Early Life Antibiotic Exposure Research Articles

Early-life antibiotic exposure aggravate the metabolic dysfunction-associated steatotic liver disease associated hepatocellular carcinoma

BackgroundMetabolic dysfunction-associated steatotic liver disease (MASLD) asscociated hepatocellular carcinoma (HCC) is becoming a growing concern in global healthcare. The early-life gut microbiota plays a crucial role in maintaining healthy. However, the impact of early-life gut microbiota dysbiosis on the advancement of MASLD-HCC remains inadequately understood.MethodsIn the present study, we investigated the role of early-life gut microbiota in the development of MASLD-HCC in streptozotocin and high-fat diet (STZ-HFD) induced mouse model. We recorded the body weight and lifespan, and dynamically monitored the level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), total cholesterol (T-CHO) and blood glucose in the serum monthly. In addition, we examined various immune cells present in the liver, such as T cells, B cells, NK cells, NKT cells, αβT cells, γδT cells, macrophage and MDSC cells by flow cytometry and conducted liquid chromatography mass spectrometry (LC–MS) based analysis on liver tissue from control and early-life antibiotic exposure mice (early-Abx) MASLD-HCC mice.ResultsWe found that early-Abx mice suffered from more severe tumor burden and further confirmed that hepatocytes and immune cells were all disturbed. Importantly, early-life antibiotic exposure alters the liver metabolic profiling especially glycerophospholipids and lipid accumulation. Furthermore, mice exposed to antibiotics in early-life showed disturbances in glucose metabolism and developed insulin resistance.ConclusionsCollectively, our findings revealed that early-life antibiotic exposure accelerated the progression of MASLD-HCC by impairing the hepatocytes, immune homeostasis and metabolites persistently, highlighting the importance of the early-life microbiota in the development of MASLD-HCC.

Oral supplementation with Bifidobacterium infantis and 2′-fucosyllactose revives gut microbiota perturbation and intestinal and immune developmental delay following early-life antibiotic challenge in BALB/c mice

Probiotics and synbiotics can mitigate the negative health consequences of early-life antibiotic exposure. This study aimed to determine whether supplementation with Bifidobacterium longum ssp. infantis 79 (B79) or synbiotics composed of B79 and 2'-fucosyllactose (2'-FL) could mitigate the negative impact of ceftriaxone exposure in early-life. We found that antibiotic-treated mice exhibited lower body weight, crypt depth, short-chain fatty acid content, and α-diversity indices at weaning, while they increased the relative abundance of opportunistic pathogens (such as Enterococcus and Staphylococcus) and decreased the relative abundance of intestinal commensal bacteria. Supplementation with B79 and 2'-FL revived these antibiotic-induced negative effects and reduced the mRNA expression of IL-6, IL-12p40, and TNF-α in the spleen at weaning. Moreover, B79 and 2'-FL supplementation persistently improved crypt depth, propionic acid synthesis, and IgG and sIgA production and revived the gut microbiota structure and composition in adulthood. In conclusion, our study suggests that early-life supplementation with B79 alone or in combination with 2'-FL can mitigate ceftriaxone-induced negative effects on the gut microbiota and intestinal and immune development of mice, and these improvements can partially last into adulthood.

Neonatal and early infancy antibiotic exposure is associated with childhood atopic dermatitis, wheeze and asthma

