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Broad-spectrum antibiotics for suspected early-onset neonatal sepsis (sEONS) may have pronounced effects on gut microbiome development and selection of antimicrobial resistance when administered in the first week of life, during the assembly phase of the neonatal microbiome. Here, 147 infants born at ≥36 weeks of gestational age, requiring broad-spectrum antibiotics for treatment of sEONS in their first week of life were randomized 1:1:1 to receive three commonly prescribed intravenous antibiotic combinations, namely penicillin + gentamicin, co-amoxiclav + gentamicin or amoxicillin + cefotaxime (ZEBRA study, Trial Register NL4882). Average antibiotic treatment duration was 48 hours. A subset of 80 non-antibiotic treated infants from a healthy birth cohort served as controls (MUIS study, Trial Register NL3821). Rectal swabs and/or faeces were collected before and immediately after treatment, and at 1, 4 and 12 months of life. Microbiota were characterized by 16S rRNA-based sequencing and a panel of 31 antimicrobial resistance genes was tested using targeted qPCR. Confirmatory shotgun metagenomic sequencing was executed on a subset of samples. The overall gut microbial community composition and antimicrobial resistance gene profile majorly shift directly following treatment (R 2  = 9.5%, adjusted p -value = 0.001 and R 2  = 7.5%, adjusted p -value = 0.001, respectively) and normalize over 12 months (R 2  = 1.1%, adjusted p -value = 0.03 and R 2  = 0.6%, adjusted p -value = 0.23, respectively). We find a decreased abundance of Bifidobacterium spp. and increased abundance of Klebsiella and Enterococcus spp. in the antibiotic treated infants compared to controls. Amoxicillin + cefotaxime shows the largest effects on both microbial community composition and antimicrobial resistance gene profile, whereas penicillin + gentamicin exhibits the least effects. These data suggest that the choice of empirical antibiotics is relevant for adverse ecological side-effects. Here, in a randomized trial of 147 infants receiving distinct antibiotic regimens for early-onset neonatal sepsis, Reyman et al. characterize the gut microbiome and resistance profiles, finding differential effects of antibiotic combinations on microbial community composition and antimicrobial resistance genes.

Key Points The anatomical development and maturation of the human respiratory tract is a complex multistage process that occurs not only in prenatal life but also postnatally. This maturation process depends, in part, on exposure to microbial and environmental triggers, and results in a highly specialized organ system that contains several distinct niches, each of which is subjected to specific microbial, cellular and physiological gradients. The respiratory microbiome during early life is dynamic and its development is affected by a range of host and environmental factors, including mode of birth, feeding type, antibiotic treatment and crowding conditions, such as the presence of siblings and day-care attendance. The upper respiratory tract is colonized by specialized resident bacterial, viral and fungal assemblages, which presumably prevent potential pathogens from overgrowing and disseminating towards the lungs, thereby functioning as gatekeepers to respiratory health. The upper respiratory tract is the primary source of the lung microbiome. In healthy individuals, the lung microbiome seems to largely consist of transient microorganisms and its composition is determined by the balance between microbial immigration and elimination. Next-generation sequencing has identified intricate interbacterial association networks that comprise true mutualistic, commensal or antagonistic direct or indirect relationships. Alternatively, bacterial co-occurrence seems to be driven by host and environmental factors, as well as by interactions with viruses and fungi. The respiratory microbiome provides cues to the host immune system that seem to be vital for immune training, organogenesis and the maintenance of immune tolerance. Increasing evidence supports the existence of a window of opportunity early in life, during which adequate microbiota sensing is essential for immune maturation and consecutive respiratory health. Future studies should focus on large-scale, multidisciplinary holistic approaches and adequately account for host and environmental factors. Associations that are identified by these studies can then be corroborated in reductionist surveys; for example, by using in vitro or animal studies. The respiratory tract spans from the nostrils to the lung alveoli and these distinct niches host a diverse microbiota. In this Review, Man, de Steenhuijsen Piters and Bogaert discuss the role of the respiratory microbiota in the maintenance of human health. The respiratory tract is a complex organ system that is responsible for the exchange of oxygen and carbon dioxide. The human respiratory tract spans from the nostrils to the lung alveoli and is inhabited by niche-specific communities of bacteria. The microbiota of the respiratory tract probably acts as a gatekeeper that provides resistance to colonization by respiratory pathogens. The respiratory microbiota might also be involved in the maturation and maintenance of homeostasis of respiratory physiology and immunity. The ecological and environmental factors that direct the development of microbial communities in the respiratory tract and how these communities affect respiratory health are the focus of current research. Concurrently, the functions of the microbiome of the upper and lower respiratory tract in the physiology of the human host are being studied in detail. In this Review, we will discuss the epidemiological, biological and functional evidence that support the physiological role of the respiratory microbiota in the maintenance of human health.

