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1.
Nat Microbiol ; 4(12): 2285-2297, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31501537

RESUMO

Hospitalized preterm infants receive frequent and often prolonged exposures to antibiotics because they are vulnerable to infection. It is not known whether the short-term effects of antibiotics on the preterm infant gut microbiota and resistome persist after discharge from neonatal intensive care units. Here, we use complementary metagenomic, culture-based and machine learning techniques to study the gut microbiota and resistome of antibiotic-exposed preterm infants during and after hospitalization, and we compare these readouts to antibiotic-naive healthy infants sampled synchronously. We find a persistently enriched gastrointestinal antibiotic resistome, prolonged carriage of multidrug-resistant Enterobacteriaceae and distinct antibiotic-driven patterns of microbiota and resistome assembly in extremely preterm infants that received early-life antibiotics. The collateral damage of early-life antibiotic treatment and hospitalization in preterm infants is long lasting. We urge the development of strategies to reduce these consequences in highly vulnerable neonatal populations.

2.
Infect Control Hosp Epidemiol ; 40(10): 1181-1183, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31352907

RESUMO

Antimicrobial stewardship programs typically use days of therapy to assess antimicrobial use. However, this metric does not account for the antimicrobial spectrum of activity. We applied an antibiotic spectrum index to a population of very-low-birth-weight infants to assess its utility to evaluate the impact of antimicrobial stewardship interventions.

3.
Infect Dis Ther ; 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30825133

RESUMO

INTRODUCTION: Very low birth weight (VLBW) neonates (< 1500 g) are commonly exposed to prolonged antibiotic courses related to concerns for presumed early onset sepsis often with unclear indications. While antibiotics can be life-saving medications, prolonged antibiotic exposure (> 5 days) increases an infant's risk for necrotizing enterocolitis, late onset sepsis, colonization or infection with resistant organisms, and death. The aim of this study is to describe clinical and laboratory factors that influence the length of initial antibiotic courses in VLBW neonates. METHODS: Demographics, perinatal factors, and neonatal clinical and laboratory data were compared in a single-center retrospective cohort of VLBW neonates who received ≤ 3 days versus > 5 days of initial antibiotics. RESULTS: A total of 121 patients were analyzed of which 117 (97%) were started on antibiotics empirically on admission, and 71 (59%) received ≤ 3 days and 50 (41%) received > 5 days of antibiotics. One (0.8%) infant had a positive blood culture (S. oralis). Demographics [gestational age (p < 0.001) and birth weight (p < 0.001)] and neonatal clinical status [Apgar score at 5 min (p = 0.001), CRIB II (p < 0.001), need for inotropes (p = 0.001), and maximum ventilator support (p < 0.001)] were significantly different between the short and prolonged course of antibiotics groups on bivariate analysis. There were no significant differences in perinatal factors or common laboratory markers of sepsis. Maximum ventilator support remained significant on multivariate analysis (p = 0.007). CONCLUSION: In the VLBW population, the clinical status of the neonate, as represented by maximum ventilator support in this study, was the most important factor in determining the duration of initial antibiotic treatment. Laboratory values and perinatal risk factors did not significantly influence prescribing patterns.

4.
Birth Defects Res ; 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30430765

RESUMO

Maternal immune activation (MIA) refers to a maternal immune system triggered by infectious or infectious-like stimuli. A cascade of cytokines and immunologic alterations are transmitted to the fetus, resulting in adverse phenotypes most notably in the central nervous system. Epidemiologic studies implicate maternal infections in a variety of neuropsychiatric disorders, most commonly autism spectrum disorders and schizophrenia. In animal models, MIA causes neurochemical and anatomic changes in the brain that correspond to those found in humans with the disorders. As our understanding of the interactions between environment, genetics, and immune system grows, the role of alternative, noninfectious risk factors, such as prenatal stress, obesity, and the gut microbiome also becomes clearer. This review considers how infectious and noninfectious etiologies activate the maternal immune system. Their impact on fetal programming and neuropsychiatric disorders in offspring is examined in the context of human and animal studies.