Antibiotics are frequently administered in the neonatal period and early infancy. Little is known about the long-term health consequences of early life antibiotic exposure. The objective is to investigate the association between neonatal and early life (0–6 months) antibiotic treatment and the development of atopic dermatitis, asthma and the use of inhaled corticosteroid medication later in childhood. We analyzed data obtained from hospital records and national registers in a cohort of 11,255 children. The association between early antibiotic exposure and the outcomes were analyzed using logistic regression. Confounding factors were included in the model. Neonatal antibiotic therapy for confirmed infection was associated with childhood atopic dermatitis (adjusted odds ratio 1.49; 95% confidence interval 1.15–1.94). Antibiotic therapy by six months of age was more common in children developing atopic dermatitis (adjusted odds ratio 1.38; 95% confidence interval 1.15–1.64), asthma (adjusted odds ratio 1.56; 95% confidence interval 1.32- 1.85) and inhaled corticosteroid medication use (adjusted odds ratio 1.88; 95% confidence interval 1.66–2.13). Conclusions: Neonatal antibiotic therapy for confirmed or clinically diagnosed infection is associated with increased risk of atopic dermatitis later in childhood. Antibiotic treatment before six months of age is associated with atopic dermatitis, asthma and inhaled corticosteroid use.What is known:• The use of antibiotics early in life has been associated with an increased risk of developing atopic dermatitis or asthma.• Confounding by indication or reverse causation may underlie the observed associations.What is new:• Our results demonstrate that neonatal antibiotic therapy for confirmed or clinically diagnosed infection was associated with increased risk of atopic dermatitis and antibiotic treatment before six months of age was associated with atopic dermatitis, asthma and inhaled corticosteroid use in analyses adjusted for confounding factors.

Antibiotic exposure for culture-negative early-onset sepsis in late-preterm and term newborns: an international study.

Early-life antibiotic exposure is disproportionately high compared to the burden of culture-proven early-onset sepsis (CP-EOS). We assessed the contribution of culture-negative cases to the overall antibiotic exposure in the first postnatal week. We conducted a retrospective analysis across eleven countries in Europe, North America, and Australia. All late-preterm and term infants born between 2014 and 2018 who received intravenous antibiotics during the first postnatal week were classified as culture-negative cases treated for ≥5 days (CN ≥ 5d), culture-negative cases treated for <5 days (CN < 5d), or CP-EOS cases. Out of 757,979 infants, 21,703 (2.9%) received intravenous antibiotics. The number of infants classified as CN ≥ 5d, CN < 5d, and CP-EOS was 7996 (37%), 13,330 (61%), and 375 (1.7%). The incidence of CN ≥ 5d, CN < 5d, and CP-EOS was 10.6 (95% CI 10.3-10.8), 17.6 (95% CI 17.3-17.9), and 0.49 (95% CI 0.44-0.54) cases per 1000 livebirths. The median (IQR) number of antibiotic days administered for CN ≥ 5d, CN < 5d, and CP-EOS was 77 (77-78), 53 (52-53), and 5 (5-5) per 1000 livebirths. CN ≥ 5d substantially contributed to the overall antibiotic exposure, and was 21-fold more frequent than CP-EOS. Antimicrobial stewardship programs should focus on shortening antibiotic treatment for culture-negative cases. In a study of 757,979 infants born in high-income countries, we report a presumed culture-negative early-onset sepsis incidence of 10.6/1000 livebirths with an associated antibiotic exposure of 77 antibiotic days per 1000 livebirths. This study sheds light on the major contribution of presumed culture-negative early-onset sepsis to early-life antibiotic exposure. Given the diagnostic uncertainty surrounding culture-negative early-onset sepsis, the low mortality rate, and the disproportionate antibiotic exposure associated with this condition, our study emphasizes the importance of targeting culture-negative early-onset sepsis in antimicrobial stewardship programs.

Alzheimer's Disease Has Its Origins in Early Life via a Perturbed Microbiome.

Alzheimer's disease (AD) is a neurodegenerative disorder with limited therapeutic options. Accordingly, new approaches for prevention and treatment are needed. One focus is the human microbiome, the consortium of microorganisms that live in and on us, which contributes to human immune, metabolic, and cognitive development and that may have mechanistic roles in neurodegeneration. AD and Alzheimer's disease-related dementias (ADRD) are recognized as spectrum disorders with complex pathobiology. AD/ADRD onset begins before overt clinical signs, but initiation triggers remain undefined. We posit that disruption of the normal gut microbiome in early life leads to a pathological cascade within septohippocampal and cortical brain circuits. We propose investigation to understand how early-life microbiota changes may lead to hallmark AD pathology in established AD/ADRD models. Specifically, we hypothesize that antibiotic exposure in early life leads to exacerbated AD-like disease endophenotypes that may be amenable to specific microbiological interventions. We propose suitable models for testing these hypotheses.

