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Development of gut mycobiome in infants and young children: a prospective cohort study
Background
The composition of the gut fungal microbiome, mycobiome, is likely associated with human health. Yet, the development of gut mycobiome is poorly understood in infants and children. Here we investigate how perinatal events influence the development of gut mycobiome.
Methods
In this prospective cohort study of 140 infants, we used ITS gene sequencing of fecal samples from birth to the age of 18 months. We compared gut mycobiome composition according to delivery mode and exposure to intrapartum antibiotics during vaginal delivery.
Results
At birth, gut mycobiome were dominated by the genus
Candida
, at 6-month stool samples by
Malassezia
and
Cystofilobasidium
, and the 18-month stool samples by
Trichosporon
and unidentified fungi. Perinatal factors altered mycobiome. At 18 months, gut mycobiome of infants born vaginally consisted mostly of
Trichosporon
(32%) and unidentified fungi (31%), while those born via Cesarean section delivery samples had mycobiome dominated by
Saccharomyces
(50%). At the age of 18 months, those exposed to intrapartum antibiotics had mycobiome dominated by
Trichosporon
(66%) not seen in those unexposed to antibiotics.
Conclusions
Delivery mode and exposure to intrapartum antibiotic prophylaxis were markedly associated with gut mycobiome composition from birth to 18 months of age.
Impact
The composition of the gut mycobiome is likely associated with human health. Yet, the development of gut mycobiome is poorly understood in infants and children.
In this prospective cohort study, delivery mode and exposure to intrapartum antibiotic prophylaxis were markedly associated with gut mycobiome composition from birth to 18 months of age.
The impact of intrapartum antibiotic prophylaxis on fungal microbiome in vaginally born infants, previously shown to influence gut bacteriome composition, may be explained by the interaction between bacteria and fungi.
Gut mycobiome composition likely deserves further investigation in relation to gut microbiome and health in children.
Journal Article
The basic minimum : a welfarist approach
\"A common presupposition in contemporary moral and political philosophy is that individuals should be provided with some basic threshold of goods, capabilities, or well-being. But if there is such a basic minimum, how should this be understood? Dale Dorsey offers an underexplored answer: that the basic minimum should be characterized not as the achievement of a set of capabilities, or as access to some specified bundle of resources, but as the maintenance of a minimal threshold of human welfare. In addition, Dorsey argues that though political institutions should be committed to the promotion of this minimal threshold, we should reject approaches that seek to cast the basic minimum as a human right. His book will be important for all who are interested in theories of political morality\"-- Provided by publisher.
Book
Caffeine treatment started before injury reduces hypoxic–ischemic white-matter damage in neonatal rats by regulating phenotypic microglia polarization
BackgroundReducing neuroinflammatory damage is an effective strategy for treating white-matter damage (WMD) in premature infants. Caffeine can ameliorate hypoxia–ischemia-induced brain WMD; however, its neuroprotective effect and mechanism against hypoxic–ischemic WMD remain unclear.MethodsWe used 3-day-old Sprague–Dawley rats to establish a model of cerebral hypoxia–ischemia-induced brain WMD after unilateral common carotid artery ligation and hypoxia exposure (8% O2 + 92% N2) for 2.5 h. Mechanism experiments were conducted to detect M1/M2 polarization and activation of microglia and NLRP3 inflammasome.ResultsCaffeine inhibited NLRP3 inflammasome activation, reduced microglial Iba-1 activation, inhibited microglia M1 polarization, and promoted microglia M2 polarization by downregulating CD86 and iNOS protein expression, inhibiting the transcription of the proinflammatory TNF-α and IL-1β, upregulating CD206 and Arg-1 expression, and promoting the transcription of the anti-inflammatory factors IL-10 and TGF-β. Importantly, we found that these caffeine-mediated effects could be reversed after inhibiting A2aR activity.ConclusionsCaffeine improved long-term cognitive function in neonatal rats with hypoxic–ischemic WMD via A2aR-mediated inhibition of NLRP3 inflammasome activation, reduction of microglial activation, regulation of the phenotypic polarization of microglia and the release of inflammatory factors, and improvement of myelination development.ImpactThe direct protective effect of caffeine on hypoxic–ischemic white-matter damage (WMD) and its mechanism remains unclear. This study elucidated this mechanism using neonatal rats as an animal model of hypoxia–ischemia-induced cerebral WMD.The findings demonstrated caffeine as a promising therapeutic tool against immature WMD to protect neonatal cognitive function.We found that caffeine pretreatment reduced WMD in immature brains via regulation of microglial activation and polarization by adenosine A2a receptor, thereby, providing a scientific basis for future clinical application of caffeine.
