular diet displayed normal social In addition, reintroduction of behavior. L reuteri (lacking in offspring mice of a mother on a high-fat diet) restored normal social behavior in these mice The authors generated a mouse model of Abundance of Bacteroides fragilis at 3 and 26 Limited-nesting pups had A maternal high-fat diet induces – 20 wk) – 12-wk-old offspring Health Outcome and Timing of Assessment measured in adulthood (16 from postnatal days 2 – 10 7 and 3 y of age mice Body composition Limited nesting stress Behavior exams on Adiposity at 18 mo of age Infants with high Bifidobacterium and BMI SD score between 1 Timing of Microbiome microbiome measured before sacrifice microbiome composition 21 d post birth (at weaning) microbiome composition in offspring microbiome before 6 mo of age microbiome composition within the first year of age Analysis or Intervention Variations in the Variations in the Timing of Exposure Early-Life Factors and delivery mode Antibiotic-induced Variations in the Limited nesting stress Variations in the gut Gestational age and None t t Animal Model Study Population or induced adiposity nesting stress analysis ( n = 75) analysis ( n = 138) Prospective human cohor Mouse model of antibiotic- Prospective human cohor Rat model of limited High-fat diet mouse model Maternal high-fat diet Variations in the gut Continued ticosterone levels, and
1 early-life factors on the trajectory of gut microbial development and childhood adiposity subtherapeutic antibiotic administration on the gut microbiome and host metabolism between the early-life gut microbiome composition and BMI in childhood nesting stress alters offspring microbiota, cor intestinal permeability high-fat-diet-induced obesity is associated with social behavioral deficits and altered microbiota in the offspring E L To investigate the effects of To analyze the effect of To analyze the association To determine if limited To determine if maternal AB Research Objective
Neurodevelopment T
Downloaded from www.aappublications.org/news by guest on September 28, 2021 12 Stiemsma and Michels 7 95 96 97 94 Ref. No. ticosterone and β in the placenta and ticosterone levels and altered Summary of Findings colonic mucosal barrier function in maternally separated rat pups. Early-life administration of probiotics (composed Lactobacillus rhamnosus and helveticus strains) to rat pups ameliorates these findings and persists to adulthood α increased tumor necrosis factor- and interferon- γ . Also, the microbiome composition varied in the maternally separated group compared with the rats that were not maternally separated behavior in male and female adolescent offspring. Postnatal propionic acid increased anxiety-like behavior in female offspring only. Prenatal propionic acid and LPS induced developmental delays (including delays in eye opening) on the basis of their microbiome. Group 1 displayed high abundance of Faecalibacterium , group 2 displayed high abundance of Bacteroides , and group 3 displayed high abundance of ruminococcaceae. Individual Mullen scales differed between groups. α diversity was negatively associated with individual Mullen scales at 2 y of age (expressive language and visual reception) with variations in the microbiome of dams, offspring, and in the placenta. Additionally, prenatal stress is associated with increased IL-1 reduced brain-derived neurotrophic factor in placenta and adult offspring amygdala Increased cor Increased plasma cor Three groups of subjects were identified Prenatal maternal stress was associated Health Outcome and Timing of Assessment adrenal axis activity disorders and irritable bowel syndrome offspring and 2 y of age Hypothalamus-pituitary- Symptoms of psychiatric Behavior traits in offspring Prenatal propionic acid increased anxiety-like Anxiety-like behavior in Cognitive outcomes at 1 Timing of Microbiome and gut function in offspring composition in rat pups propionic acid exposure microbiome and fecal microbiome of offspring identified on the basis of their 1-y microbiome analysis Analysis or Intervention Variations in microbiome Variations in microbiome Pre- and postnatal LPS or Variations in placental 3 groups of subjects were Timing of Exposure Early-Life Factors and early life (day 4 to day 19) early life to have been breastfed, less likely to have been born by cesarean delivery, and associated with white ethnicity. Having older siblings was associated with increased α diversity Maternal separation in Maternal separation in None Prenatal stress Group 2 was more likely Animal Model Study Population or induced by maternal separation) induced by maternal separation) stress analysis ( n = 89) Rat model (stress Rat model (stress Rat model Mouse model of prenatal Prospective human cohort Continued ticular infant gut