5.
Nat Med ; 24(12): 1822-1829, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30374198

RESUMO

Commensal gut bacterial communities (microbiomes) are predicted to influence human health and disease1,2. Neonatal gut microbiomes are colonized with maternal and environmental flora and mature toward a stable composition over 2-3 years3,4. To study pre- and postnatal determinants of infant microbiome development, we analyzed 402 fecal metagenomes from 60 infants aged 0-8 months, using longitudinal generalized linear mixed models (GLMMs). Distinct microbiome signatures correlated with breastfeeding, formula ingredients, and maternal gestational weight gain (GWG). Amino acid synthesis pathway accretion in breastfed microbiomes complemented normative breastmilk composition. Prebiotic oligosaccharides, designed to promote breastfed-like microflora5, predicted functional pathways distinct from breastfed infant microbiomes. Soy formula in six infants was positively associated with Lachnospiraceae and pathways suggesting a short-chain fatty acid (SCFA)-rich environment, including glycerol to 1-butanol fermentation, which is potentially dysbiotic. GWG correlated with altered carbohydrate degradation and enriched vitamin synthesis pathways. Maternal and postnatal antibiotics predicted microbiome alterations, while delivery route had no persistent effects. Domestic water source correlates suggest water may be an underappreciated determinant of microbiome acquisition. Clinically important microbial pathways with statistically significant dietary correlates included dysbiotic markers6,7, core enterotype features8, and synthesis pathways for enteroprotective9 and immunomodulatory10,11 metabolites, epigenetic mediators1, and developmentally critical vitamins12, warranting further investigation.

6.
Pediatr Res ; 2018 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-30283047

RESUMO

Bidirectional communication between the gut and brain is well recognized, with data now accruing for a specific role of the gut microbiota in that link, referred to as the microbiome-gut-brain axis. This review will discuss the emerging role of the gut microbiota in brain development and behavior. Animal studies have clearly demonstrated effects of the gut microbiota on gene expression and neurochemical metabolism impacting behavior and performance. Based on these changes, a modulating role of the gut microbiota has been demonstrated for a variety of neuropsychiatric disorders, including depression, anxiety, and movement including Parkinson's, and importantly for the pediatric population autism. Critical developmental windows that influence early behavioral outcomes have been identified that include both the prenatal environment and early postnatal colonization periods. The clearest data regarding the role of the gut microbiota on neurodevelopment and psychiatric disorders is from animal studies; however, human data have begun to emerge, including an association between early colonization patterns and cognition. The importance of understanding the contribution of the gut microbiota to the development and functioning of the nervous system lies in the potential to intervene using novel microbial-based approaches to treating neurologic conditions. While pathways of communication between the gut and brain are well established, the gut microbiome is a new component of this axis. The way in which organisms that live in the gut influence the central nervous system (CNS) and host behavior is likely to be multifactorial in origin. This includes immunologic, endocrine, and metabolic mechanisms, all of which are pathways used for other microbial-host interactions. Germ-free (GF) mice are an important model system for understanding the impact of gut microbes on development and function of the nervous system. Alternative animal model systems have further clarified the role of the gut microbiota, including antibiotic treatment, fecal transplantation, and selective gut colonization with specific microbial organisms. Recently, researchers have started to examine the human host as well. This review will examine the components of the CNS potentially influenced by the gut microbiota, and the mechanisms mediating these effects. Links between gut microbial colonization patterns and host behavior relevant to a pediatric population will be examined, highlighting important developmental windows in utero or early in development.