Antibiotic use and risk of autism spectrum disorder and attention-deficit/hyperactivity disorder: a population-based cohort study

BackgroundThe gut microbiota is believed to influence neurodevelopment through the gut–brain axis, but prior studies have shown inconsistent results regarding early childhood antibiotic exposure and subsequent risk of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). The purpose of this study was to evaluate the hypothesis that exposure to antibacterial agents in the first 2 years of life increases the risk of ASD and/or ADHD.MethodsThis was a retrospective cohort study using 2003–2019 data from the National Health Insurance Research Database in Taiwan. Livebirths born between 2004 and 2016 were identified and separated into singleton, full sibling, and exposure-discordant sibling pair cohorts. The exposure group included children who filled at least one prescription for antibacterial agents between 0 and 2 years old in outpatient settings. The outcome, ASD and/or ADHD, was defined by at least one inpatient or outpatient diagnosis. The maximum follow-up age was 15 years in this study. Potential neonatal, maternal and paternal confounders were adjusted for. Cox proportional hazards models were used to estimate the relative event risk.ResultsThe final sample contained 946,581 children in the singleton cohort, 1,142,693 children in the full sibling cohort, and 352,612 children in the exposure-discordant sibling pair cohort. Antibiotic exposure marginally increased the risk of ASD and/or ADHD in the singleton cohort (adjusted hazard ratio [aHR]: 1.06, 95% confidence interval [CI]: 1.04–1.07) and in the full sibling cohort (aHR: 1.03, 95% CI: 1.01–1.04). A slight decrease in the risk of ASD and/or ADHD was observed in the exposure-discordant sibling pair cohort (aHR: 0.92, 95% CI: 0.90–0.94).ConclusionsThe results suggest that early life antibiotic exposure has minimal impact on the risk of ASD and/or ADHD. Given that the estimated effects are marginal and close to null, concerns about ASD and/or ADHD risk increase should not postpone or deter timely and reasonable antibiotic use.

The role of antibiotic exposure and the effects of breastmilk and human milk feeding on the developing infant gut microbiome.

The World Health Organization (WHO) recommends exclusive breastfeeding for the first 6 months of life followed by complementary foods and sustained breastfeeding for at least 2 years, underscoring its pivotal role in reducing infant mortality and preventing various illnesses. This perspective delves into the intricate relationship between breastfeeding practices, early life antibiotic exposure, and infant gut microbiome development, highlighting their profound influence on child health outcomes. Antibiotics are extensively prescribed during pregnancy and childhood, disrupting the microbiome, and are related to increased risks of allergies, obesity, and neurodevelopmental disorders. Breastfeeding is a significant determinant of a healthier gut microbiome, characterized by higher levels of beneficial bacteria such as Bifidobacterium and lower levels of potential pathogens. Despite widespread recognition of the benefits of breastfeeding, gaps persist in healthcare practices and support mechanisms, exacerbating challenges faced by breastfeeding families. This highlights the pressing need for comprehensive research encompassing breastfeeding behaviors, human milk intake, and their impact on infant health outcomes. Additionally, promoting awareness among healthcare providers and families regarding the detrimental effects of unnecessary formula supplementation could facilitate informed decision-making and bolster exclusive breastfeeding rates. Moreover, donor human milk (DHM) is a promising alternative to formula, potentially mitigating disruptions to the infant gut microbiome after antibiotic exposure. Overall, prioritizing breastfeeding support interventions and bridging research gaps are essential steps towards improving child health outcomes on a global scale.

Association Between Early-Life Exposure to Antibiotics and Development of Child Obesity: Population-Based Study in Italy.