1 administration in early life modifies maternal separation-induced gut dysfunction stress alters the gut-brain axis prenatal and early-life exposure to propionic acid and LPS on offspring gut microbial metabolism, locomotor activity, and anxiety-like behavior ability is associated with par prenatal stress alters the microbial intrauterine environment and behavior in offspring microbiota profiles E L To determine if probiotic To determine if early-life To examine the effects of To determine if cognitive To determine if maternal AB Research Objective
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Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 141, number 4, April 2018 13 76 98 99 101 100 Ref. No. . Offspring abundance is decreased in the Summary of Findings microbiota compared with GF conditions protected mice from oxazolone-induced colitis vaginal microbiome and in neonates born to dams exposed early prenatal stress. Other bacterial population abundances also varied in offspring exposed to early prenatal stress. Early stress altered metabolic profiles and amino acid availability in the brain behaviors compared with SPF mice. These mice spent less time exploring the open arms in the maze (less locomotor activity). Additionally, colonized mice expressed less synaptophysin and PSD-95 in the striatum compared with GF mice, suggesting the microbiome is involved in programming brain development high-fat-diet- or control low-fat-diet- associated gut microbiome. Offspring of these mice displayed altered behavior in a sex-dependent manner mice displayed less stress after maternal separation. Male offspring displayed decreased exploratory and cognitive behaviors, which is indicative of increased anxiety. Female mice displayed increases in adiposity and body wt in differential gene expression, exon usage, RNA editing, and upstream gene regulation in the amygdala. This was similar to mice who were raised GF for their entire lives but varied when compared with conventionalized mice Lactobacillus Absence of a microbiota in early life results Health Outcome and Timing of Assessment programming and in offspring amygdala Colitis induced later in life Neonatal exposure to a conventional Metabolic and neurologic Behavior in adulthood Adult colonized offspring displayed similar Behavior traits in offspring Female mice were transplanted with a Neuronal activity in the Timing of Microbiome pregnancy lead to SPF- colonized offspring vaginal and neonatal gut microbiome mice colonized with SPF microbiota with high-fat diet microbiome weaning Analysis or Intervention SPF-colonization during Variations in the maternal Offspring of previously GF GF mice colonized after Timing of Exposure Early-Life Factors and None Prenatal stress Maternal high-fat diet Female mice transplanted None Animal Model Study Population or oxazolone-induced colitis stress with maternal high-fat- diet-shaped microbiota raised mouse models Mouse model of Mouse model of prenatal GF and SPF mouse models None Mouse model colonized GF and conventionally Continued
1 microbial modulation of iNKTs in mouse models of IBD and asthma variations in the vaginal microbiome are associated with varied offspring programming by gut microbiota in early life impacts brain development and adult behavior high-fat-diet-altered microbiome can modify offspring behavior molecular mechanisms that underlie the gut-brain axis E L To investigate age-dependent To examine whether To determine if colonization To determine if a maternal To analyze the microbial and Immune-mediated diseases (IBD, T1D, etc)
AB Research Objective