Journal Article
Skin color influences transcutaneous bilirubin measurements: a systematic in vitro evaluation
Objective
Concerns have been raised about the effect of skin color on the accuracy of transcutaneous bilirubin (TcB) measurements, a widely used method for hyperbilirubinemia diagnosis in newborns. Literature is inconclusive, with both reported under- and overestimations of the TcB with increasing skin pigmentation. Therefore, the influence of skin color on TcB measurements was systematically evaluated in a controlled, in vitro setting.
Methods
A bilirubin meter (JM-105) was evaluated on layered phantoms that mimic neonatal skin with varying dermal bilirubin concentrations (0–250 µmol/L) and varying epidermal melanosome volume fractions (0–40%; light-dark skin color).
Results
TcB measurements were influenced by skin pigmentation. Larger mimicked melanosome volume fractions and higher bilirubin levels led to larger underestimations of the measured TcB, compared to an unpigmented epidermis. In the in vitro setting of this study, these underestimations amounted to 26–132 µmol/L at a TcB level of 250 µmol/L.
Conclusion
This in vitro study provides insight into the effect of skin color on TcB measurements: the TcB is underestimated as skin pigmentation increases and this effect becomes more pronounced at higher bilirubin levels. Our results highlight the need for improved TcB meter design and cautious interpretation of TcB readings on newborns with dark skin.
Impact
Key message: Skin color influences transcutaneous bilirubin measurements: the darker the skin, the larger the underestimation.
What this study adds to existing literature: Existing literature is inconclusive regarding the influence of skin color on transcutaneous bilirubin measurements. This study systematically evaluates and clarifies the influence of skin color on transcutaneous bilirubin measurements in a controlled, in vitro setting.
Impact: This study aids to better interpret the measured TcB level in patients with varying skin colors, and is particularly important when using TcB meters on patients with dark skin colors.
Journal Article
Investigating prenatal and perinatal factors on meconium microbiota: a systematic review and cohort study
Background
The first-pass meconium has been suggested as a proxy for the fetal gut microbiota because it is formed
in utero
. This systematic review and cohort study investigated how pre- and perinatal factors influence the composition of the meconium microbiota.
Methods
We performed the systematic review using Covidence by searching PubMed, Scopus, and Web of Science databases with the search terms “meconium microbiome” and “meconium microbiota”. In the cohort study, we performed 16 S rRNA gene sequencing on 393 meconium samples and analyzed the sequencing data using QIIME2.
Results
Our systematic review identified 69 studies exploring prenatal factors, immediate perinatal factors, and microbial composition in relation to subsequent health of infants but gave only limited comparative evidence regarding factors related to the composition of the meconium microbiota. The cohort study pointed to a low-biomass microbiota consisting of the phyla Firmicutes, Proteobacteria and Actinobacteriota and the genera
Staphylococcus
,
Escherichia-Shigella
and
Lactobacillus
, and indicated that immediate perinatal factors affected the composition of the meconium microbiota more than did prenatal factors.
Conclusions
This finding supports the idea that the meconium microbiota mostly starts developing during delivery.
Impact
It is unclear when the first-pass meconium microbiota develops, and what are the sources of the colonization.
In this systematic review, we found 69 studies exploring prenatal factors, immediate perinatal factors, and microbial composition relative to subsequent health of infants, but there was no consensus on the factors affecting the meconium microbiota development.
In this cohort study, immediate perinatal factors markedly affected the meconium microbiota development while prenatal factors had little effect on it.
As the meconium microbiota composition was influenced by immediate perinatal factors, the present study supports the idea that the initial gut microbiota develops mainly during delivery.