Childhood obesity is a significant public health problem representing the most severe challenge in the world. Antibiotic exposure in early life has been identified as a potential factor that can disrupt the development of the gut microbiome, which may have implications for obesity. This study aims to evaluate the risk of developing obesity among children exposed to antibiotics early in life. An Italian retrospective pediatric population-based cohort study of children born between 2004 and 2018 was adopted using the Pedianet database. Children were required to be born at term, with normal weight, and without genetic diseases or congenital anomalies. We assessed the timing of the first antibiotic prescription from birth to 6, 12, and 24 months of life and the dose-response relationship via the number of antibiotic prescriptions recorded in the first year of life (none, 1, 2, and ≥3 prescriptions). Obesity was defined as a BMI z score >3 for children aged ≤5 years and >2 for children aged >5 years, using the World Health Organization growth references. The obese incidence rate (IR) × 100 person-years and the relative 95% CI were computed using infant sex, area of residence, preschool and school age, and area deprivation index, which are the covariates of interest. A mixed-effect Cox proportional hazards model was used to estimate the hazard ratio and 95% CI for the association between antibiotic exposure in early life and child obesity between 24 months and 14 years of age, considering the family pediatricians as a random factor. Several subgroup and sensitivity analyses were performed to assess the robustness of our results. Among 121,540 children identified, 54,698 were prescribed at least an antibiotic within the first year of life and 26,990 were classified as obese during follow-up with an incidence rate of 4.05 cases (95% CI 4.01-4.10) × 100 person-year. The risk of obesity remained consistent across different timings of antibiotic prescriptions at 6 months, 1 year, and 2 years (fully adjusted hazard ratio [aHR] 1.07, 95% CI 1.04-1.10; aHR 1.06, 95% CI 1.03-1.09; and aHR 1.07, 95% CI 1.04-1.10, respectively). Increasing the number of antibiotic exposures increases the risk of obesity significantly (P trend<.001). The individual-specific age analysis showed that starting antibiotic therapy very early (between 0 and 5 months) had the greatest impact (aHR 1.12, 95% CI 1.08-1.17) on childhood obesity with respect to what was observed among those who were first prescribed antibiotics after the fifth month of life. These results were consistent across subgroup and sensitivity analyses. The results from this large population-based study support the association between early exposure to antibiotics and an increased risk of childhood obesity. This association becomes progressively stronger with both increasing numbers of antibiotic prescriptions and younger age at the time of the first prescription.

Short-term exposure to antibiotics begets long-term disturbance in gut microbial metabolism and molecular ecological networks

BackgroundAntibiotic exposure can occur in medical settings and from environmental sources. Long-term effects of brief antibiotic exposure in early life are largely unknown.ResultsPost a short-term treatment by ceftriaxone to C57BL/6 mice in early life, a 14-month observation was performed using 16S rRNA gene-sequencing technique, metabolomics analysis, and metagenomics analysis on the effects of ceftriaxone exposure. Firstly, the results showed that antibiotic pre-treatment significantly disturbed gut microbial α and β diversities (P < 0.05). Both Chao1 indices and Shannon indices manifested recovery trends over time, but they didn’t entirely recover to the baseline of control throughout the experiment. Secondly, antibiotic pre-treatment reduced the complexity of gut molecular ecological networks (MENs). Various network parameters were affected and manifested recovery trends over time with different degrees, such as nodes (P < 0.001, R2 = 0.6563), links (P < 0.01, R2 = 0.4543), number of modules (P = 0.0672, R2 = 0.2523), relative modularity (P = 0.6714, R2 = 0.0155), number of keystones (P = 0.1003, R2 = 0.2090), robustness_random (P = 0.79, R2 = 0.0063), and vulnerability (P = 0.0528, R2 = 0.28). The network parameters didn't entirely recover. Antibiotic exposure obviously reduced the number of key species in gut MENs. Interestingly, new keystones appeared during the recovery process of network complexity. Changes in network stability might be caused by variations in network complexity, which supports the ecological theory that complexity begets stability. Besides, the metabolism profiles of the antibiotic group and control were significantly different. Correlation analysis showed that antibiotic-induced differences in gut microbial metabolism were related to MEN changes. Antibiotic exposure also caused long-term effects on gut microbial functional networks in mice.ConclusionsThese results suggest that short-term antibiotic exposure in early life will cause long-term negative impacts on gut microbial diversity, MENs, and microbial metabolism. Therefore, great concern should be raised about children’s brief exposure to antibiotics if the results observed in mice are applicable to humans.D3-AZHri_jesG1CHKmDZa1Video