7.
J Am Coll Surg ; 227(4): 439-449, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30077861

RESUMO

BACKGROUND: Pediatric short bowel syndrome (SBS) is a malabsorptive state placing patients at risk for malnutrition, dehydration, and bacterial overgrowth. These patients are often dependent on parenteral nutrition (PN) while intestinal adaptation is underway. The aim of this study was to characterize the effect of remnant small bowel length on the gut microbiome. Further, we sought to examine the contribution of clinical and nutritional variables to the gut microbiota and anthropometric growth. STUDY DESIGN: Clinical data, anthropometrics, and fecal samples were collected from 14 SBS patients and 10 age- and sex-matched controls. Fecal bacterial DNA composition was analyzed using 16s ribosomal RNA gene sequencing. Statistical analysis was completed using the Mann-Whitney or Fisher's exact tests when applicable and linear mixed effect modeling. RESULTS: Distinct microbiota changes were found among those with the least remaining small bowel (<35 cm) compared with those with longer remaining bowel and controls. Those with <35 cm small bowel displayed an increased relative abundance of Proteobacteria, while those with longer remaining small bowel had a higher proportion of Firmicutes. Further, patients with less remaining bowel required more PN (p < 0.01), with a tendency to be shorter in height (p = 0.05) and with a higher BMI (p = 0.05). CONCLUSIONS: Remnant small bowel length appears to be a predictor of stunting with diminished linear growth, parenteral nutrition dependency, and a greater relative abundance of Proteobacteria in the gut. These findings suggest an integrated adaptive response predicted by remnant intestinal length. Further research is necessary to examine the effects of intestinal dysbiosis on clinical outcomes.

8.
Clin Infect Dis ; 67(2): 269-274, 2018 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-29394356

RESUMO

Background: Cronobacter sakazakii causes severe neonatal infections, but we know little about gut carriage of this pathogen in very low birthweight infants. Methods: We sequenced 16S ribosomal RNA (rRNA) genes from 2304 stools from 121 children at St Louis Children's Hospital whose birthweight was ≤1500 g, attempted to isolate C. sakazakii from 157 of these stools, genome-sequenced the recovered isolates, and sought correlations between indices of Cronobacter excretion, host characteristics, and unit formula use. Results: Of these 2304 stools, 1271 (55.2%) contained Cronobacter rRNA gene sequences. The median (interquartile range) per-subject percentage of specimens with at least 1 Cronobacter sequence and the median per-subject read density were 57.1 (25.5-87.3) and 0.07 (0.01-0.67), respectively. There was no variation according to commercially prepared liquid vs powdered formula use in the neonatal intensive care unit, or the day of life that specimens were produced. However, the proportion of specimens containing >4.0% of reads mapping to Cronobacter fell from 4.3% to 0.9% after powdered infant formula was discontinued (P < .0001). We isolated sequence type 4 (ST4) C. sakazakii from multiple specimens from 2 subjects; 1 also harbored sequence type 233. The sequenced ST4 isolates from the 2 subjects had >99.9% sequence identity in the approximately 93% of best-match reference genome that they contained, and shared multiple virulence loci. Conclusions: Very low birthweight infants excrete putatively pathogenic Cronobacter. High-density Cronobacter sequence samples were more common during the use of powdered infant formula. Better understanding of the ecology of Cronobacter in infant guts will inform future prevention and control strategies.

9.
Hum Mutat ; 38(11): 1477-1484, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28726266

RESUMO

Biallelic GLDN mutations have recently been identified among infants with lethal congenital contracture syndrome 11 (LCCS11). GLDN encodes gliomedin, a protein required for the formation of the nodes of Ranvier and development of the human peripheral nervous system. We report six infants and children from four unrelated families with biallelic GLDN mutations, four of whom survived beyond the neonatal period into infancy, childhood, and late adolescence with intensive care and chronic respiratory and nutritional support. Our findings expand the genotypic and phenotypic spectrum of LCCS11 and demonstrate that the condition may not necessarily be lethal in the neonatal period.


Assuntos
Artrogripose/diagnóstico , Artrogripose/genética , Genes Letais , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , Fenótipo , Artrogripose/mortalidade , Biópsia , Análise Mutacional de DNA , Evolução Fatal , Estudos de Associação Genética , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Raízes Nervosas Espinhais/ultraestrutura , Sequenciamento Completo do Exoma
11.
J Pediatr Surg ; 52(6): 993-998, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28410788