Journal Article
Neutrophil extracellular trap inhibition improves survival in neonatal mouse infectious peritonitis
Background
Treatment of neonatal peritonitis and sepsis is challenging. Following infection, neutrophils elaborate neutrophil extracellular traps (NETs)—extracellular lattices of decondensed chromatin decorated with antimicrobial proteins. NETs, however, can augment pathogenic inflammation causing collateral damage. We hypothesized that NET inhibition would improve survival in experimental neonatal infectious peritonitis.
Methods
We induced peritonitis in 7 to 10-day-old mice by intraperitoneal injection with cecal slurry. We targeted NETs by treating mice with neonatal NET-Inhibitory Factor (nNIF), an endogenous NET-inhibitor; Cl-amidine, a PAD4 inhibitor; DNase I, a NET degrading enzyme, or meropenem (an antibiotic). We determined peritoneal NET and cytokine levels and circulating platelet–neutrophil aggregates. Survival from peritonitis was followed for 6 days.
Results
nNIF, Cl-amidine, and DNase I decreased peritoneal NET formation and inflammatory cytokine levels at 24 h compared to controls. nNIF, Cl-amidine, and DNase I decreased circulating platelet–neutrophil aggregates, and NET-targeting treatments significantly increased survival from infectious peritonitis compared to controls. Finally, nNIF administration significantly improved survival in mice treated with sub-optimal doses of meropenem even when treatment was delayed until 2 h after peritonitis induction.
Conclusions
NET inhibition improves survival in experimental neonatal infectious peritonitis, suggesting that NETs participate pathogenically in neonatal peritonitis and sepsis.
Impact
Neutrophil extracellular trap formation participates pathogenically in experimental neonatal infectious peritonitis.
NET-targeting strategies improve outcomes in a translational model of neonatal infectious peritonitis.
NET inhibition represents a potential target for drug development in neonatal sepsis and infectious peritonitis.
Journal Article
Exposure to Δ9-tetrahydrocannabinol during rat pregnancy leads to impaired cardiac dysfunction in postnatal life
Background
Cannabis use in pregnancy leads to fetal growth restriction (FGR), but the long-term effects on cardiac function in the offspring are unknown, despite the fact that fetal growth deficits are associated with an increased risk of developing postnatal cardiovascular disease. We hypothesize that maternal exposure to Δ9-tetrahydrocannabinol (Δ9-THC) during pregnancy will impair fetal development, leading to cardiac dysfunction in the offspring.
Methods
Pregnant Wistar rats were randomly selected and administered 3 mg/kg of Δ9-THC or saline as a vehicle daily via intraperitoneal injection from gestational days 6 to 22, followed by echocardiogram analysis of cardiac function on offspring at postnatal days 1 and 21. Heart tissue was harvested from the offspring at 3 weeks for molecular analysis of cardiac remodelling.
Results
Exposure to Δ9-THC during pregnancy led to FGR with a significant decrease in heart-to-body weight ratios at birth. By 3 weeks, pups exhibited catch-up growth associated with significantly greater left ventricle anterior wall thickness with a decrease in cardiac output. Moreover, these Δ9-THC-exposed offsprings exhibited increased expression of collagen I and III, decreased matrix metallopeptidase-2 expression, and increased inactivation of glycogen synthase kinase-3β, all associated with cardiac remodelling.
Conclusions
Collectively, these data suggest that Δ9-THC-exposed FGR offspring undergo postnatal catch-up growth concomitant with cardiac remodelling and impaired cardiac function early in life.
Impact
To date, the long-term effects of perinatal Δ9-THC (the main psychoactive component) exposure on the cardiac function in the offspring remain unknown.
We demonstrated, for the first time, that exposure to Δ9-THC alone during rat pregnancy results in significantly smaller hearts relative to body weight.
These Δ9-THC-exposed offsprings exhibited postnatal catch-up growth concomitant with cardiac remodelling and impaired cardiac function.
Given the increased popularity of
cannabis
use in pregnancy along with rising Δ9-THC concentrations, this study, for the first time, identifies the risk of perinatal Δ9-THC exposure on early postnatal cardiovascular health.