Intrapartum antibiotic use is associated with higher child body mass index (BMI) z-score at 4 years of age

Early life antibiotic exposure may increase obesity risk. We investigated if prenatal, intrapartum, or childhood antibiotic use is associated with child zBMI score at 4 yrs of age. We included data from the Alberta Pregnancy Outcomes and Nutrition (APrON) study, a prospective cohort study, on maternal and child antibiotic exposure and clinic measures of height and weight at age 4 (n = 408). Prenatal and childhood antibiotic exposure was not associated with zBMI score. Maternal intrapartum antibiotic exposure was associated with a zBMI score increase of 0.12 (95 % CI; 0.04, 0.46) in children at 4 years of age compared to non-exposure intrapartum.

Early life exposure of infants to benzylpenicillin and gentamicin is associated with a persistent amplification of the gut resistome

BackgroundInfant gut microbiota is highly malleable, but the long-term longitudinal impact of antibiotic exposure in early life, together with the mode of delivery on infant gut microbiota and resistome, is not extensively studied.MethodsTwo hundred and eight samples from 45 infants collected from birth until 2 years of age over five time points (week 1, 4, 8, 24, year 2) were analysed. Based on shotgun metagenomics, the gut microbial composition and resistome profile were compared in the early life of infants divided into three groups: vaginal delivery/no-antibiotic in the first 4 days of life, C-section/no-antibiotic in the first 4 days of life, and C-section/antibiotic exposed in first 4 days of life. Gentamycin and benzylpenicillin were the most commonly administered antibiotics during this cohort’s first week of life.ResultsNewborn gut microbial composition differed in all three groups, with higher diversity and stable composition seen at 2 years of age, compared to week 1. An increase in microbial diversity from week 1 to week 4 only in the C-section/antibiotic-exposed group reflects the effect of antibiotic use in the first 4 days of life, with a gradual increase thereafter. Overall, a relative abundance of Actinobacteria and Bacteroides was significantly higher in vaginal delivery/no-antibiotic while Proteobacteria was higher in C-section/antibiotic-exposed infants. Strains from species belonging to Bifidobacterium and Bacteroidetes were generally persistent colonisers, with Bifidobacterium breve and Bifidobacterium bifidum species being the major persistent colonisers in all three groups. Bacteroides persistence was dominant in the vaginal delivery/no-antibiotic group, with species Bacteroides ovatus and Phocaeicola vulgatus found to be persistent colonisers in the no-antibiotic groups. Most strains carrying antibiotic-resistance genes belonged to phyla Proteobacteria and Firmicutes, with the C-section/antibiotic-exposed group presenting a higher frequency of antibiotic-resistance genes (ARGs).ConclusionThese data show that antibiotic exposure has an immediate and persistent effect on the gut microbiome in early life. As such, the two antibiotics used in the study selected for strains (mainly Proteobacteria) which were multiple drug-resistant (MDR), presumably a reflection of their evolutionary lineage of historical exposures—leading to what can be an extensive and diverse resistome.31ajk8a-14RKZLdCXmKHuwVideo