RESUMO

INTRODUCTION: Necrotizing enterocolitis (NEC) is a common and devastating gastrointestinal disease of premature infants. NEC severity varies widely. Recent data have demonstrated a strong link between gut microbial dysbiosis and development of NEC. We tested the hypothesis that alterations in the gut microbiome at the time of diagnosis predict the severity of NEC. METHODS: We used prospectively collected fecal samples from very low birth weight infants who developed NEC, stratifying by NEC severity. Fecal bacterial DNA was sequenced using 16S rRNA pyrosequencing. A generalized Wald-type test based on the Dirichlet multinomial distribution was used to test for differences in microbial communities. RESULTS: Of 489 infants at risk, 30 NEC cases had 410 fecal samples collected in the 28days prior to the onset of NEC available for analysis. There were no differences in the pre-NEC gut microbial community between infants treated medically vs. surgically, or those with NEC totalis. Furthermore, neither treatment of NEC significantly changed the gut microbiome post-NEC among the survivors. CONCLUSION: We found no evidence that the gut microbiome, prior to the onset of disease, differentiates the clinical course of NEC. These data suggest that factors other than the gut microbiome may dictate disease severity. LEVEL OF EVIDENCE: Level 4.


Assuntos
Enterocolite Necrosante/microbiologia , Microbioma Gastrointestinal , Doenças do Prematuro/microbiologia , Índice de Gravidade de Doença , Enterocolite Necrosante/diagnóstico , Fezes/microbiologia , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/diagnóstico , Recém-Nascido de muito Baixo Peso , Masculino , Estudos Prospectivos
12.
Microbiome ; 5(1): 31, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28274256

RESUMO

BACKGROUND: Necrotizing enterocolitis (NEC) is a catastrophic disease of preterm infants, and microbial dysbiosis has been implicated in its pathogenesis. Studies evaluating the microbiome in NEC and preterm infants lack power and have reported inconsistent results. METHODS AND RESULTS: Our objectives were to perform a systematic review and meta-analyses of stool microbiome profiles in preterm infants to discern and describe microbial dysbiosis prior to the onset of NEC and to explore heterogeneity among studies. We searched MEDLINE, PubMed, CINAHL, and conference abstracts from the proceedings of Pediatric Academic Societies and reference lists of relevant identified articles in April 2016. Studies comparing the intestinal microbiome in preterm infants who developed NEC to those of controls, using culture-independent molecular techniques and reported α and ß-diversity metrics, and microbial profiles were included. In addition, 16S ribosomal ribonucleic acid (rRNA) sequence data with clinical meta-data were requested from the authors of included studies or searched in public data repositories. We reprocessed the 16S rRNA sequence data through a uniform analysis pipeline, which were then synthesized by meta-analysis. We included 14 studies in this review, and data from eight studies were available for quantitative synthesis (106 NEC cases, 278 controls, 2944 samples). The age of NEC onset was at a mean ± SD of 30.1 ± 2.4 weeks post-conception (n = 61). Fecal microbiome from preterm infants with NEC had increased relative abundances of Proteobacteria and decreased relative abundances of Firmicutes and Bacteroidetes prior to NEC onset. Alpha- or beta-diversity indices in preterm infants with NEC were not consistently different from controls, but we found differences in taxonomic profiles related to antibiotic exposure, formula feeding, and mode of delivery. Exploring heterogeneity revealed differences in microbial profiles by study and the target region of the 16S rRNA gene (V1-V3 or V3-V5). CONCLUSIONS: Microbial dysbiosis preceding NEC in preterm infants is characterized by increased relative abundances of Proteobacteria and decreased relative abundances of Firmicutes and Bacteroidetes. Microbiome optimization may provide a novel strategy for preventing NEC.