The early-life microbiome appears to be affected by mode of delivery, but this effect may depend on intrapartum antibiotic exposure. Here, we assess the effect of delivery mode on gut microbiota, independent of intrapartum antibiotics, by postponing routine antibiotic administration to mothers until after cord clamping in 74 vaginally delivered and 46 caesarean section born infants. The microbiota differs between caesarean section born and vaginally delivered infants over the first year of life, showing enrichment of Bifidobacterium spp., and reduction of Enterococcus and Klebsiella spp. in vaginally delivered infants. The microbiota composition at one week of life is associated with the number of respiratory infections over the first year. The taxa driving this association are more abundant in caesarean section born children, providing a possible link between mode of delivery and susceptibility to infectious outcomes. Here, in a cohort of infants unexposed to maternal antibiotics, the authors analyse the gut microbiome development of children born naturally and by caesarean section, finding a higher abundance of known pathogens in the latter group, and an association between these bacteria and a higher incidence of respiratory infections in the first year of life.

Many bacterial pathogens causing respiratory infections in children are common residents of the respiratory tract. Insight into bacterial colonization patterns and microbiota stability at a young age might elucidate healthy or susceptible conditions for development of respiratory disease. To study bacterial succession of the respiratory microbiota in the first 2 years of life and its relation to respiratory health characteristics. Upper respiratory microbiota profiles of 60 healthy children at the ages of 1.5, 6, 12, and 24 months were characterized by 16S-based pyrosequencing. We determined consecutive microbiota profiles by machine-learning algorithms and validated the findings cross-sectionally in an additional cohort of 140 children per age group. Overall, we identified eight distinct microbiota profiles in the upper respiratory tract of healthy infants. Profiles could already be identified at 1.5 months of age and were associated with microbiota stability and change over the first 2 years of life. More stable patterns were marked by early presence and high abundance of Moraxella and Corynebacterium/Dolosigranulum and were positively associated with breastfeeding in the first period of life and with lower rates of parental-reported respiratory infections in the consecutive periods. Less stable profiles were marked by high abundance of Haemophilus or Streptococcus. These findings provide novel insights into microbial succession in the respiratory tract in infancy and link early-life profiles to microbiota stability and respiratory health characteristics. New prospective studies should elucidate potential implications of our findings for early diagnosis and prevention of respiratory infections. Clinical trial registered with www.clinicaltrials.gov (NCT00189020).

The infection fatality rate of COVID-19 is several-fold higher than that of seasonal influenza,2 and infection can lead to persisting illness, including in young, previously healthy people (ie, long COVID).3 It is unclear how long protective immunity lasts,4 and, like other seasonal coronaviruses, SARS-CoV-2 is capable of re-infecting people who have already had the disease, but the frequency of re-infection is unknown.5 Transmission of the virus can be mitigated through physical distancing, use of face coverings, hand and respiratory hygiene, and by avoiding crowds and poorly ventilated spaces. PK reports personal fees from Kymab, outside the submitted work; PK also has a patent ‘Monoclonal antibodies to treat and prevent infection by SARS-CoV-2 (Kymab)’ pending and is a scientific advisor to the Serology Working Group (Public Heath England), Testing Advisory Group (Department of Health and Social Care) and the Vaccines Task force (Department for Business, Energy and Industrial Strategy). CS reports grants from BMS, Ono-Pharmaceuticals, and Archer Dx (collaboration in minimal residual disease sequencing technologies), outside the submitted work; personal fees from Bristol Myers Squibb, Roche-Ventana, Ono Pharmaceutical, GlaxoSmithKline, Novartis, Celgene, Illumina, MSD, Sarah Canon Research Institute, Genentech, Bicycle Therapeutics, and Medicixi, outside the submitted work; personal fees and stock options from GRAIL and Achilles Therapeutics, outside the submitted work; and stock options from Epic Biosciences and Apogen Biotechnologies, outside the submitted work.