Early life antibiotic exposure and inflammatory bowel disease

Inflammatory bowel disease (IBD) is known to affect millions of people worldwide and is primarily caused due to abnormal due to abnormal immune responses to intestinal microbes. IBD is primarily categorized under two main types – ulcerative colitis and Crohn’s disease. Although the cause of IBD is still an unsolved puzzle, its development can be attributed to the presence of various risk factors including antibiotic use. The intestinal immune system is the point of genesis of IBD and anything that creates an imbalance can trigger IBD. Alterations in the gut microbiota can lead to reduced microbial populations and lead a chronic inflammation state. Antibiotics may influence microbial maturity and can hamper the formation of a strong immune system. This makes an individual vulnerable to the threat of infections and subsequent development of a chronic inflammation state. Studies have implicated that the use of antibiotics during pregnancy, antepartum, and among neonates is associated with the development of IBD. Adequate development of the microbial niche takes place within the first 2 years of life and extensive administration of antibiotics during this period can pose a significant risk for the development of IBD. Animal studies have also documented the role of in utero antibiotic exposure during the antepartum period and the subsequent risk of developing IBD in the offspring. This review summarizes the role of antibiotic exposure during pregnancy and infancy in the development of IBD.

Early-life antibiotic exposure promotes house dust mite-induced allergic airway inflammation by impacting gut microbiota and lung lipid metabolism

Asthma is a chronic inflammatory respiratory disease. Early-life antibiotic exposure is a unique risk factor for the incidence and severity of asthma later in life. Perturbations in microbial–metabolite–immune interaction caused by antibiotics are closely associated with the pathogenesis of allergy and asthma. We investigated the effect of early intervention with common oral antibiotics on later asthma exacerbations and found that different antibiotic exposures can amplify different types of immune responses induced by HDM. Cefixime (CFX) promoted a biased type 2 inflammation, azithromycin (AZM) enhanced Th17 immune response, and cefuroxime axetil (CFA) induced eosinophils recruitment. Moreover, early-life antibiotic exposure can have short- and long-term effects on the abundance, composition, and diversity of the gut microbiota. In the model of CFX-promoted type 2 airway inflammation, fecal metabolomics indicated abnormal lipid metabolism and T cell response. Lipidomic also suggested allergic airway inflammation amplified by CFX is closely associated with abnormal lipid metabolism in lung tissues. Moreover, abnormalities in lipid metabolism–related genes (LMRGs) were found to have cellular heterogeneity be associated with asthma severity by bioinformatics analysis.

Atopic Dermatitis and Eczema Association Between Early Life Antibiotic Exposure and Development of Early Childhood Atopic Dermatitis.

Atopic Dermatitis and Eczema Association Between Early Life Antibiotic Exposure and Development of Early Childhood Atopic Dermatitis.

In utero or early-in-life exposure to antibiotics and the riskof childhood atopic dermatitis, a population-based cohort study.

Atopic dermatitis (AD) is a common inflammatory disease of the skin that begins early in life and can be lifelong. The purpose of our study was to evaluate whether fetal exposure and/or early-life exposure of a child to antibiotics increases the risk of early-onset AD. We hypothesize that antibiotic exposure in utero or early in life (e.g. first 90 days) increases the likelihood that children developAD. Utilizing a large, prospectively collected electronic medical records database, we studied the association of antibiotic exposure received in utero or very early in life and the relative risk of onset of AD in a population-based cohort study. Associations were estimated using proportional hazards models as hazard ratios (HRs) with 95% confidence intervals (CIs). The risk of AD in childhood was increased after in utero or early-life antibiotic exposure. For any in utero antibiotic exposure the HR (CI) was 1.38 (1.36-1.39). However, penicillin demonstrated the strongest association with AD for both in utero exposure [1.43 (1.41-1.44)] and for childhood exposure [1.81 (1.79-1.82)]. HRs were higher in children born to mothers without AD than in those with AD pointing to effect modification by maternal AD status. Children born to mothers exposed to antibiotics while in utero had, depending on the mother's history of AD, approximately a 20-40% increased risk of developing AD. Depending on the antibiotic, children who received antibiotics early in life had a 40-80% increased risk of developing AD. Our study supports and refines the association between incident AD and antibiotic administration. It also adds population-based support to therapeutic attempts to treat AD by modifying the skin microbiome.

Vancomycin-induced gut microbial dysbiosis alters enteric neuron-macrophage interactions during a critical period of postnatal development.