Assuntos
Disbiose , Enterocolite Necrosante/microbiologia , Fezes/microbiologia , Microbioma Gastrointestinal , Intestinos/fisiopatologia , Bactérias/isolamento & purificação , Bacteroides/genética , Bacteroides/isolamento & purificação , Firmicutes/genética , Firmicutes/isolamento & purificação , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro , Intestinos/microbiologia , Proteobactérias/genética , Proteobactérias/isolamento & purificação , RNA Ribossômico 16S
14.
Nat Microbiol ; 1: 16024, 2016 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-27572443

RESUMO

Development of the preterm infant gut microbiota is emerging as a critical research priority(1). Since preterm infants almost universally receive early and often extended antibiotic therapy(2), it is important to understand how these interventions alter gut microbiota development(3-6). Analysis of 401 stools from 84 longitudinally sampled preterm infants demonstrates that meropenem, cefotaxime and ticarcillin-clavulanate are associated with significantly reduced species richness. In contrast, vancomycin and gentamicin, the antibiotics most commonly administered to preterm infants, have non-uniform effects on species richness, but these can be predicted with 85% accuracy based on the relative abundance of only two bacterial species and two antibiotic resistance (AR) genes at treatment initiation. To investigate resistome development, we functionally selected resistance to 16 antibiotics from 21 faecal metagenomic expression libraries. Of the 794 AR genes identified, 79% had not previously been classified as AR genes. Combined with deep shotgun sequencing of all stools, we find that multidrug-resistant members of the genera Escherichia, Klebsiella and Enterobacter, genera commonly associated with nosocomial infections, dominate the preterm infant gut microbiota. AR genes that are enriched following specific antibiotic treatments are generally unique to the specific treatment and are highly correlated with the abundance of a single species. The most notable exceptions include ticarcillin-clavulanate and ampicillin, both of which enrich for a large number of overlapping AR genes, and are correlated with Klebsiella pneumoniae. We find that all antibiotic treatments are associated with widespread collateral microbiome impact by enrichment of AR genes that have no known activity against the specific antibiotic driver.


Assuntos
Antibacterianos/uso terapêutico , Farmacorresistência Bacteriana , Microbioma Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/microbiologia , Genes Bacterianos , Humanos , Recém-Nascido Prematuro , Estudos Longitudinais , Análise de Sequência de DNA
15.
Gut Microbes ; 7(5): 443-9, 2016 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-27472377

RESUMO

The gut microbiota plays important roles in nutrient absorption, immune system development, and pathogen colonization resistance. Perturbations early in life may be detrimental to host health in the short and the long-term. Antibiotics are among the many factors that influence the development of the microbiota. Because antibiotics are heavily administered during the first critical years of gut microbiota development, it is important to understand the effects of these interventions. Infants, particularly those born prematurely, represent an interesting population because they receive early and often extensive antibiotic therapy in the first months after birth. Gibson et al. recently demonstrated that antibiotic therapy in preterm infants can dramatically affect the gut microbiome. While meropenem, ticarcillin-clavulanate, and cefotaxime treatments were associated with decreased species richness, gentamicin and vancomycin had variable effects on species richness. Interestingly, the direction of species richness response could be predicted based on the abundance of 2 species and 2 genes in the microbiome prior to gentamicin or vancomycin treatment. Nonetheless, all antibiotic treatments enriched the presence of resistance genes and multidrug resistant organisms. Treatment with different antibiotics further resulted in unique population shifts of abundant organisms and selection for different sets of resistance genes. In this addendum, we provide an extended discussion of these recent findings, and outline important future directions for elucidating the interplay between antibiotics and preterm infant gut microbiota development.


Assuntos
Antibacterianos/uso terapêutico , Bactérias/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Doenças do Recém-Nascido/tratamento farmacológico , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/microbiologia , Humanos , Lactente , Recém-Nascido , Doenças do Recém-Nascido/microbiologia , Recém-Nascido Prematuro
16.
Semin Fetal Neonatal Med ; 21(6): 388-393, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27345372

RESUMO

Late-onset neonatal bloodstream infections remain challenges in neonatology. Hand hygiene, line care, and judicious use of indwelling lines are welcome interventions, but might not reduce the incidence of late-onset neonatal bloodstream infections from bacteria originating in the gut. Accumulating data suggest that many pathogens causing late-onset neonatal bloodstream infections are of gut origin, including Gram-positive cocci. In addition to the host-canonical paradigm (i.e., all bacteria have equal risk of invasion and bloodstream infections are functions of variable infant susceptibility), we should now consider bacteria-canonical paradigms, whereby late-onset neonatal bloodstream infection is a function of colonization with a specific subset of bacteria with exceptional invasive potential. In either event, we can no longer be content to reactively approach late-onset neonatal bloodstream infections; instead we need to reduce the occurrences of these infections by broadening our scope of effort beyond line care, and determine the pre-invasive habitat of these pathogens.