BackgroundSubstantial evidence indicates that dysbiosis of the gut microbial community is associated with colorectal neoplasia. This review aims to systematically summarise the microbial markers associated with colorectal neoplasia and to assess their predictive performance.MethodsA comprehensive literature search of MEDLINE and EMBASE databases was performed to identify eligible studies. Observational studies exploring the associations between microbial biomarkers and colorectal neoplasia were included. We also included prediction studies that constructed models using microbial markers to predict CRC and adenomas. Risk of bias for included observational and prediction studies was assessed.ResultsForty-five studies were included to assess the associations between microbial markers and colorectal neoplasia. Nine faecal microbiotas (i.e., Fusobacterium, Enterococcus, Porphyromonas, Salmonella, Pseudomonas, Peptostreptococcus, Actinomyces, Bifidobacterium and Roseburia), two oral pathogens (i.e., Treponema denticola and Prevotella intermedia) and serum antibody levels response to Streptococcus gallolyticus subspecies gallolyticus were found to be consistently associated with colorectal neoplasia. Thirty studies reported prediction models using microbial markers, and 83.3% of these models had acceptable-to-good discrimination (AUROC > 0.75). The results of predictive performance were promising, but most of the studies were limited to small number of cases (range: 9–485 cases) and lack of independent external validation (76.7%).ConclusionsThis review provides insight into the evidence supporting the association between different types of microbial species and their predictive value for colorectal neoplasia. Prediction models developed from case-control studies require further external validation in high-quality prospective studies. Further studies should assess the feasibility and impact of incorporating microbial biomarkers in CRC screening programme.

Respiratory tract infections are a major global health concern, accounting for high morbidity and mortality, especially in young children and elderly individuals. Traditionally, highly common bacterial respiratory tract infections, including otitis media and pneumonia, were thought to be caused by a limited number of pathogens including Streptococcus pneumoniae and Haemophilus influenzae. However, these pathogens are also frequently observed commensal residents of the upper respiratory tract (URT) and form—together with harmless commensal bacteria, viruses and fungi—intricate ecological networks, collectively known as the ‘microbiome’. Analogous to the gut microbiome, the respiratory microbiome at equilibrium is thought to be beneficial to the host by priming the immune system and providing colonization resistance, while an imbalanced ecosystem might predispose to bacterial overgrowth and development of respiratory infections. We postulate that specific ecological perturbations of the bacterial communities in the URT can occur in response to various lifestyle or environmental effectors, leading to diminished colonization resistance, loss of containment of newly acquired or resident pathogens, preluding bacterial overgrowth, ultimately resulting in local or systemic bacterial infections. Here, we review the current body of literature regarding niche-specific upper respiratory microbiota profiles within human hosts and the changes occurring within these profiles that are associated with respiratory infections.

Respiratory infectious diseases are mainly caused by viruses or bacteria that often interact with one another. Although their presence is a prerequisite for subsequent infections, viruses and bacteria may be present in the nasopharynx without causing any respiratory symptoms. The upper respiratory tract hosts a vast range of commensals and potential pathogenic bacteria, which form a complex microbial community. This community is assumed to be constantly subject to synergistic and competitive interspecies interactions. Disturbances in the equilibrium, for instance due to the acquisition of new bacteria or viruses, may lead to overgrowth and invasion. A better understanding of the dynamics between commensals and pathogens in the upper respiratory tract may provide better insight into the pathogenesis of respiratory diseases. Here we review the current knowledge regarding specific bacterial-bacterial and viral-bacterial interactions that occur in the upper respiratory niche, and discuss mechanisms by which these interactions might be mediated. Finally, we propose a theoretical model to summarize and illustrate these mechanisms.

Breastfeeding elicits significant protection against respiratory tract infections in infancy. Modulation of respiratory microbiota might be part of the natural mechanisms of protection against respiratory diseases induced by breastfeeding. To study the association between breastfeeding and nasopharyngeal microbial communities, including all cultivable and noncultivable bacteria. In this observational study, we analyzed the microbiota of infants that had received exclusive breastfeeding (n = 101) and exclusive formula feeding (n = 101) at age 6 weeks and 6 months by 16S-based GS-FLX-titanium-pyrosequencing. At 6 weeks of age the overall bacterial community composition was significantly different between breastfed and formula-fed children (nonmetric multidimensional scaling, P = 0.001). Breastfed children showed increased presence and abundance of the lactic acid bacterium Dolosigranulum (relative effect size [RES], 2.61; P = 0.005) and Corynebacterium (RES, 1.98; P = 0.039) and decreased abundance of Staphylococcus (RES, 0.48; P 0.03) and anaerobic bacteria, such as Prevotella (RES, 0.25; P < 0.001) and Veillonella (RES, 0.33; P < 0.001). Predominance (>50% of the microbial profile) of Corynebacterium and Dolosigranulum was observed in 45 (44.6%) breastfed infants compared with 19 (18.8%) formula-fed infants (relative risk, 2.37; P = 0.006). Dolosigranulum abundance was inversely associated with consecutive symptoms of wheezing and number of mild respiratory tract infections experienced. At 6 months of age associations between breastfeeding and nasopharyngeal microbiota composition had disappeared. Our data suggest a strong association between breastfeeding and microbial community composition in the upper respiratory tract of 6-week-old infants. Observed differences in microbial community profile may contribute to the protective effect of breastfeeding on respiratory infections and wheezing in early infancy. Clinical trial registered with www.clinicaltrials.gov (NCT 00189020).