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Downloaded from www.aappublications.org/news by guest on September 28, 2021 14 Stiemsma and Michels 105 104 103 102 Ref. No. t reatment with antibiotics -cell – mediated inflammation Summary of Findings mixture (neomycin, polymyxin B, and streptomycin) were protected from T1D compared with mice treated postnatally. Microbiota transfer from these mice to untreated mice resulted in protection from T1D resulted in differential shifts the offspring and maternal microbiomes. Offspring treated prenatally with neomycin were protected from T1D development, whereas offspring treated prenatally with vancomycin displayed accelerated T1D development. The antibiotic treatment also resulted in altered immune profiles, such as increased T in mice treated with vancomycin and altered antigen-presenting cell phenotypes in mice treated with neomycin increased incidence of T1D in male mice. Antibiotic treatment also resulted in near ablation of the gut microbiome at 8 wk of age, which may partially explain the increased T1D incidence in male mice from conception until 40 wk postnatal development. T microbial compositional alterations, including eradication of segmented filamentous bacteria. In addition, after DSS- induced colitis, LDP mice displayed reduced colitis symptoms, Il-17 expression, and ileal Th17 differentiation compared with mice exposed to metronidazole, enrofloxacin, and controls. Finally, the authors repor penicillin ’ s effects are dependent on eradiation of segmented filamentous bacteria, implicating the microbiome as mediator between this early life exposure and colitis development Pregnant, NOD mice treated with an antibiotic Prenatal neomycin and vancomycin treatment Antibiotics were administered to NOD mice Health Outcome and Timing of Assessment later in life later in life later in life Spontaneous diabetes Spontaneous diabetes Spontaneous diabetes Colitis induced later in life LDP-treated mice displayed transient gut Timing of Microbiome treatment induced variations in offspring microbiome treatment induced variations in offspring and maternal microbiomes life (conception until 40 wk postnatal) Analysis or Intervention Timing of Exposure Early-Life Factors and Antibiotic-induced LDP after weaning Animal Model Study Population or colitis NOD mouse model Antibiotic-induced Prenatal antibiotic NOD mouse model Antibiotic-induced Prenatal antibiotic NOD mouse model Antibiotic-induced Antibiotic treatment in early Mouse model DSS-induced Continued geting Gram-negative
1 tar gut bacteria at various time points in early life on T1D development prenatal antibiotics can protect offspring from T1D of gut dysbiosis in the progression of T1D early-life exposure to antibiotics changes susceptibility to IBD E L To determine the impact of To determine if exposure to To explore the influence To determine if and how
AB Research Objective
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Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 141, number 4, April 2018 15 46 108 107 106 Ref. No. Summary of Findings fed a normal diet, high-fiber diet during pregnancy and breastfeeding resulted in increased plasma SCFAs in the offspring. These offspring also displayed higher frequencies of thymic and peripheral cells, which may be prompted T-regulatory by increased SCFA levels increases risk of spontaneous colitis in offspring. Antibiotics also contribute to immune skewing and promote gut dysbiosis that persists to adulthood. Additionally, as demonstrated by fecal transplant to GF IL-10 knock-out dams, immune skewing is mediated by the antibiotic-induced dysbiosis by the gut microbiome composition. Seroconverted subjects diagnosed with T1D displayed a marked decrease in α diversity before diagnosis when compared with seroconverted subjects not diagnosed with T1D and nonseroconverted subjects altered the mouse microbiome and accelerated T1D development compared with mice treated subtherapeutic penicillin from pregnancy to week 12 Compared with offspring from maternal mice Peripartum exposure to cefoperazone T1D disease state was distinguishable Pulsed postnatal treatment with tylosin Health Outcome and Timing of Assessment peripheral T-regulatory peripheral T-regulatory cells in life of age later in life Spontaneous colitis later T1D diagnosis at ∼ 3 y Spontaneous diabetes Timing of Microbiome treatment induced gut dysbiosis in offspring that persists to adulthood microbiome before diagnosis with T1D induced variations in 6-wk-old microbiome Analysis or Intervention Increased plasma SCFAs Increased thymic and Variations in the Timing of Exposure Early-Life Factors and during pregnancy and breastfeeding Maternal high-fiber diet Antibiotic-induced Peripartum antibiotic None t Animal Model Study Population or model model combined with DSS-induced colitis analysis ( n = 33) SPF GPR41 − / mouse SPF IL-10 knock-out mouse Prospective human cohor NOD mouse model Antibiotic-induced Pulsed antibiotic treatment -regulatory cell tum cefoperazone Continued