Assuntos
Bacteriemia/prevenção & controle , Microbioma Gastrointestinal , Bacteriemia/microbiologia , Humanos , Recém-Nascido
17.
Semin Fetal Neonatal Med ; 21(6): 394-399, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27343151

RESUMO

Necrotizing enterocolitis remains an intractable consequence of preterm birth. Gut microbial communities, especially bacterial communities, have long been suspected to play a role in the development of necrotizing enterocolitis. Direct-from-stool nucleic acid sequencing technology now offers insights into the make-up of these communities. Data are now converging on the roles of Gram-negative bacteria as causative agents, despite the dynamic nature of bacterial populations, the varying technologies and sampling strategies, and the overall small sample sizes in these case-control studies. Bacteria that confer protection from necrotizing enterocolitis have not been identified across studies. The beneficial effect of probiotics is not apparent in infants with birth weights <1000 g (these infants are at greatest risk of, and have the highest case fatality rate from, necrotizing enterocolitis). Further work should be directed to the modulating gut microbes, or the products they produce, to prevent this devastating complication of preterm birth.


Assuntos
Enterocolite Necrosante/microbiologia , Microbioma Gastrointestinal , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Nascimento Prematuro , Probióticos
18.
Nature ; 534(7606): 263-6, 2016 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-27279225

RESUMO

Immunoglobulin A (IgA), the major class of antibody secreted by the gut mucosa, is an important contributor to gut barrier function. The repertoire of IgA bound to gut bacteria reflects both T-cell-dependent and -independent pathways, plus glycans present on the antibody's secretory component. Human gut bacterial taxa targeted by IgA in the setting of barrier dysfunction are capable of producing intestinal pathology when isolated and transferred to gnotobiotic mice. A complex reorientation of gut immunity occurs as infants transition from passively acquired IgA present in breast milk to host-derived IgA. How IgA responses co-develop with assembly of the microbiota during this period remains poorly understood. Here, we (1) identify a set of age-discriminatory bacterial taxa whose representations define a program of microbiota assembly and maturation during the first 2 postnatal years that is shared across 40 healthy twin pairs in the USA; (2) describe a pattern of progression of gut mucosal IgA responses to bacterial members of the microbiota that is highly distinctive for family members (twin pairs) during the first several postnatal months then generalizes across pairs in the second year; and (3) assess the effects of zygosity, birth mode, and breast feeding. Age-associated differences in these IgA responses can be recapitulated in young germ-free mice, colonized with faecal microbiota obtained from two twin pairs at 6 and 18 months of age, and fed a sequence of human diets that simulate the transition from milk feeding to complementary foods. Most of these responses were robust to diet, suggesting that 'intrinsic' properties of community members play a dominant role in dictating IgA responses. The approach described can be used to define gut mucosal immune development in health and disease states and to help discover ways of repairing or preventing perturbations in this facet of host immunity.


Assuntos
Envelhecimento/imunologia , Microbioma Gastrointestinal/imunologia , Vida Livre de Germes , Imunidade nas Mucosas/imunologia , Imunoglobulina A/imunologia , Modelos Animais , Gêmeos , Animais , Aleitamento Materno , Pré-Escolar , Dieta , Transplante de Microbiota Fecal , Feminino , Voluntários Saudáveis , Humanos , Lactente , Intestinos/imunologia , Intestinos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Desmame
19.
Lancet ; 387(10031): 1928-36, 2016 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-26969089