Vancomycin is a broad-spectrum antibiotic widely used in cases of suspected sepsis in premature neonates. While appropriate and potentially lifesaving in this setting, early-life antibiotic exposure alters the developing microbiome and is associated with an increased risk of deadly complications, including late-onset sepsis (LOS) and necrotizing enterocolitis (NEC). Recent studies show that neonatal vancomycin treatment disrupts postnatal enteric nervous system (ENS) development in mouse pups, which is in part dependent upon neuroimmune interactions. This suggests that early-life antibiotic exposure could disrupt these interactions in the neonatal gut. Notably, a subset of tissue-resident intestinal macrophages, muscularis macrophages, has been identified as important contributors to the development of postnatal ENS. We hypothesized that vancomycin-induced neonatal dysbiosis impacts postnatal ENS development through its effects on macrophages. Using a mouse model, we found that exposure to vancomycin in the first 10 days of life, but not in adult mice, resulted in an expansion of pro-inflammatory colonic macrophages by increasing the recruitment of bone-marrow-derived macrophages. Single-cell RNA sequencing of neonatal colonic macrophages revealed that early-life vancomycin exposure was associated with an increase in immature and inflammatory macrophages, consistent with an influx of circulating monocytes differentiating into macrophages. Lineage tracing confirmed that vancomycin significantly increased the non-yolk-sac-derived macrophage population. Consistent with these results, early-life vancomycin exposure did not expand the colonic macrophage population nor decrease enteric neuron density in CCR2-deficient mice. Collectively, these findings demonstrate that early-life vancomycin exposure alters macrophage number and phenotypes in distinct ways compared with vancomycin exposure in adult mice and results in altered ENS development.

Very early life microbiome and metabolome correlates with primary vaccination variability in children.

Despite multiple vaccine doses early in life, a substantial proportion of infants do not mount protective responses. In this study, we followed a cohort of children over the first 2 years of life, collecting microbiome and metabolome data longitudinally to investigate correlates of lower and higher responses to primary vaccinations. We found that the stool and nasopharyngeal microbiome developed with age, though demonstrated divergent timing and patterns in maturation. When measured at child age 2 months, evenness of genera in the stool microbiome correlated with lower vaccine responses, upregulated metabolome genes that encode for lipid A biosynthesis and oxidative phosphorylation correlated with higher vaccine responses, and abundance of phenylpyruvic acid in serum correlated with lower vaccine responses, measured 10 months later. Antibiotic exposure was associated with low vaccine response, and microbiome/metabolome features at child age 2 months, before childhood vaccinations commenced, correlated with variations in vaccine responses measured at child age 1 year. These results indicate that there may be potential to intervene before first childhood vaccinations to improve later protection. IMPORTANCE We show that simultaneous study of stool and nasopharyngeal microbiome reveals divergent timing and patterns of maturation, suggesting that local mucosal factors may influence microbiome composition in the gut and respiratory system. Antibiotic exposure in early life as occurs commonly, may have an adverse effect on vaccine responsiveness. Abundance of gut and/or nasopharyngeal bacteria with the machinery to produce lipopolysaccharide-a toll-like receptor 4 agonist-may positively affect future vaccine protection, potentially by acting as a natural adjuvant. The increased levels of serum phenylpyruvic acid in infants with lower vaccine-induced antibody levels suggest an increased abundance of hydrogen peroxide, leading to more oxidative stress in low vaccine-responding infants.

A dose-dependent increase in the risk of inflammatory bowel disease after exposure to broad-spectrum antibiotics: A national population study in Korea.