1 a maternal high-fiber diet on T differentiation in the offspring peripar administration on the maternal and offspring microbiota and IBD in the offspring between the infant gut microbiome and T1D development of pulsed therapeutic antibiotics or continuous low-dose antibiotics in early life on T1D development E L To analyze the impact of To analyze the effect of To analyze the association To compare the effects
AB Research Objective
T airwaysprotein – coupled receptor 43; Grx1, Glutaredoxin-1; GI, gastrointestinal; GPR41, G protein – coupled receptor 41; GPR43, 16; DSS, dextran sodium sulfate; chemokine ligand 4; CXCL16, differentiation cluster of disease; CD4+, allergic AAD, invariant natural killer T cell; LPS, lipopolysaccharide; NOD, nonobese diabetic; PD-L1, programmed death ligand-1; PSD-95, HDAC9, histone deacetylase 9; IgA, immunoglobulin A; IL-1 β , interleukin 1 beta; IL-10, 10; IL-17, 17; iNKT, 17; TLR, Toll-like receptor; T1D, type 1 diabetes. 1; Th17, T-helper postsynaptic density protein 95; Ref., reference; Th1, T-helper
Downloaded from www.aappublications.org/news by guest on September 28, 2021 16 Stiemsma and Michels 3 months of age and an increased be transferred6 to GF mice to induce report impaired social behavior enterobacteriaceae/bacteroidaceae obesity. It will be important for (similar to that observed in autism ratio at 3 months and 1 year of age, future researchers to incorporate spectrum disorder) in the offspring which was associated with increased both prospective human studies of dams that were fed a high-fat diet, food sensitization among 1-year- and animal models to determine which is mediated by variations old children. Variations in the gut the microbiome-associated effects in the offspring microbiome. In microbiome at 3 and 6 months of age of early-life antibiotic exposure on addition, using shotgun Lactobacillusmetagenomic have also been associated with the human health. Neurodevelopmental Disorders reuterisequencing, this group identified a resolution of a milk allergy by 8 years significant reduction in 75 – of age. Thus, authors of the current among the 93maternalL reuteri high-fat microbiome research for asthma A less intuitive role of the gut diet fed offspring. Supplementation and allergies suggest the time period microbiome in human health and of drinking water with between birth and 1 year of age as development is the impact of resulted in restoration93 of offspring the developmental origins window early-life microbial dysbiosis in social deficits. Notably, the majority for this disease. These immune neurodevelopment (ie, the gut-brain of studies with researchers focusing hypersensitivities persist into later axis). There is increasing evidence on the early-life critical window childhood and adulthood despite to support early-life microbial in relation to neurodevelopment the transient nature of microbial compositional variations in stress have been conducted in animal dysbiosis. Obesity response and anxiety. In animal models, models. However, there is recent it is suggested that neonatal stress evidence to support a role of the after maternal separation results infant gut microbiome in cognitive development in humans. Carlson Similar to asthma and atopic disease, in long-term compositional 95,changes96 94 α prospective studies reveal early- to the intestinal microbiota, et al reported variations in gut life gut microbiome compositional and treating rat pups with probiotics microbiome diversity in 1-year- variations, which precede88, 91the can counter the resulting95 elevated old children, which correlated with development of obesity. A corticosterone levels. Prenatal their cognitive abilities measured at recent study reveals temporal exposure to the SCFA, propionic age 2. Additional studies in humans and compositional microbiome acid, was also reported to increase97 will substantiate this evidence. associationsStreptococcus89 with early childhood anxiety-like behavior in mice.7 However, it is interesting to note adiposity. Specifically, infants with In a recent study, Gur et al report that researchers consistently identify high abundance at 6 the influence of prenatal maternal the time period between pregnancy months of age displayed increased89 stress in mice and its ability to alter and the first year of life as the most adiposity at 18 months of age. This both the maternal and neonatal influential in human development. emphasizes the importance of both intestinal microbiomes. Adult microbiome composition and timing offspring exposed to prenatal Collectively, this disease-specific of microbiome maturation