Journal Article
Human milk extracellular vesicles modulate inflammation and cell survival in intestinal and immune cells
Human milk contains extracellular vesicles (EVs) that carry bioactive molecules such as microRNA, to the newborn intestine. The downstream effects of EV cargo on signaling and immune modulation may shield neonates against inflammatory diseases, including necrotizing enterocolitis. Premature infants are especially at risk, while human milk-feeding may offer protection. The effect of gestational-age specific term and preterm EVs from transitional human milk was characterized on human intestinal epithelial cells (HIECs and Caco-2), primary macrophages, and THP-1 monocytes. We hypothesized that term and preterm EVs differentially influence immune-related cytokines and cell death. We found that preterm EVs were enriched in CD14 surface marker, while both term and preterm EVs increased epidermal growth factor secretion. Following inflammatory stimuli, only term EVs inhibited secretion of IL-6 in HIECs, and reduced expression of pro-inflammatory cytokine IL-1β in macrophages. Term and preterm EVs inhibited secretion of IL-1β and reduced inflammasome related cell death. We proposed that human milk EVs regulate immune-related signaling via their conserved microRNA cargo, which could promote tolerance and a homeostatic immune response. These findings provide basis for further studies into potential therapeutic supplementation with EVs in vulnerable newborn populations by considering functional, gestational age-specific effects.
Impact
This study reveals distinct functional differences between term and preterm transitional human milk extracellular vesicles (EVs) highlighting the importance of gestational age in their bioactivity.
Term EVs uniquely inhibited IL-6 secretion, IL-1β expression, and apoptosis following inflammatory stimuli.
Both term and preterm human milk EVs reduced IL-1β secretion and inflammasome-induced cell death.
Conserved human milk extracellular vesicle microRNA cargo could be a mediator of the anti-inflammatory effects, particularly targeting cytokine production, the inflammasome, and programmed cell death.
These findings underscore the importance of considering gestational age in future research exploring the therapeutic potential of human milk extracellular vesicles to prevent or treat intestinal inflammatory diseases in neonates.
Journal Article
Lung ultrasound detects regional aeration inhomogeneity in ventilated preterm lambs
Background
Inhomogeneous lung aeration is a significant contributor to preterm lung injury. EIT detects inhomogeneous aeration in the research setting. Whether LUS detects inhomogeneous aeration is unknown. The aim was to determine whether LUS detects regional inhomogeneity identified by EIT in preterm lambs.
Methods
LUS and EIT were simultaneously performed on mechanically ventilated preterm lambs. LUS images from non-dependent and dependent regions were acquired and reported using a validated scoring system and computer-assisted quantitative LUS greyscale analysis (Q-LUS
MGV
). Regional inhomogeneity was calculated by observed over predicted aeration ratio from the EIT reconstructive model. LUS scores and Q-LUS
MGV
were compared with EIT aeration ratios using one-way ANOVA.
Results
LUS was performed in 32 lambs (~125d gestation, 128 images). LUS scores were greater in upper anterior (non-dependent) compared to lower lateral (dependent) regions of the left (3.4 vs 2.9,
p
= 0.1) and right (3.4 vs 2.7,
p
< 0.0087). The left and right upper regions also had greater LUS scores compared to right lower (3.4 vs 2.7,
p
< 0.0087) and left lower (3.7 vs 2.9,
p
= 0.1). Q-LUS
MGV
yielded similar results. All LUS findings corresponded with EIT regional differences.
Conclusion
LUS may have potential in measuring regional aeration, which should be further explored in human studies.
Impact
Inhomogeneous lung aeration is an important contributor to preterm lung injury, however, tools detecting inhomogeneous aeration at the bedside are limited.
Currently, the only tool clinically available to detect this is electrical impedance tomography (EIT), however, its use is largely limited to research.
Lung ultrasound (LUS) may play a role in monitoring lung aeration in preterm infants, however, whether it detects inhomogeneous lung aeration is unknown.
Visual LUS scores and mean greyscale image analysis using computer assisted quantitative LUS (Q-LUS
MGV
) detects regional lung aeration differences when compared to EIT.
This suggests LUS reliably detects aeration inhomogeneity warranting further investigation in human trials.
Journal Article