The association between antibiotic use and risk of inflammatory bowel disease (IBD), particularly among adults, remains unclear. Furthermore, there is a scarcity of data among non-Western countries. To investigate the association and dose-response relationships between antibiotic use and subsequent IBD risk across all ages METHODS: This population-based case-control analysis used data from the Korean National Health Insurance Service database (2004-2018). We compared 68,633 patients with new-onset IBD to matched controls (n = 343,165) using multivariable conditional logistic regression analysis. We also examined the dose-response relationship using non-linear regression analysis, and separately analysed childhood-onset IBD (aged ≤14 years) risk following early-life antibiotic exposure. The mean age at diagnosis was 45.2 ± 16.8 years. Antibiotic prescriptions between 2 and 5 years before diagnosis significantly increased the odds of developing IBD (adjusted odds ratio [OR], 1.24; 95% confidence interval [CI]: 1.21-1.27). Additionally, sensitivity analysis revealed an elevated risk up to 9 years before diagnosis. Broad-spectrum antibiotics increased IBD risk, independent of gastroenteritis. A distinct dose-response relationship was observed irrespective of the IBD subtype and study population (all p < 0.001). Furthermore, antibiotic exposure within the first year of life was linked with the risk of childhood-onset IBD (OR, 1.51; 95% CI: 1.25-1.82). Broad-spectrum antibiotics dose-dependently increased the risk for IBD in the Korean population. Our findings provide a fundamental epidemiological basis for identifying antibiotic use as a significant risk factor for IBD across different environmental backgrounds.

Early Life Antibiotic Exposures Inhibits Postnatal Enteric Nervous System Maturation and Alters Neonatal Neuroimmune Interactions

Abstract The enteric nervous system (ENS) regulates intestinal homeostasis via interactions with smooth muscle, epithelium, and immune cells. To assess the impact of early life antibiotics on postnatal ENS development, we performed neuron specific translating ribosome affinity purification to isolate RNA from control and antibiotic exposed enteric neurons for RNA sequencing. Colonic enteric neurons from antibiotic exposed pre-weaning mice expressed significantly less mature neuron markers, and acquired a more inflammatory cytokine signaling signature (e.g. IL18, MCP-1, TLR4). Immunofluorescence staining and ELISA revealed increased enteric neuron density in antibiotic exposed colons, yet reduced expression of neuronal markers including Tuj1 (neuron specific tubulin), synaptophysin (synapse marker) and acetylcholine. Notably, antibiotics did not affect ENS development in germ free mice. By confocal microscopy, antibiotic exposure appeared to reduce phagocytosis of neuronal cell bodies by macrophages, but phagocytosis of synapses by macrophages was increased. Flow cytometry revealed that antibiotic exposure reduced the proportion of macrophages expressing the “M2” marker CD163 compared to controls. This observation is reminiscent of Hirschsprung disease (HSCR), a congenital absence of the ENS from the distal intestine, which causes intestinal macrophages to adopt a pro-inflammatory phenotype and predisposes patients for HSCR-associated enterocolitis secondary to decreased cholinergic signaling. These data suggest that early life antibiotic exposure disrupts how macrophages participate in postnatal ENS development in a microbiota dependent mechanism. NIH NIAID U01AI131342, NIH NIDDK P30DK052574, T32DK077653, NIH T32HD43010 American Academy of Pediatrics Marshall Klaus 2022

Knowledge of molar incisor hypomineralization among physicians and dentists

Background: Molar incisor hypomineralization (MIH) is a global dental condition. Early intake of antibiotics can increase the risk of MIH. Purpose: To assess the knowledge of physicians and dentists on MIH and its associations with antibiotics exposure during early childhood. Methods: This cross-sectional study surveyed the above health professionals utilizing an electronically distributed questionnaire. The chi-square test was used to compare differences in levels of knowledge between the study groups. Results: There were 335 participants in the study; general physicians (n=79), pediatricians (n=98) and dentists (n=158). A significantly lower proportion of general physicians and pediatricians had knowledge of MIH compared to dentists (19% and 18% vs. 82%, respectively, P&lt;0.001). There was no statistically significant difference between all groups regarding their knowledge about the association between antibiotics prescribed during the first four years of life and MIH development (P=0.07). Conclusions: Physicians and pediatricians lacked knowledge about the dental condition of MIH. Most study respondents did not know the association between frequent antibiotic intake during early childhood and the development of MIH. Since medical practitioners are more likely to prescribe antibiotics and have a greater impact on early childhood health, raising awareness of MIH and its relationship with antibiotic exposure in early life among medical practitioners is essential.