in the maternal stress also displayed 7 research is used to support a role development of childhood obesity. increased anxiety-like behavior. of the early-life microbiome in Additionally, prenatal stress also Mouse model studies have been fetal and childhood development induced variations in the placental used to mechanistically support 7 in a variety of contexts. However, microbiome. This suggests that the the potential metabolic effects prediagnostic variations in the early- intrauterine microbial environment of early-life microbial dysbiosis life microbiome composition have is a potential mediator of maternal and emphasize the obesity- been associated with other chronic prenatal stress and resulting stress in inducing abilities of antibiotics. In noncommunicable diseases in later 90 the offspring. a study by Cho et al, antibiotics childhood and adulthood (ie, IBD1 administered to mice in early life Variations in the gut microbiome and type 1 diabetes, Table112 1). In resulted in subsequent increases have also been associated with addition, Harris et al identified an association between adolescent in adiposity and metabolic6 many facets of social behavior. hormones. Cox et al furthered Adult offspring of conventionalized diet and breast cancer diagnosed in this research by manipulating the dams (previously GF but colonized adulthood, suggesting that the timing – early-life microbiota using low- with the microbiome of specific of susceptibility for the microbiome dose penicillin (LDP). Here, they pathogen free [SPF] mice) were may also be disease specific. The report LDP exposure during early reported to display decreased motor future of research surrounding the life increased the effect of a high-fat activity compared98 with offspring93 microbiome in DOHaD is thus ripe diet on the microbiota, which could from GF dams. Buffington et al with opportunity. Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 141, number 4, April 2018 17 Conclusions and Future References 11. Barker DJ, Osmond C. Infant mortality, Directions childhood nutrition, and ischaemic 1. Stiemsma LT, Reynolds LA, Turvey SE, heart disease in England and Wales. Finlay BB. The hygiene hypothesis: Lancet. 1986;1(8489):1077–1081 current perspectives and future In this review, we summarize therapies. Immunotargets Ther. 12. Hjalgrim LL, Westergaard T, Rostgaard K, et al. Birth weight as a risk factor evidence supporting the role of 2015;4:143–157 the microbiome as a fundamental for childhood leukemia: a meta- part of human physiology and key 2. Stiemsma LT, Turvey SE. Asthma and analysis of 18 epidemiologic studies. the microbiome: defining the critical to our understanding of DOHaD. Am J Epidemiol. 2003;158(8):724–735 window in early life. Allergy Asthma 13. T richopoulos D. Hypothesis: does Pre- and postbirth exposures Clin Immunol. 2017;13:3 alter the microbiome composition breast cancer originate in utero? and functional potential in the 3. Tamburini S, Shen N, Wu HC, Clemente Lancet. 1990;335(8695):939–940 neonate. In turn, this dysbiosis JC. The microbiome in early life: 14. Strachan DP. Hay fever, hygiene, results in a number of health and implications for health outcomes. Nat and household size. BMJ. Med. 2016;22(7):713 722 disease outcomes later in life. – 1989;299(6710):1259–1260 Collaborative translational efforts 4. Arrieta MC, Stiemsma LT, Dimitriu 15. Shreiner A, Huffnagle GB, Noverr using both animal models and PA, et al; CHILD Study Investigators. MC. The “Microflora Hypothesis” of human samples will mechanistically Early infancy microbial and allergic disease. Adv Exp Med Biol. define the extent to which the metabolic alterations affect risk of 2008;635:113–134 microbiome plays a causal role childhood asthma. Sci Transl Med. 2015;7(307):307ra152 16. Ursell LK, Metcalf JL, Parfrey LW, Knight during this critical window of R. Defining the human microbiome. developmental plasticity. Multiomics 5. Stiemsma LT, Arrieta MC, Dimitriu Nutr Rev. 2012;70(suppl 1):S38–S44 approaches, combining epigenetic, PA, et al; Canadian Healthy Infant 17. Robinson CM, Pfeiffer JK. Viruses Longitudinal Development (CHILD) transcriptome, and microbiome and the microbiota. Annu Rev Virol. Study Investigators. Shifts in analyses in large, prospective, 2014;1:55–69 human birth cohorts will enhance Lachnospira and Clostridium sp. in 18. Arrieta MC, Stiemsma LT, Amenyogbe our current understanding of the 3-month stool microbiome are associated with preschool age asthma. N, Brown EM, Finlay B. The intestinal how the microbiome may interact Clin Sci (Lond). 