RESUMO

BACKGROUND: Gut bacteria might predispose to or protect from necrotising enterocolitis, a severe illness linked to prematurity. In this observational prospective study we aimed to assess whether one or more bacterial taxa in the gut differ between infants who subsequently develop necrotising enterocolitis (cases) and those who do not (controls). METHODS: We enrolled very low birthweight (1500 g and lower) infants in the primary cohort (St Louis Children's Hospital) between July 7, 2009, and Sept 16, 2013, and in the secondary cohorts (Kosair Children's Hospital and Children's Hospital at Oklahoma University) between Sept 12, 2011 and May 25, 2013. We prospectively collected and then froze stool samples for all infants. Cases were defined as infants whose clinical courses were consistent with necrotising enterocolitis and whose radiographs fulfilled criteria for Bell's stage 2 or 3 necrotising enterocolitis. Control infants (one to four per case; not fixed ratios) with similar gestational ages, birthweight, and birth dates were selected from the population after cases were identified. Using primers specific for bacterial 16S rRNA genes, we amplified and then pyrosequenced faecal DNA from stool samples. With use of Dirichlet multinomial analysis and mixed models to account for repeated measures, we identified host factors, including development of necrotising enterocolitis, associated with gut bacterial populations. FINDINGS: We studied 2492 stool samples from 122 infants in the primary cohort, of whom 28 developed necrotising enterocolitis; 94 infants were used as controls. The microbial community structure in case stools differed significantly from those in control stools. These differences emerged only after the first month of age. In mixed models, the time-by-necrotising-enterocolitis interaction was positively associated with Gammaproteobacteria (p=0·0010) and negatively associated with strictly anaerobic bacteria, especially Negativicutes (p=0·0019). We studied 1094 stool samples from 44 infants in the secondary cohorts. 18 infants developed necrotising enterocolitis (cases) and 26 were controls. After combining data from all cohorts (166 infants, 3586 stools, 46 cases of necrotising enterocolitis), there were increased proportions of Gammaproteobacteria (p=0·0011) and lower proportions of both Negativicutes (p=0·0013) and the combined Clostridia-Negativicutes class (p=0·0051) in infants who went on to develop necrotising enterocolitis compared with controls. These associations were strongest in both the primary cohort and the overall cohort for infants born at less than 27 weeks' gestation. INTERPRETATION: A relative abundance of Gammaproteobacteria (ie, Gram-negative facultative bacilli) and relative paucity of strict anaerobic bacteria (especially Negativicutes) precede necrotising enterocolitis in very low birthweight infants. These data offer candidate targets for interventions to prevent necrotising enterocolitis, at least among infants born at less than 27 weeks' gestation. FUNDING: National Institutes of Health (NIH), Foundation for the NIH, the Children's Discovery Institute.


Assuntos
Disbiose/microbiologia , Enterocolite Necrosante/microbiologia , Infecções por Bactérias Gram-Negativas , Infecções por Bactérias Gram-Positivas , Estudos de Casos e Controles , Fezes/microbiologia , Feminino , Idade Gestacional , Bactérias Gram-Negativas/isolamento & purificação , Bactérias Gram-Positivas/isolamento & purificação , Humanos , Lactente , Recém-Nascido , Recém-Nascido de muito Baixo Peso , Masculino , Estudos Prospectivos
20.
Nat Med ; 21(10): 1228-34, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26366711

RESUMO

The early years of life are important for immune development and influence health in adulthood. Although it has been established that the gut bacterial microbiome is rapidly acquired after birth, less is known about the viral microbiome (or 'virome'), consisting of bacteriophages and eukaryotic RNA and DNA viruses, during the first years of life. Here, we characterized the gut virome and bacterial microbiome in a longitudinal cohort of healthy infant twins. The virome and bacterial microbiome were more similar between co-twins than between unrelated infants. From birth to 2 years of age, the eukaryotic virome and the bacterial microbiome expanded, but this was accompanied by a contraction of and shift in the bacteriophage virome composition. The bacteriophage-bacteria relationship begins from birth with a high predator-low prey dynamic, consistent with the Lotka-Volterra prey model. Thus, in contrast to the stable microbiome observed in adults, the infant microbiome is highly dynamic and associated with early life changes in the composition of bacteria, viruses and bacteriophages with age.


Assuntos
Intestinos/microbiologia , Microbiota , Estudos de Coortes , Humanos , Lactente , Intestinos/virologia
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