2016;130(23):2199–2207 microbiome in early life: health and with host components to drive disease. Front Immunol. 2014;5:427 aspects of infant development. In 6. Cox LM, Yamanishi S, Sohn J, 19. Steel JH, Malatos S, Kennea N, et al. addition, as it is becoming clearer et al. Altering the intestinal Bacteria and inflammatory cells that the microbiota (both maternal microbiota during a critical developmental window has lasting in fetal membranes do not always and placental) can influence fetal cause preterm labor. Pediatr Res. development, more research metabolic consequences. Cell. 2014;158(4):705 721 2005;57(3):404–411 surrounding the vaginal and – 20. Satokari R, Gr nroos T, Laitinen K, intrauterine microbiomes is needed 7. Gur TL, Shay L, Palkar AV, et al. Prenatal ö Salminen S, Isolauri E. Bifidobacterium to paint a fuller picture of the fetal stress affects placental cytokines and and Lactobacillus DNA in the human neurotrophins, commensal microbes, and neonatal origins of disease. placenta. Lett Appl Microbiol. and anxiety-like behavior in adult We propose revisiting DOHaD and 2009;48(1):8–12 incorporating the microbiome female offspring. Brain Behav Immun. 2017;64:50 58 21. Collado MC, Rautava S, Aakko J, into our current understanding of – Isolauri E, Salminen S. Human gut the many aspects of early human 8. Mueller NT, Bakacs E, Combellick J, colonisation may be initiated in utero development associated with long- Grigoryan Z, Dominguez-Bello MG. by distinct microbial communities in term health. The infant microbiome development: the placenta and amniotic fluid.Sci mom matters. Trends Mol Med. Rep. 2016;6:23129 Abbreviations 2015;21(2):109–117 22. Gomez de Agüero M, Ganal-Vonarburg 9. Waterland RA, Michels KB. Epigenetic SC, Fuhrer T, et al. The maternal epidemiology of the developmental microbiota drives early postnatal DOHaD: Developmental Origins origins hypothesis. Annu Rev Nutr. innate immune development. Science. of Health and Disease 2007;27:363–388 2016;351(6279):1296–1302 GF: germ free 10. Osmond C, Barker DJ, Winter PD, 23. Bassols J, Serino M, Carreras-Badosa IBD: inflammatory bowel disease Fall CH, Simmonds SJ. Early growth G, et al. Gestational diabetes is LDP: low-dose penicillin and death from cardiovascular associated with changes in placental NEC: necrotizing enterocolitis disease in women. BMJ. microbiota and microbiome. Pediatr SCFA: short-chain fatty acid 1993;307(6918):1519–1524 Res. 2016;80(6):777–784 SPF: specific pathogen free Downloaded from www.aappublications.org/news by guest on September 28, 2021 18 Stiemsma and Michels 24. Zheng J, Xiao X, Zhang Q, Mao L, Yu chronic immune disorders. Pediatrics. maternal asthma and wheezing in M, Xu J. The placental microbiome 2015;135(1). Available at: www. the first year of life: a longitudinal varies in association with low birth pediatrics.org/cgi/content/full/135/1/ birth cohort study. Eur Respir J. weight in full-term neonates. Nutrients. e92 2017;49(5):1602019 2015;7(8):6924 6937 – 34. Dominguez-Bello MG, De Jesus-Laboy 44. Ma J, Prince AL, Bader D, et al. High- 25. Prince AL, Ma J, Kannan PS, et al. The KM, Shen N, et al. Partial restoration fat maternal diet during pregnancy placental membrane microbiome of the microbiota of cesarean-born persistently alters the offspring is altered among subjects with infants via vaginal microbial transfer. microbiome in a primate model. Nat spontaneous preterm birth with and Nat Med. 2016;22(3):250–253 Commun. 2014;5:3889 without chorioamnionitis. Am J Obstet 35. Yatsunenko T, Rey FE, Manary MJ, 45. Chu DM, Antony KM, Ma J, et al. The Gynecol. 2016;214(5):627.e1 627.e16 – et al. Human gut microbiome viewed early infant gut microbiome varies in 26. Antony KM, Ma J, Mitchell KB, Racusin across age and geography. Nature. association with a maternal high-fat DA, Versalovic J, Aagaard K. The 2012;486(7402):222–227 diet. Genome Med. 2016;8(1):77 preterm placental microbiome varies 36. Cabrera-Rubio R, Collado MC, Laitinen 46. Nakajima A, Kaga N, Nakanishi Y, in association with excess maternal K, Salminen S, Isolauri E, Mira A. The et al. 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Downloaded from www.aappublications.org/news by guest on September 28, 2021 The Role of the Microbiome in the Developmental Origins of Health and Disease Leah T. Stiemsma and Karin B. Michels Pediatrics originally published online March 8, 2018;
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